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ad034bddf4471e2032d9a429373e87eb6511dfe5 | wikidoc | Potassium | Potassium
# Overview
Potassium is a chemical element. It has the symbol K and atomic number 19. The name "potassium" comes from the word "potash", as potassium was first isolated from potash. Potassium is a soft silvery-white metallic alkali metal that occurs naturally bound to other elements in seawater and many minerals. It oxidizes rapidly in air and is very reactive, especially towards water. In many respects, potassium and sodium are chemically similar, although organisms in general, and animal cells in particular, treat them very differently.
# Occurrence
Potassium makes up about 1.5% of the weight of the Earth's crust and is the seventh most abundant element. As it is very electropositive, potassium metal is difficult to obtain from its minerals. It is never found free in nature, as it reacts violently with water.
Potassium can be isolated through electrolysis of its hydroxide in a process that has changed little since Davy. Thermal methods also are employed in potassium production, using potassium chloride.
# Properties
## Physical properties
Potassium is the second least dense metal; only lithium is less dense. It is a soft, low-melting solid that can easily be cut with a knife. Freshly cut potassium is silvery in appearance, but in air it begins to tarnish toward grey immediately.
Potassium and its compounds emit a violet color in a flame. This fact is the basis of the flame test for the presence of potassium in a sample. Potassium concentration in solution is commonly determined by flame photometry, atomic absorption spectrophotometry, inductively coupled plasma, or ion selective electrodes.
## Chemical properties
Potassium must be protected from air for storage to prevent disintegration of the metal from oxide and hydroxide corrosion. Often samples are maintained under a reducing medium such as kerosene.
Like the other alkali metals, potassium reacts violently with water producing hydrogen. The reaction is notably more violent than that of lithium or sodium with water, and is sufficiently exothermic that the evolved hydrogen gas ignites.
Because potassium reacts quickly with even traces of water, and its reaction products are nonvolatile, it is sometimes used alone, or as NaK (an alloy with sodium which is liquid at room temperature) to dry solvents prior to distillation. In this role, it serves as a potent desiccant.
Potassium hydroxide reacts strongly with carbon dioxide to produce potassium carbonate, and is used to remove traces of CO2 from air.
Potassium compounds generally have excellent water solubility, due to the high hydration energy of the K+ ion. The potassium ion is colorless in water.
Methods of separating potassium by precipitation, sometimes used for gravimetric analysis, include the use of sodium tetraphenyl boron, dihydrogen hexachloroplatinate (IV) hexahydrate, and sodium cobaltinitrite.
# Potassium in The Body
## Biochemical function
Potassium is important in nerve function and in influencing osmotic balance between cells and the interstitiual fluid.
Potassium may be detected by taste because it triggers three of the five types of tastebuds, according to concentration. Dilute solutions of potassium ion taste sweet (allowing moderate concentrations in milk and juices), while higher concentrations become increasingly bitter/alkaline, and finally also salty to the taste. The combined bitterness and saltiness of high potassium content solutions makes high-dose potassium supplementation by liquid drinks a palatability challenge.
## Membrane polarization
Potassium is also important in allowing muscle contraction and the sending of all nerve impulses in animals through action potentials. Because of the interaction of the charge on a potassium ion and its surrounding water molecules, K+ ions are larger than Na+ ions, and ion channels and pumps in cell membranes can easily distinguish between the two types of ions, actively pumping or passively allowing one of the two ions to pass, while blocking the other.
A shortage of potassium in body fluids may cause a potentially fatal condition known as hypokalemia, typically resulting from diarrhea, increased diuresis and vomiting. Deficiency symptoms include muscle weakness, paralytic ileus, ECG abnormalities, decreased reflex response and in severe cases respiratory paralysis, alkalosis and cardiac arrhythmia.
## Filtration and excretion
Potassium is an essential mineral macronutrient in human nutrition; it is the major cation (positive ion) inside animal cells, and it is thus important in maintaining fluid and electrolyte balance in the body. Sodium makes up most of the cations of blood plasma at about 145 milliequivalents per liter (3345 milligrams) and potassium makes up most of the cell fluid cations at about 150 millequivalents per liter (4800 milligrams). Plasma is filtered through the glomerulus of the kidneys in enormous amounts, about 180 liters per day. Thus 602,000 milligrams of sodium and 33,000 milligrams of potassium are filtered each day. All but the 1000-10,000 milligrams of sodium and the 1000-4000 milligrams of potassium likely to be in the diet must be reabsorbed. Sodium must be reabsorbed in such a way as to keep the blood volume exactly right and the osmotic pressure correct; potassium must be reabsorbed in such a way as to keep serum concentration as close as possible to to 4.8 milliequivalents (about 190 milligrams) per liter. Sodium pumps must always operate to conserve sodium. Potassium must sometimes be conserved also, but since the amount of potassium in the blood plasma is very small and the pool of potassium in the cells is about thirty times as large, the situation is not so critical for potassium. Since potassium is moved passively in counter flow to sodium in response to an apparent (but not actual) Donnan equilibrium, the urine can never sink below the concentration of potassium in serum except sometimes by actively excreting water at the end of the processing. Potassium is secreted twice and reabsorbed three times before the urine reaches the collecting tubules. At that point, it usually has about the same potassium concentration as plasma. If potassium were removed from the diet, there would remain a minimum obligatory kidney excretion of about 200 mg per day when the serum declines to 3.0-3.5 milliequivalents per liter in about one week, and can never be cut off completely. Because it cannot be cut off completely, death will result when the whole body potassium declines to the vicinity of one-half full capacity. At the end of the processing, potassium is secreted one more time if the serum levels are too high.
The potassium moves passively through pores in the cell wall. When ions move through pumps there is a gate in the pumps on either side of the cell wall and only one gate can be open at once. As a result 100 ions are forced through per second. Pores have only one gate and there one kind of ion only can stream through at 10 million to 100 million ions per second. The pores require calcium in order to open although it is thought that the calcium works in reverse by blocking at least one of the pores. Carbonyl groups inside the pore on the amino acids mimics the water hydration that takes place in water solution by the nature of the electrostatic charges on four carbonyl groups inside the pore.
## Potassium in The Diet
Adequate intake can generally be guaranteed by eating a variety of foods containing potassium and deficiency is rare in healthy individuals eating a balanced diet. Foods with high sources of potassium include in order from highest to lowest avocados, potatoes, bananas, broccoli, orange juice, soybeans and apricots, although it is also common in most fruits, vegetables and meats. Diets high in potassium can reduce the risk of hypertension and a potassium deficiency combined with an adequate thiamine intake has produced heart disease in rats. The 2004 guidelines of the Institute of Medicine specify an DRI of 4,000mg of potassium, though most Americans consume only half that amount per day. Similarly, in the European Union, particularly in Germany and Italy, insufficient potassium intake is somewhat common.
Supplements of potassium in medicine are most widely used in conjunction with loop diuretics and thiazides, classes of diuretics which rid the body of sodium and water, but have the side effect of also causing potassium loss in urine. A variety of medical supplements are available. If potassium supplements are used, such as sodium free baking powder and sodium free table salt, inadequate thiamine can cause beriberi. A vitamin B-1 deficiency is possible if food containing sulfite or sulfur dioxide is eaten or an alcoholic drink fermented with sulfur dioxide is consumed during the meal, since sulfite destroys vitamin B-1 in the intestines.
Individuals suffering from kidney diseases may suffer adverse health effects from consuming large quantities of dietary potassium. End stage renal failure patients undergoing therapy by renal dialysis must observe strict dietary limits on potassium intake, since the kidneys control potassium excretion, and buildup of blood concentrations of potassium may trigger fatal cardiac arrhythmia. Acute hyperkalemia can be reduced through eating baking soda, or glucose, hyperventilation and perspiration.
# Applications
## Agriculture and health
- In animal cells, potassium ions are vital to keeping cells alive (see Na-K pump)
- Potassium chloride is used as a substitute for table salt and is also used to stop the heart, e.g. in cardiac surgery and in executions by lethal injection in a solution.
- Potassium sodium tartrate, or Rochelle salt (KNaC4H4O6) is used in baking powder and medicine.
- Potassium pyrophosphate (K4P2O7) is used in soaps and detergents.
# Precautions
Solid potassium reacts violently with water, and should therefore be kept under a mineral oil such as kerosene and handled with care. Unlike lithium and sodium, however, potassium cannot be stored under oil indefinitely. If stored longer than 6 months to a year, dangerous shock-sensitive peroxides can form on the metal and under the lid of the container, which can detonate upon opening. It is recommended that potassium, rubidium or caesium not be stored for longer than three months unless stored in an inert (oxygen free) atmosphere, or under vacuum.
The extremely alkaline potassium hydroxide (KOH) residue on the surface of potassium which has been exposed to moisture, is a caustic hazard. As with sodium metal, the "soapy" feel of potassium metal on skin is due to caustic breakdown of the fats in skin into crude soft potassium soap, and represents the beginning of an alkali burn. Potassium should obviously be handled with care, with full skin and eye protection.
Potassium fires are exacerbated by water, and only a few dry chemicals are effective for them.
Potassium has also been discovered to react violently with iodine. | Potassium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Potassium is a chemical element. It has the symbol K and atomic number 19. The name "potassium" comes from the word "potash", as potassium was first isolated from potash. Potassium is a soft silvery-white metallic alkali metal that occurs naturally bound to other elements in seawater and many minerals. It oxidizes rapidly in air and is very reactive, especially towards water. In many respects, potassium and sodium are chemically similar, although organisms in general, and animal cells in particular, treat them very differently.
# Occurrence
Potassium makes up about 1.5% of the weight of the Earth's crust and is the seventh most abundant element. As it is very electropositive, potassium metal is difficult to obtain from its minerals. It is never found free in nature, as it reacts violently with water.
Potassium can be isolated through electrolysis of its hydroxide in a process that has changed little since Davy. Thermal methods also are employed in potassium production, using potassium chloride.
# Properties
## Physical properties
Potassium is the second least dense metal; only lithium is less dense. It is a soft, low-melting solid that can easily be cut with a knife. Freshly cut potassium is silvery in appearance, but in air it begins to tarnish toward grey immediately.
Potassium and its compounds emit a violet color in a flame. This fact is the basis of the flame test for the presence of potassium in a sample. Potassium concentration in solution is commonly determined by flame photometry, atomic absorption spectrophotometry, inductively coupled plasma, or ion selective electrodes.
## Chemical properties
Potassium must be protected from air for storage to prevent disintegration of the metal from oxide and hydroxide corrosion. Often samples are maintained under a reducing medium such as kerosene.
Like the other alkali metals, potassium reacts violently with water producing hydrogen. The reaction is notably more violent than that of lithium or sodium with water, and is sufficiently exothermic that the evolved hydrogen gas ignites.
Because potassium reacts quickly with even traces of water, and its reaction products are nonvolatile, it is sometimes used alone, or as NaK (an alloy with sodium which is liquid at room temperature) to dry solvents prior to distillation. In this role, it serves as a potent desiccant.
Potassium hydroxide reacts strongly with carbon dioxide to produce potassium carbonate, and is used to remove traces of CO2 from air.
Potassium compounds generally have excellent water solubility, due to the high hydration energy of the K+ ion. The potassium ion is colorless in water.
Methods of separating potassium by precipitation, sometimes used for gravimetric analysis, include the use of sodium tetraphenyl boron, dihydrogen hexachloroplatinate (IV) hexahydrate, and sodium cobaltinitrite.
# Potassium in The Body
## Biochemical function
Potassium is important in nerve function and in influencing osmotic balance between cells and the interstitiual fluid.[1]
Potassium may be detected by taste because it triggers three of the five types of tastebuds, according to concentration. Dilute solutions of potassium ion taste sweet (allowing moderate concentrations in milk and juices), while higher concentrations become increasingly bitter/alkaline, and finally also salty to the taste. The combined bitterness and saltiness of high potassium content solutions makes high-dose potassium supplementation by liquid drinks a palatability challenge.
## Membrane polarization
Potassium is also important in allowing muscle contraction and the sending of all nerve impulses in animals through action potentials. Because of the interaction of the charge on a potassium ion and its surrounding water molecules, K+ ions are larger than Na+ ions, and ion channels and pumps in cell membranes can easily distinguish between the two types of ions, actively pumping or passively allowing one of the two ions to pass, while blocking the other.
A shortage of potassium in body fluids may cause a potentially fatal condition known as hypokalemia, typically resulting from diarrhea, increased diuresis and vomiting. Deficiency symptoms include muscle weakness, paralytic ileus, ECG abnormalities, decreased reflex response and in severe cases respiratory paralysis, alkalosis and cardiac arrhythmia.
## Filtration and excretion
Potassium is an essential mineral macronutrient in human nutrition; it is the major cation (positive ion) inside animal cells, and it is thus important in maintaining fluid and electrolyte balance in the body. Sodium makes up most of the cations of blood plasma at about 145 milliequivalents per liter (3345 milligrams) and potassium makes up most of the cell fluid cations at about 150 millequivalents per liter (4800 milligrams). Plasma is filtered through the glomerulus of the kidneys in enormous amounts, about 180 liters per day.[2] Thus 602,000 milligrams of sodium and 33,000 milligrams of potassium are filtered each day. All but the 1000-10,000 milligrams of sodium and the 1000-4000 milligrams of potassium likely to be in the diet must be reabsorbed. Sodium must be reabsorbed in such a way as to keep the blood volume exactly right and the osmotic pressure correct; potassium must be reabsorbed in such a way as to keep serum concentration as close as possible to to 4.8 milliequivalents (about 190 milligrams) per liter.[3] Sodium pumps must always operate to conserve sodium. Potassium must sometimes be conserved also, but since the amount of potassium in the blood plasma is very small and the pool of potassium in the cells is about thirty times as large, the situation is not so critical for potassium. Since potassium is moved passively[4][5] in counter flow to sodium in response to an apparent (but not actual) Donnan equilibrium,[6] the urine can never sink below the concentration of potassium in serum except sometimes by actively excreting water at the end of the processing. Potassium is secreted twice and reabsorbed three times before the urine reaches the collecting tubules.[7] At that point, it usually has about the same potassium concentration as plasma. If potassium were removed from the diet, there would remain a minimum obligatory kidney excretion of about 200 mg per day when the serum declines to 3.0-3.5 milliequivalents per liter in about one week,[8] and can never be cut off completely. Because it cannot be cut off completely, death will result when the whole body potassium declines to the vicinity of one-half full capacity. At the end of the processing, potassium is secreted one more time if the serum levels are too high.
The potassium moves passively through pores in the cell wall. When ions move through pumps there is a gate in the pumps on either side of the cell wall and only one gate can be open at once. As a result 100 ions are forced through per second. Pores have only one gate and there one kind of ion only can stream through at 10 million to 100 million ions per second.[9] The pores require calcium in order to open[10] although it is thought that the calcium works in reverse by blocking at least one of the pores.[11] Carbonyl groups inside the pore on the amino acids mimics the water hydration that takes place in water solution[12] by the nature of the electrostatic charges on four carbonyl groups inside the pore.[13]
## Potassium in The Diet
Adequate intake can generally be guaranteed by eating a variety of foods containing potassium and deficiency is rare in healthy individuals eating a balanced diet. Foods with high sources of potassium include in order from highest to lowest avocados, potatoes, bananas, broccoli, orange juice, soybeans and apricots, although it is also common in most fruits, vegetables and meats. Diets high in potassium can reduce the risk of hypertension and a potassium deficiency combined with an adequate thiamine intake has produced heart disease in rats.[14] The 2004 guidelines of the Institute of Medicine specify an DRI of 4,000mg of potassium, though most Americans consume only half that amount per day.[15] Similarly, in the European Union, particularly in Germany and Italy, insufficient potassium intake is somewhat common.[16]
Supplements of potassium in medicine are most widely used in conjunction with loop diuretics and thiazides, classes of diuretics which rid the body of sodium and water, but have the side effect of also causing potassium loss in urine. A variety of medical supplements are available. If potassium supplements are used, such as sodium free baking powder and sodium free table salt, inadequate thiamine can cause beriberi.[17][18] A vitamin B-1 deficiency is possible if food containing sulfite or sulfur dioxide is eaten or an alcoholic drink fermented with sulfur dioxide is consumed during the meal, since sulfite destroys vitamin B-1 in the intestines.[19]
Individuals suffering from kidney diseases may suffer adverse health effects from consuming large quantities of dietary potassium. End stage renal failure patients undergoing therapy by renal dialysis must observe strict dietary limits on potassium intake, since the kidneys control potassium excretion, and buildup of blood concentrations of potassium may trigger fatal cardiac arrhythmia. Acute hyperkalemia can be reduced through eating baking soda,[20] or glucose,[21][22] hyperventilation[23] and perspiration.[24]
# Applications
## Agriculture and health
- In animal cells, potassium ions are vital to keeping cells alive (see Na-K pump)
- Potassium chloride is used as a substitute for table salt and is also used to stop the heart, e.g. in cardiac surgery and in executions by lethal injection in a solution.
- Potassium sodium tartrate, or Rochelle salt (KNaC4H4O6) is used in baking powder and medicine.
- Potassium pyrophosphate (K4P2O7) is used in soaps and detergents.
# Precautions
Solid potassium reacts violently with water, and should therefore be kept under a mineral oil such as kerosene and handled with care. Unlike lithium and sodium, however, potassium cannot be stored under oil indefinitely. If stored longer than 6 months to a year, dangerous shock-sensitive peroxides can form on the metal and under the lid of the container, which can detonate upon opening. It is recommended that potassium, rubidium or caesium not be stored for longer than three months unless stored in an inert (oxygen free) atmosphere, or under vacuum.[25]
The extremely alkaline potassium hydroxide (KOH) residue on the surface of potassium which has been exposed to moisture, is a caustic hazard. As with sodium metal, the "soapy" feel of potassium metal on skin is due to caustic breakdown of the fats in skin into crude soft potassium soap, and represents the beginning of an alkali burn. Potassium should obviously be handled with care, with full skin and eye protection.
Potassium fires are exacerbated by water, and only a few dry chemicals are effective for them.
Potassium has also been discovered to react violently with iodine. | https://www.wikidoc.org/index.php/Cena_K | |
f49ae67678a1eb74c613b9aa0a33f399d4b492e5 | wikidoc | Centipede | Centipede
Centipedes (from Latin prefix centi-, "hundred", and Greek ποδός podos, "foot") are arthropods belonging to the class Chilopoda and the Subphylum Myriapoda. They are elongated metameric animals with one pair of legs per body segment. A key trait uniting this group is a pair of poison claws or forcipules formed from a modified first appendage. This also means that centipedes are an exclusively predatory taxa, which is uncommon.
Centipedes normally have a drab coloration combining shades of brown and red. Template:Wict and subterranean species may lack pigmentation and many tropical Scolopendromorphs have bright aposematic colors. Size can range from a few millimeters in the smaller Lithobiomorphs and Geophilomorphs to about a foot in the largest Scolopendromorphs.
Worldwide there are estimated to be 8,000 species . Currently there are about 3,000 described species. Geographically, centipedes have a wide range, which reaches beyond the Arctic Circle . Centipedes are found in an array of terrestrial habitats from tropical rainforests to deserts. Within these habitats centipedes require a moist micro-habitat due to their rapid rates of water loss. Accordingly, they are found in soil and leaf litter, under stones and deadwood, and inside logs. In addition, centipedes are among the largest terrestrial invertebrate predators and often they contribute a significant proportion to invertebrate predatory biomass in terrestrial ecosystems.
# Anatomy
Centipedes have elongated dorsal-ventrally flattened bodies, and comprise two segmented tagmata; a head and trunk, which bear different hox gene expression. Each segment bears a single pair of legs and has a dorsal plate (tergite) and a ventral plate (sternite). Laterally each segment has a soft less scelerotized region known as the plueral membrane. This is where the spiracles for gas exchange are located in all orders except for the Scutigeromorpha (where they are located mid dorsally). The legs are segmented and segments are named proximal to distal: coxa, trachanter, prefemur, femur, tibia, and tarsus. Each leg terminates in a claw.
At the anterior end of the centipede is the head. Dorsally the head consists of a cephalic plate which is distinct in appearance from the tergites. Laterally on the head some centipedes have eyes. The order Geophilomorpha is blind. Scutigeromorphs have compound eyes and the other orders have no eyes or simple ocelli ranging from one pair to many. The ventral view of the head reveals the centipede's most prominent characteristic, its poison claws or forcipules. There are also three pairs of mouthparts all derived from the modification of appendages. There is a mandible with a first maxillae ventral to it and a second maxillae ventral to the first. These mouthparts are used for both feeding and grooming. At the anterior of the head there is a pair of antennae which vary in length and number of segments (except for the Geophilomorpha where the number of segments is fixed at 14).
The posterior end of a centipede has a conspicuous pair of legs named the ultimate or anal legs. These legs are not used for walking and are usually morphologically distinct from other pairs. Instead, they are used for defense and mating and so they often are morphologically distinct between the sexes. Ultimate legs can be inflated, excessively spined, and or morphologically complex with crests and furrows. The sexual organs are also located on the posterior end of the centipede. Sexual organs are externally visible in Scutigeromorpha and Lithobiomorpha, and some Geophilomorpha whereby males and females are easily distinguished. Scolopendromorpha do not have externally visible sexual organs, which makes sexing difficult. Scolopendromorph females may be larger or wider than males. Precise determination of sex can be accomplished upon dissection or by gently applying pressure and warm water to the genital sternite of a specimen to cause the sexual organs to emerge externally.
It also notable that centipedes have distinct sensory structures. The Tomosvary organ in Lithobiomorphs and Scutigeromorphs is located just anterior to the position of the eyes. The organ appears externally as an ellipse and its function is largely unknown. It has been suggested that it is a pressure, light, or humidity sensor. There is some evidence that it functions as a pressure sensor to detect sounds . There are mechanoreceptors in the form of spines or hairs covering the legs and antennae. Lithobiomorphs have coxal pores on the ventral surface of the coxae of legs 12-15 in adults. These pores are present in pore fields consisting of 3-4 rows of pores. They are suspected to function in both osmoregulation and pheromone release . Pore fields are found on some Geophilomorph and Scolopendromorph species on various sternites and on the ultimate coxae. It is not certain if their function is similair across the orders.
# Hazards to humans
Some species of centipedes can be hazardous to humans because of their poisonous bites. Although a bite to an adult human may only be painful, to those with allergies that are similar to that of bee stings and small children are at greater risk.
# Evolution
Internal phylogeny of the Chilopoda. The upper three groups form the paraphyletic Anamorpha.
Centipedes have a fossil record dating back 420 million years to the late Silurian . They belong to the subphylum Myriapoda which includes Diplopoda, Symphyla, and Pauropoda. The oldest known fossil land animal is a MyriapodTemplate:Clarifyme. Being one of the earliest terrestrial animals, centipedes were one of the first to fill a fundamental niche as ground level generalist predators in detrital food webs. Today centipedes are abundant and exist in many harsh habitats.
Within the myriapods, centipedes are believed to be the first of the extant classes to branch from a common ancestor. There are five orders of centipede: Craterostigmomorpha, Geophilomorpha, Lithobiomorpha, Scolopendromorpha, and Scutigeromorpha. These orders are united into the clade Chilopoda by the following synapomorphies: 1) first post-cephalic appendage modified to poison claws. 2) embryonic cuticle on second maxilliped has egg tooth. 3) the trochanter-prefemur joint is fixed. 4) a spiral ridge on the nucleus of spermatazoan . Chilopoda is then split into two clades: the Notostigmomorpha including the Scutigeromorpha and the Pluerostigmomorpha including the other four orders. The main difference is that the Notostigmomorpha have their spiracles located mid-dorsally. It was previously believed that Chilopoda was split into Anamorpha including the Lithobiomorpha and the Scutigeromorpha, and Epimorpha including the Geophilomorpha and Scolopendromorpha based on developmental modes, with the relationship of Craterostigmomorpha being uncertain. Recent phylogenetic analyses using combined molecular and morphological characters supports the previous phylogeny . The Epimorpha group still exists as monophyletic within the Pleurostigmomorpha, but the Anamorpha group is paraphyletic.
Geophilomorph centipedes are used to argue for the developmental constraint of evolution,Template:Clarifyme because they have variable segment numbers within species, yet (as with all centipedes) they always have an odd number of pairs of legs.
# Life history
Centipede mating does not involve copulation. Males deposit a spermatophore for the female to take up. In one clade, this spermatophore is deposited in a web, and the male undertakes a courtship dance to encourage the female to engulf his sperm. In other cases, the males just leave them for the females to find. In temperate areas egg laying occurs in spring and summer but in subtropical and tropical areas there appears to be little seasonality to centipede breeding. It is also notable that there are a few known species of parthenogenetic centipedes.
The Lithobiomorpha, and Scutigeromorpha lay their eggs singly in holes in the soil, the female fills the hole in on the egg and leaves it. Number of eggs laid ranges from about 10 to 50. Time of development of the embryo to hatching is highly variable and may take from one to a few months. Time of development to reproductive period is highly variable within and among species. For example, it can take 3 years for S. coleoptera to achieve adulthood, whereas under the right conditions Lithiobiomorph species may reach a reproductive period in 1 year. In addition, centipedes are relatively long-lived when compared to their insect cousins, for example: the European Lithobius forficatus can live for 5 or 6 years. The combination of a small number of eggs laid, long gestation period, and long time of development to reproduction has led authors to label Lithobiomorph centipedes as K-selected .
Females of Geophilomorpha and Scolopendromorpha show far more parental care, the eggs 15 to 60 in number are laid in a nest in the soil or in rotten wood, the female stays with the eggs, guarding and licking them to protect them from fungi. The female in some species stays with the young after they have hatched, guarding them until they are ready to leave. If disturbed the females tend to either abandon the eggs or young or to eat them; abandoned eggs tend to fall prey to fungi rapidly. Some species of Scolopendromorpha are matriphagic, meaning that the offspring eat their mother.
Little is known of the life history of Craterostigmomorpha.
## Anamorphy vs. epimorphy
Centipedes acquire their legs at different points in their development. In the primitive condition, exhibited by the Lithobiomorpha, Scutigeromorpha and Craterostigmomorpha, development is anamorphic. That is to say, more pairs of legs are grown between moults; for example, Scutigera coleoptera, the American house centipede, hatches with only 4 pairs of legs and in successive moults has 5, 7, 9, 11, 15, 15, 15 and 15 before becoming a sexually mature adult. Life stages with fewer than 15 pairs of legs are called larval stadia (~5 stages). After the full complement of legs is achieved, the now post-larval stadia (~5 stages) develop gonopods, sensory pores, more antennal segments, and more ocelli. All mature apomorphic centipedes have 15 leg-bearing segments.
The Craterostigmomorpha only have one phase of anamorphis, with embryos having 12 pairs, and moultees 15.
The clade Epimorpha, consisting of orders Geophilomorpha and Scolopendromorpha, derived epimorphy. Here, all pairs of legs are developed in the embryonic stages, offspring do not develop more legs between moults. Interestingly, it is this clade that contains the longest centipedes; the maximum number of thoratic segments may also very intra-specifically, often on a geographical basis; in most cases, females bear more legs than males.
The number of leg-bearing pairs varies widely, from 15 to 191 -- but the developmental mode of their creation means that they are always added in pairs - hence the total number present is always odd.
# Ecology
Centipedes are an exclusively predatory taxa. They are known as generalist predators which means that they have adapted to eat a variety of different available prey items. Centipedes are also known to be nocturnal. Studies on centipede activity rhythms confirm this, although there are a few observations of centipedes active during the day and one species Strigamia chinophila that is diurnal. What centipedes actually eat is not well known because of their cryptic lifestyle and thorough mastication of food. Laboratory feeding trials support that they will feed as generalists, taking most anything that is soft-bodied and in a reasonable size range. It has been suggested that earthworms provide the bulk of diets for Geophilomorphs, since geophilomorphs burrow through the soil and earthworm bodies would be easily pierced by their poison claws. Observations suggest that Geophilomorphs cannot subdue earthworms larger than themselves, and so smaller earthworms may be a substantial proportion of their diet . Scolopendromorphs, given their size, are able to feed on vertebrates as well as invertebrates. They have been observed eating reptiles, amphibians, small mammals, bats and birds. Collembola may provide a large proportion of Lithiobiomorph diet. Little is known about Scutigeromorph or Craterostigmomorph diets. All centipedes are potential intraguild predators. Centipedes and spiders may frequently prey on one anotherVideo.
Centipedes are eaten by a great many vetebrates and invetebrates, and form the staple diet of some. The African ant Amblyopone pluto feeds solely on Geophilomorphs and the South African Cape Black-headed snake Aparallactus capensis mainly feeds on centipedes.
Centipedes are found in moist microhabitats. Water relations are an important aspect of their ecology, since they lose water rapidly in dry conditions. Water loss is a result of centipedes lacking a waxy covering of their exoskeleton and excreting waste nitrogen as ammonia, which requires extra water. Centipedes deal with water loss through a variety of adaptations. Geophilomorphs lose water less rapidly than Lithobiomorps even though they have a greater surface area to volume ratio. This may be explained by the fact that Geophilomorphs have a more heavily sclerotized pleural membrane. Spiracle shape, size and ability to constrict also have an influence on rate of water loss. In addition, it has been suggested that number and size of coxal pores may be variables affecting centipede water balance.
Centipedes live in many different habitat types; forest, savannah, prairie, and desert to name a few. Some Geophilomorphs are adapted to littoral habitats, where they feed on barnacles . Species of all orders excluding Craterostigmomorpha have adapted to caves. Centipede densities have been recorded as high as 600/m2 and biomass as high as 500 mg/m2 wet weight. Small Geophilomorphs attain highest densities, followed by small Lithobiomorphs. Large Lithobiomorphs attain densities of 20/m2. One study of Scolopendromorphs records Scolopendra morsitans in a Nigerian savannah at a density of 0.16/m2 and a biomass of 140 mg/m2 wet weight .
# Largest centipede
Scolopendra gigantea, also known as the Amazonian giant centipede, is the largest existing species of centipede in the world, reaching over 30 cm (12 inches) in length. It is known to eat bats, catching them in midflight, as well as rodents and spiders. The prehistoric Euphoberia was the largest known centipede, growing up to one metre (39 inches) in length.
There are rumors that state that the Galápagos Islands giant centipede (Scolopendra galapagoensis) can reach sizes of up to 60 cm (over 25 in), although these rumours may result from the rarity of the particular centipede. Captive Galapagos centipedes don't often exceed 20 cm (8 inches) in body length.
# Orders and families
The orders of centipedes are considered below, from primitive to derived.
## Scutigeromorpha
The Scutigeromorpha are anamorphic, reaching 15 leg-bearing segments in length. They are very fast creatures, and able to withstand falling at great speed: they reach up to 15 body-lengths per second when dropped, surviving the fall.
They are the only centipede group to retain their original compound eyes, with which a crystalline layer analogous to that seen in chelicerates and insects can be observed. They also bear long and multisegmented antennae. Adaptions to a burrowing lifestyle has led to the degeneration of compound eyes in other orders. This feature is of great use in phylogenetic anaylsis.
The group is the sole Template:Wict representative of the Notostigmomorpha, defined by having single spiracle openings on the back of their ventral plates. The more derived groups bear a plurality of spiracular openings on their sides, and are termed the Pleurostigmomorpha. Some even have 7 unpaired spiracles that can be found along the middorsal line and closer to their posterior section of tergites.
## Lithobiomorpha
The lithobiomorpha represent the other main group of anamorphic centipedes; they also reach a mature length of 15 thoratic segments. This group has lost the compound eyes, and sometimes has no eyes altogether. Instead, it eyes have facets or groups of facets. It's spiracles are paired and can be found laterally. Every leg-bearing segment of this organism has a separate tergite. It also has relatively short antennae and legs.
## Craterostigmomorpha
The craterostigmomorpha are the least diverse centipede clade, comprising only two species.. Their geographic range is restricted to the south of Africa. They have a distinct body plan; their anamorphosis comprises a single stage; they grow from 12 to 15 segments in their first moult. Their low diversity and intermediate position between the primitive Anamorphic centipedes and the derived Epimorpha has led to them being described as the "platypus of the centipede world" . They represent a "highly pruned" version of a once diverse clade.
Maternal brooding unites Craterostigomomorpha with the Epimorphs into the clade Phylactometria. This trait is thought to be closely linked with the presence of sternal pores, which secrete sticky or noxious secretions, which mainly serve to repel predators and parasites. The presence of these pores on the Devonian Devonobius permits its inclusion in this clade, allowing its divergence to be dated to 375 (or more) million years ago.
## Scolopendromorpha
The more primitive of the Epimorpha, the Scolopendromorpha comprise 21 or more segments with the same number of paired legs. Their antennae have 17 or more segments. Their eyes will have at least 4 facets on each side.
## Geophilomorpha
The Geophilomorpha are the most derived group of centipedes, and bear upwards of 27 leg-bearing segments. They are without fail eyeless and blind, and bear spiracles on all leg-bearing segments - in contrast to other groups, who only bear them on their 3rd, 5th, 8th, 10th and 12th segments -- a "mid-body break", accompanied by a change in tagmatic shape, occurring roughly at the interchange from odd to even segments. This group, at 1260 spp. the most diverse, also contains the largest and leggiest specimens at 29 or more pairs of legs. They also have 14 segmented antennae.
# List of common species
- Arizona tiger centipede Scolopendra polymorpha
- Blue ring centipede Ethmostigmus trigonopodus
- Earth centipede Pachymerium ferrugineum
- Feather tail centipede Alipes sp.
- Galápagos centipede Scolopendra galapagoensis
- Giant Sonoran centipede Scolopendra heros
- House centipede Scutigera coleoptrata
- Peruvian giant orange leg centipede Scolopendra gigantea
- Red-headed centipede Scolopendra morsitans
- Stone centipede Lithobius forficatus
- Vietnamese centipede Scolopendra subspinipes | Centipede
Centipedes (from Latin prefix centi-, "hundred", and Greek ποδός podos, "foot") are arthropods belonging to the class Chilopoda and the Subphylum Myriapoda. They are elongated metameric animals with one pair of legs per body segment. A key trait uniting this group is a pair of poison claws or forcipules formed from a modified first appendage. This also means that centipedes are an exclusively predatory taxa, which is uncommon.
Centipedes normally have a drab coloration combining shades of brown and red. Template:Wict and subterranean species may lack pigmentation and many tropical Scolopendromorphs have bright aposematic colors. Size can range from a few millimeters in the smaller Lithobiomorphs and Geophilomorphs to about a foot in the largest Scolopendromorphs.
Worldwide there are estimated to be 8,000 species [1]. Currently there are about 3,000 described species. Geographically, centipedes have a wide range, which reaches beyond the Arctic Circle [2]. Centipedes are found in an array of terrestrial habitats from tropical rainforests to deserts. Within these habitats centipedes require a moist micro-habitat due to their rapid rates of water loss. Accordingly, they are found in soil and leaf litter, under stones and deadwood, and inside logs. In addition, centipedes are among the largest terrestrial invertebrate predators and often they contribute a significant proportion to invertebrate predatory biomass in terrestrial ecosystems.
# Anatomy
Centipedes have elongated dorsal-ventrally flattened bodies, and comprise two segmented tagmata; a head and trunk, which bear different hox gene expression. Each segment bears a single pair of legs and has a dorsal plate (tergite) and a ventral plate (sternite). Laterally each segment has a soft less scelerotized region known as the plueral membrane. This is where the spiracles for gas exchange are located in all orders except for the Scutigeromorpha (where they are located mid dorsally). The legs are segmented and segments are named proximal to distal: coxa, trachanter, prefemur, femur, tibia, and tarsus. Each leg terminates in a claw.
At the anterior end of the centipede is the head. Dorsally the head consists of a cephalic plate which is distinct in appearance from the tergites. Laterally on the head some centipedes have eyes. The order Geophilomorpha is blind. Scutigeromorphs have compound eyes and the other orders have no eyes or simple ocelli ranging from one pair to many. The ventral view of the head reveals the centipede's most prominent characteristic, its poison claws or forcipules. There are also three pairs of mouthparts all derived from the modification of appendages. There is a mandible with a first maxillae ventral to it and a second maxillae ventral to the first. These mouthparts are used for both feeding and grooming. At the anterior of the head there is a pair of antennae which vary in length and number of segments (except for the Geophilomorpha where the number of segments is fixed at 14).
The posterior end of a centipede has a conspicuous pair of legs named the ultimate or anal legs. These legs are not used for walking and are usually morphologically distinct from other pairs. Instead, they are used for defense and mating and so they often are morphologically distinct between the sexes. Ultimate legs can be inflated, excessively spined, and or morphologically complex with crests and furrows. The sexual organs are also located on the posterior end of the centipede. Sexual organs are externally visible in Scutigeromorpha and Lithobiomorpha, and some Geophilomorpha whereby males and females are easily distinguished. Scolopendromorpha do not have externally visible sexual organs, which makes sexing difficult. Scolopendromorph females may be larger or wider than males. Precise determination of sex can be accomplished upon dissection or by gently applying pressure and warm water to the genital sternite of a specimen to cause the sexual organs to emerge externally.
It also notable that centipedes have distinct sensory structures. The Tomosvary organ in Lithobiomorphs and Scutigeromorphs is located just anterior to the position of the eyes. The organ appears externally as an ellipse and its function is largely unknown. It has been suggested that it is a pressure, light, or humidity sensor. There is some evidence that it functions as a pressure sensor to detect sounds [3]. There are mechanoreceptors in the form of spines or hairs covering the legs and antennae. Lithobiomorphs have coxal pores on the ventral surface of the coxae of legs 12-15 in adults. These pores are present in pore fields consisting of 3-4 rows of pores. They are suspected to function in both osmoregulation and pheromone release [4]. Pore fields are found on some Geophilomorph and Scolopendromorph species on various sternites and on the ultimate coxae. It is not certain if their function is similair across the orders.
# Hazards to humans
Some species of centipedes can be hazardous to humans because of their poisonous bites. Although a bite to an adult human may only be painful, to those with allergies that are similar to that of bee stings and small children are at greater risk.
# Evolution
Template:Userboxtop
Template:Clade
Internal phylogeny of the Chilopoda. The upper three groups form the paraphyletic Anamorpha.
Template:Userboxbottom
Centipedes have a fossil record dating back 420 million years to the late Silurian [5]. They belong to the subphylum Myriapoda which includes Diplopoda, Symphyla, and Pauropoda. The oldest known fossil land animal is a MyriapodTemplate:Clarifyme. Being one of the earliest terrestrial animals, centipedes were one of the first to fill a fundamental niche as ground level generalist predators in detrital food webs. Today centipedes are abundant and exist in many harsh habitats.
Within the myriapods, centipedes are believed to be the first of the extant classes to branch from a common ancestor. There are five orders of centipede: Craterostigmomorpha, Geophilomorpha, Lithobiomorpha, Scolopendromorpha, and Scutigeromorpha. These orders are united into the clade Chilopoda by the following synapomorphies: 1) first post-cephalic appendage modified to poison claws. 2) embryonic cuticle on second maxilliped has egg tooth. 3) the trochanter-prefemur joint is fixed. 4) a spiral ridge on the nucleus of spermatazoan [6]. Chilopoda is then split into two clades: the Notostigmomorpha including the Scutigeromorpha and the Pluerostigmomorpha including the other four orders. The main difference is that the Notostigmomorpha have their spiracles located mid-dorsally. It was previously believed that Chilopoda was split into Anamorpha including the Lithobiomorpha and the Scutigeromorpha, and Epimorpha including the Geophilomorpha and Scolopendromorpha based on developmental modes, with the relationship of Craterostigmomorpha being uncertain. Recent phylogenetic analyses using combined molecular and morphological characters supports the previous phylogeny [7]. The Epimorpha group still exists as monophyletic within the Pleurostigmomorpha, but the Anamorpha group is paraphyletic.
Geophilomorph centipedes are used to argue for the developmental constraint of evolution,Template:Clarifyme because they have variable segment numbers within species, yet (as with all centipedes[8]) they always have an odd number of pairs of legs[9][10].
# Life history
Centipede mating does not involve copulation. Males deposit a spermatophore for the female to take up. In one clade, this spermatophore is deposited in a web, and the male undertakes a courtship dance to encourage the female to engulf his sperm. In other cases, the males just leave them for the females to find. In temperate areas egg laying occurs in spring and summer but in subtropical and tropical areas there appears to be little seasonality to centipede breeding. It is also notable that there are a few known species of parthenogenetic centipedes[11].
The Lithobiomorpha, and Scutigeromorpha lay their eggs singly in holes in the soil, the female fills the hole in on the egg and leaves it. Number of eggs laid ranges from about 10 to 50. Time of development of the embryo to hatching is highly variable and may take from one to a few months. Time of development to reproductive period is highly variable within and among species. For example, it can take 3 years for S. coleoptera to achieve adulthood, whereas under the right conditions Lithiobiomorph species may reach a reproductive period in 1 year. In addition, centipedes are relatively long-lived when compared to their insect cousins, for example: the European Lithobius forficatus can live for 5 or 6 years. The combination of a small number of eggs laid, long gestation period, and long time of development to reproduction has led authors to label Lithobiomorph centipedes as K-selected [12].
Females of Geophilomorpha and Scolopendromorpha show far more parental care, the eggs 15 to 60 in number are laid in a nest in the soil or in rotten wood, the female stays with the eggs, guarding and licking them to protect them from fungi. The female in some species stays with the young after they have hatched, guarding them until they are ready to leave. If disturbed the females tend to either abandon the eggs or young or to eat them; abandoned eggs tend to fall prey to fungi rapidly. Some species of Scolopendromorpha are matriphagic, meaning that the offspring eat their mother.
Little is known of the life history of Craterostigmomorpha.
## Anamorphy vs. epimorphy
Centipedes acquire their legs at different points in their development. In the primitive condition, exhibited by the Lithobiomorpha, Scutigeromorpha and Craterostigmomorpha, development is anamorphic. That is to say, more pairs of legs are grown between moults; for example, Scutigera coleoptera, the American house centipede, hatches with only 4 pairs of legs and in successive moults has 5, 7, 9, 11, 15, 15, 15 and 15 before becoming a sexually mature adult. Life stages with fewer than 15 pairs of legs are called larval stadia (~5 stages). After the full complement of legs is achieved, the now post-larval stadia (~5 stages) develop gonopods, sensory pores, more antennal segments, and more ocelli. All mature apomorphic centipedes have 15 leg-bearing segments.[verification needed]
The Craterostigmomorpha only have one phase of anamorphis, with embryos having 12 pairs, and moultees 15.
The clade Epimorpha, consisting of orders Geophilomorpha and Scolopendromorpha, derived epimorphy. Here, all pairs of legs are developed in the embryonic stages, offspring do not develop more legs between moults. Interestingly, it is this clade that contains the longest centipedes; the maximum number of thoratic segments may also very intra-specifically, often on a geographical basis; in most cases, females bear more legs than males.
The number of leg-bearing pairs varies widely, from 15 to 191 -- but the developmental mode of their creation means that they are always added in pairs - hence the total number present is always odd.
# Ecology
Centipedes are an exclusively predatory taxa. They are known as generalist predators which means that they have adapted to eat a variety of different available prey items. Centipedes are also known to be nocturnal. Studies on centipede activity rhythms confirm this, although there are a few observations of centipedes active during the day and one species Strigamia chinophila that is diurnal. What centipedes actually eat is not well known because of their cryptic lifestyle and thorough mastication of food. Laboratory feeding trials support that they will feed as generalists, taking most anything that is soft-bodied and in a reasonable size range. It has been suggested that earthworms provide the bulk of diets for Geophilomorphs, since geophilomorphs burrow through the soil and earthworm bodies would be easily pierced by their poison claws. Observations suggest that Geophilomorphs cannot subdue earthworms larger than themselves, and so smaller earthworms may be a substantial proportion of their diet [13]. Scolopendromorphs, given their size, are able to feed on vertebrates as well as invertebrates. They have been observed eating reptiles, amphibians, small mammals, bats and birds. Collembola may provide a large proportion of Lithiobiomorph diet. Little is known about Scutigeromorph or Craterostigmomorph diets. All centipedes are potential intraguild predators. Centipedes and spiders may frequently prey on one another[14]Video.
Centipedes are eaten by a great many vetebrates and invetebrates, and form the staple diet of some. The African ant Amblyopone pluto feeds solely on Geophilomorphs[verification needed] and the South African Cape Black-headed snake Aparallactus capensis mainly feeds on centipedes.
Centipedes are found in moist microhabitats. Water relations are an important aspect of their ecology, since they lose water rapidly in dry conditions. Water loss is a result of centipedes lacking a waxy covering of their exoskeleton and excreting waste nitrogen as ammonia, which requires extra water. Centipedes deal with water loss through a variety of adaptations. Geophilomorphs lose water less rapidly than Lithobiomorps even though they have a greater surface area to volume ratio. This may be explained by the fact that Geophilomorphs have a more heavily sclerotized pleural membrane. Spiracle shape, size and ability to constrict also have an influence on rate of water loss. In addition, it has been suggested that number and size of coxal pores may be variables affecting centipede water balance.
Centipedes live in many different habitat types; forest, savannah, prairie, and desert to name a few. Some Geophilomorphs are adapted to littoral habitats, where they feed on barnacles [15]. Species of all orders excluding Craterostigmomorpha have adapted to caves. Centipede densities have been recorded as high as 600/m2 and biomass as high as 500 mg/m2 wet weight. Small Geophilomorphs attain highest densities, followed by small Lithobiomorphs. Large Lithobiomorphs attain densities of 20/m2. One study of Scolopendromorphs records Scolopendra morsitans in a Nigerian savannah at a density of 0.16/m2 and a biomass of 140 mg/m2 wet weight [16].
# Largest centipede
Scolopendra gigantea, also known as the Amazonian giant centipede, is the largest existing species of centipede in the world, reaching over 30 cm (12 inches) in length. It is known to eat bats, catching them in midflight[17], as well as rodents and spiders. The prehistoric Euphoberia was the largest known centipede, growing up to one metre (39 inches) in length.
There are rumors that state that the Galápagos Islands giant centipede (Scolopendra galapagoensis) can reach sizes of up to 60 cm (over 25 in), although these rumours may result from the rarity of the particular centipede. Captive Galapagos centipedes don't often exceed 20 cm (8 inches) in body length.[1]
# Orders and families
The orders of centipedes are considered below, from primitive to derived.
## Scutigeromorpha
The Scutigeromorpha are anamorphic, reaching 15 leg-bearing segments in length. They are very fast creatures, and able to withstand falling at great speed: they reach up to 15 body-lengths per second when dropped, surviving the fall.
They are the only centipede group to retain their original compound eyes, with which a crystalline layer analogous to that seen in chelicerates and insects can be observed. They also bear long and multisegmented antennae. Adaptions to a burrowing lifestyle has led to the degeneration of compound eyes in other orders. This feature is of great use in phylogenetic anaylsis.
The group is the sole Template:Wict representative of the Notostigmomorpha, defined by having single spiracle openings on the back of their ventral plates. The more derived groups bear a plurality of spiracular openings on their sides, and are termed the Pleurostigmomorpha. Some even have 7 unpaired spiracles that can be found along the middorsal line and closer to their posterior section of tergites.
## Lithobiomorpha
The lithobiomorpha represent the other main group of anamorphic centipedes; they also reach a mature length of 15 thoratic segments. This group has lost the compound eyes, and sometimes has no eyes altogether. Instead, it eyes have facets or groups of facets. It's spiracles are paired and can be found laterally. Every leg-bearing segment of this organism has a separate tergite. It also has relatively short antennae and legs.
## Craterostigmomorpha
The craterostigmomorpha are the least diverse centipede clade, comprising only two species.[18]. Their geographic range is restricted to the south of Africa. They have a distinct body plan; their anamorphosis comprises a single stage; they grow from 12 to 15 segments in their first moult. Their low diversity and intermediate position between the primitive Anamorphic centipedes and the derived Epimorpha has led to them being described as the "platypus of the centipede world" [19]. They represent a "highly pruned" version of a once diverse clade.
Maternal brooding unites Craterostigomomorpha with the Epimorphs into the clade Phylactometria. This trait is thought to be closely linked with the presence of sternal pores, which secrete sticky or noxious secretions, which mainly serve to repel predators and parasites. The presence of these pores on the Devonian Devonobius permits its inclusion in this clade, allowing its divergence to be dated to 375 (or more) million years ago[20].
## Scolopendromorpha
The more primitive of the Epimorpha, the Scolopendromorpha comprise 21 or more segments with the same number of paired legs. Their antennae have 17 or more segments. Their eyes will have at least 4 facets on each side.
## Geophilomorpha
The Geophilomorpha are the most derived group of centipedes, and bear upwards of 27 leg-bearing segments. They are without fail eyeless and blind, and bear spiracles on all leg-bearing segments - in contrast to other groups, who only bear them on their 3rd, 5th, 8th, 10th and 12th segments -- a "mid-body break", accompanied by a change in tagmatic shape, occurring roughly at the interchange from odd to even segments. This group, at 1260 spp. the most diverse, also contains the largest and leggiest specimens at 29 or more pairs of legs. They also have 14 segmented antennae.
# List of common species
Template:Cleanup-laundry
- Arizona tiger centipede Scolopendra polymorpha
- Blue ring centipede Ethmostigmus trigonopodus
- Earth centipede Pachymerium ferrugineum
- Feather tail centipede Alipes sp.
- Galápagos centipede Scolopendra galapagoensis
- Giant Sonoran centipede Scolopendra heros
- House centipede Scutigera coleoptrata
- Peruvian giant orange leg centipede Scolopendra gigantea
- Red-headed centipede Scolopendra morsitans
- Stone centipede Lithobius forficatus
- Vietnamese centipede Scolopendra subspinipes | https://www.wikidoc.org/index.php/Centipede | |
f61a609846f7a7b5b198fc0d9776ac69f69c1f6f | wikidoc | Centrales | Centrales
Order Centrales is a traditional subdivision of the heterokont algae known as diatoms. The order is named for the shape of the cell walls (or valves or frustules) of centric diatoms, which are circular or ellipsoid in valve view. The valves often bear radially symmetrical ornamental patterns that can appear as dots when viewed with an optical microscope. Some also bear spines on their valves, which may either increase cell surface area and reduce sinking, or act as a deterrant to zooplankton grazers. Unlike pennate diatoms, centric diatoms never have a raphe.
In terms of cell cycle, vegetative cells are diploid and undergo mitosis during normal cell division. In sexual species, oogamous meiosis produces haploid gametes, either ova or sperm cells. These fuse to produce a zygote which expands in size to develop into an auxospore from which full-size vegetative cells are produced.
In some taxonomic schemes, the centric diatoms are known instead as Order Coscinodiscophyceae. | Centrales
Order Centrales is a traditional subdivision of the heterokont algae known as diatoms[1][2]. The order is named for the shape of the cell walls (or valves or frustules) of centric diatoms, which are circular or ellipsoid in valve view. The valves often bear radially symmetrical ornamental patterns that can appear as dots when viewed with an optical microscope. Some also bear spines on their valves, which may either increase cell surface area and reduce sinking, or act as a deterrant to zooplankton grazers. Unlike pennate diatoms, centric diatoms never have a raphe.
In terms of cell cycle, vegetative cells are diploid and undergo mitosis during normal cell division. In sexual species, oogamous meiosis produces haploid gametes, either ova or sperm cells. These fuse to produce a zygote which expands in size to develop into an auxospore from which full-size vegetative cells are produced.
In some taxonomic schemes[2], the centric diatoms are known instead as Order Coscinodiscophyceae. | https://www.wikidoc.org/index.php/Centrales | |
63f45ed3b1955ef79033bb93cf264c0305c9a6ec | wikidoc | Ceragenin | Ceragenin
Ceragenins, or cationic steroid antibiotics (CSAs), are synthetically produced small molecule chemical compounds comprised of a sterol backbone with amino acids and other chemical groups attached to them. These compounds have a net positive charge that is electrostatically attracted to the negatively charged cell membranes of certain viruses, fungi and bacteria. CSAs have a high binding affinity for such membranes (including Lipid A) and are able to rapidly disrupt the target membranes leading to rapid cell death. While CSAs have a mechanism of action that is also seen in antimicrobial peptides, which form part of the body's innate immune system, they avoid many of the difficulties associated with their use as medicines.
Ceragenins were invented by Dr. Paul B. Savage of Brigham Young University's Department of Chemistry and Biochemistry and exclusively licensed to Ceragenix. In data previously presented by Dr. Savage and other researchers, CSAs have been shown to have broad spectrum antibacterial activity. Dr. Derya Unutmaz, Associate Professor of Microbiology and Immunology at the Vanderbilt University School of Medicine, tested several CSAs in his laboratory for their ability to kill HIV directly. According to Unutmaz, "We have some preliminary but very exciting results. But we would like to formally show this before making any claims that would cause unwanted hype."
On February 6, 2006, researchers (including Dr. Paul B. Savage) announced that a Ceragenin compound, CSA-54, appears to inactivate HIV. This conclusion is still awaiting peer review. | Ceragenin
Ceragenins, or cationic steroid antibiotics (CSAs), are synthetically produced small molecule chemical compounds comprised of a sterol backbone with amino acids and other chemical groups attached to them. These compounds have a net positive charge that is electrostatically attracted to the negatively charged cell membranes of certain viruses, fungi and bacteria. CSAs have a high binding affinity for such membranes (including Lipid A[1]) and are able to rapidly disrupt the target membranes leading to rapid cell death. While CSAs have a mechanism of action that is also seen in antimicrobial peptides, which form part of the body's innate immune system, they avoid many of the difficulties associated with their use as medicines.[2]
Ceragenins were invented by Dr. Paul B. Savage of Brigham Young University's Department of Chemistry and Biochemistry and exclusively licensed to Ceragenix.[2] In data previously presented by Dr. Savage and other researchers, CSAs have been shown to have broad spectrum antibacterial activity.[3] Dr. Derya Unutmaz, Associate Professor of Microbiology and Immunology at the Vanderbilt University School of Medicine, tested several CSAs in his laboratory for their ability to kill HIV directly. According to Unutmaz, "We have some preliminary but very exciting results. But we would like to formally show this before making any claims that would cause unwanted hype."[4]
On February 6, 2006, researchers (including Dr. Paul B. Savage) announced that a Ceragenin compound, CSA-54, appears to inactivate HIV. This conclusion is still awaiting peer review.[5] | https://www.wikidoc.org/index.php/Ceragenin | |
e5f4b375bcc518cc54655dbdd68478359bd0588d | wikidoc | Cerealine | Cerealine
Cerealine, also known as malt flakes, was a popular 19th century American cereal product and the first dry breakfast food. Similar to but predating corn flakes, which appeared in 1898 and are first rolled and then toasted, cerealine is corn grits in the form of uncooked flakes. It was originally used by the brewing industry.
More popularly, Cerealine Flakes, colloquially called simply Cerealine, was also the brand name for raw-flake cereal made from grits by the Cerealine Manufacturing Company of Indianapolis, Indiana, USA.
# History
After having long been used for beer brewing, cerealine in the late 19th century became one the three most popular cereals of that time, along with cracked wheat and oatmeal. All three were typically sold by retailers who bought cereal in barrel lots and scooped it out to sell by the pound to customers. Cerealine Flakes was later sold in packages.
White-corn cerealine flakes were invented, perhaps accidentally, by Columbus, Indiana mill worker James Vannoy circa 1884 or 1887. Cerealine was established as a breakfast food by at least 1897, when the Illinois Farmer's Institute annual report noted that, "Some mills make hominy of white corn, roll it into broad, flat flakes, called cerealine, which are used here as a breakfast dish...."
## Cerealine Manufacturing
Aurora, Indiana's T. & J.W. Gaff & Co. distillery built the Cerealine Mill, at 607 Jackson Street in Columbus, Indiana, in 1867. Their Cerealine Manufacturing Company moved to Indianapolis, Indiana sometime prior to 1898, though the Columbus mill's building remained extant and was restored in the late 20th or early 21st century for use as a cafeteria and conference center by the engine manufacturing corporation Cummins Inc.
Prior to being annexed by Indianapolis in 1895, the settlement around what was then called the Cerealine Works was known as Cerealinetown.
# Footnotess
- ↑ TripTrivia.com: Columbus, Indiana Tourism
- ↑ The Evening Republican (July 22, 1902); James Vannoy obituary
- ↑ Mills, Charles F. editor, Annual Report, Illinois Farmer's Institute with Reports of County Farmers' Institutes for the Year 1897 (Phillips Bros., State Printers, Springfield, Ill.) p. 122
- ↑ Hillforest.org: History of Hillforest
- ↑ Joseph Hart and His Descendants, by Rev. Charles Coffin Hart (1901): Gideon B. Hart
- ↑ The Digital Collections of IUPUI University Library: Indianapolis Sanborn Map #61, 1898
- ↑ Repp and Mundt: Restoration. Includes image of building.
- ↑ Cartage.org: Cummins Engine Co.
- ↑ HistoricColumbusIndiana.org: "Columbus Indiana Pictures and Photos From Bygone Days", p. 8. Includes image of building.
- ↑ Historic Landmarks Foundation of Indiana: Press release (Oct. 20, 2002): "Preservationists aim to save historic schools and taxpayer money" | Cerealine
Cerealine, also known as malt flakes, was a popular 19th century American cereal product and the first dry breakfast food. Similar to but predating corn flakes, which appeared in 1898 and are first rolled and then toasted, cerealine is corn grits in the form of uncooked flakes. It was originally used by the brewing industry.
More popularly, Cerealine Flakes, colloquially called simply Cerealine, was also the brand name for raw-flake cereal made from grits by the Cerealine Manufacturing Company of Indianapolis, Indiana, USA.
# History
After having long been used for beer brewing, cerealine in the late 19th century became one the three most popular cereals of that time, along with cracked wheat and oatmeal. All three were typically sold by retailers who bought cereal in barrel lots and scooped it out to sell by the pound to customers. Cerealine Flakes was later sold in packages.
White-corn cerealine flakes were invented, perhaps accidentally, by Columbus, Indiana mill worker James Vannoy circa 1884[1] or 1887.[2] Cerealine was established as a breakfast food by at least 1897, when the Illinois Farmer's Institute annual report noted that, "Some mills make hominy of white corn, roll it into broad, flat flakes, called cerealine, which are used here as a breakfast dish...."[3]
## Cerealine Manufacturing
Aurora, Indiana's T. & J.W. Gaff & Co. distillery built the Cerealine Mill,[4] at 607 Jackson Street in Columbus, Indiana, in 1867. Their Cerealine Manufacturing Company moved to Indianapolis, Indiana[5] sometime prior to 1898,[6] though the Columbus mill's building remained extant and was restored in the late 20th or early 21st century[7] for use as a cafeteria and conference center[8] by the engine manufacturing corporation Cummins Inc.[9]
Prior to being annexed by Indianapolis in 1895, the settlement around what was then called the Cerealine Works was known as Cerealinetown.[10]
# Footnotess
- ↑ TripTrivia.com: Columbus, Indiana Tourism
- ↑ The Evening Republican (July 22, 1902); James Vannoy obituary
- ↑ Mills, Charles F. editor, Annual Report, Illinois Farmer's Institute with Reports of County Farmers' Institutes for the Year 1897 (Phillips Bros., State Printers, Springfield, Ill.) p. 122
- ↑ Hillforest.org: History of Hillforest
- ↑ Joseph Hart and His Descendants, by Rev. Charles Coffin Hart (1901): Gideon B. Hart
- ↑ The Digital Collections of IUPUI University Library: Indianapolis Sanborn Map #61, 1898
- ↑ Repp and Mundt: Restoration. Includes image of building.
- ↑ Cartage.org: Cummins Engine Co.
- ↑ HistoricColumbusIndiana.org: "Columbus Indiana Pictures and Photos From Bygone Days", p. 8. Includes image of building.
- ↑ Historic Landmarks Foundation of Indiana: Press release (Oct. 20, 2002): "Preservationists aim to save historic schools and taxpayer money" | https://www.wikidoc.org/index.php/Cerealine | |
9b1196d479c2f490a921e0defe4809db53e75b24 | wikidoc | Ceritinib | Ceritinib
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# Overview
Ceritinib is an antineoplastic agent that is FDA approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Common adverse reactions include increased ALT, nausea, increased AST, diarrhea , and vomiting and serious adverse drug reactions are convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ceritinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
- This indication is approved under accelerated approval based on tumor response rate and duration of response . An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- The recommended dose of Ceritinib is 750 mg orally once daily until disease progression or unacceptable toxicity. Administer Ceritinib on an empty stomach (i.e., do not administer within 2 hours of a meal) .
- A recommended dose has not been determined for patients with moderate to severe hepatic impairment.
- If a dose of Ceritinib is missed, make up that dose unless the next dose is due within 12 hours.
- Recommendations for dose modifications of Ceritinib for adverse reactions are provided in Table 1.
- Approximately 60% of patients initiating treatment at the recommended dose required at least one dose reduction and the median time to first dose reduction was 7 weeks.
- Discontinue Ceritinib for patients unable to tolerate 300 mg daily.
- Avoid concurrent use of strong CYP3A inhibitors during treatment with Ceritinib
- If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the Ceritinib dose by approximately one-third, rounded to the nearest 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the Ceritinib dose that was taken prior to initiating the strong CYP3A4 inhibitor.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceritinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceritinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of Ceritinib in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- The safety and effectiveness of Ceritinib in pediatric patients have not been established.
### Non–Guideline-Supported Use
- The safety and effectiveness of Ceritinib in pediatric patients have not been established.
# Contraindications
- None
# Warnings
- Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients treated with Ceritinib in Study 1. Dose modification due to diarrhea, nausea, vomiting, or abdominal pain occurred in 38% of patients.
- Monitor and manage patients using standards of care, including anti-diarrheals, anti-emetics, or fluid replacement, as indicated. Based on the severity of the adverse drug reaction, withhold Ceritinib with resumption at a reduced dose as described in Table 1 .
- Drug-induced hepatotoxicity occurred in patients treated with Ceritinib . Elevations in alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN) occurred in 27% of 255 patients in Study 1. One patient (0.4%) required permanent discontinuation due to elevated transaminases and jaundice.
- Monitor with liver laboratory tests including ALT, aspartate aminotransferase (AST), and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on the severity of the adverse drug reaction, withhold Ceritinib with resumption at a reduced dose, or permanently discontinue Ceritinib as described in Table 1
- Severe, life-threatening, or fatal ILD/pneumonitis can occur in patients treated with Ceritinib . In Study 1, pneumonitis was reported in 4% of 255 patients treated with Ceritinib . CTCAE Grade 3 or 4 ILD/pneumonitis was reported in 3% of patients, and fatal ILD/pneumonitis was reported in 1 patient (0.4%) in Study 1. One percent (1%) of patients discontinued Ceritinib in Study 1 due to ILD/pneumonitis.
- Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue Ceritinib in patients diagnosed with treatment-related ILD/pneumonitis
- QTc interval prolongation occurs in patients treated with Ceritinib . Three percent (3%) of 255 patients experienced a QTc interval increase over baseline greater than 60 msec in Study 1. Across the development program of Ceritinib , one of 304 patients (less than 1%) treated with Ceritinib doses ranging from 50 to 750 mg was found to have a QTc greater than 500 msec and 3% of patients had an increase from baseline QTc greater than 60 msec. A pharmacokinetic analysis suggested that Ceritinib causes concentration-dependent increases in the QT interval.
- When possible, avoid use of Ceritinib in patients with congenital long QT syndrome. Conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Withhold Ceritinib in patients who develop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec, then resume Ceritinib at a reduced dose as described in Table 1. Permanently discontinue Ceritinib in patients who develop QTc interval prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia.
- Hyperglycemia can occur in patients receiving Ceritinib . In Study 1, CTCAE Grade 3–4 hyperglycemia, based on laboratory values, occurred in 13% of 255 patients. There was a 6-fold increase in the risk of CTCAE Grade 3–4 hyperglycemia in patients with diabetes or glucose intolerance and a 2-fold increase in patients taking corticosteroids.
- Monitor serum glucose levels as clinically indicated. Initiate or optimize anti-hyperglycemic medications as indicated. Based on the severity of the adverse drug reaction, withhold Ceritinib until hyperglycemia is adequately controlled, then resume Ceritinib at a reduced dose as described in Table 1. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue Ceritinib .
- Bradycardia can occur in patients receiving Ceritinib . In Study 1, sinus bradycardia, defined as a heart rate of less than 50 beats per minute, was noted as a new finding in 1% of 255 patients. Bradycardia was reported as an adverse drug reaction in 3% of patients in Study 1.
- Avoid using Ceritinib in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold Ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose of Ceritinib . Permanently discontinue Ceritinib for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with a concomitant medication known to cause bradycardia or hypotension, withhold Ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if the concomitant medication can be adjusted or discontinued, resume Ceritinib at a reduced dose as described in Table 1 upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring .
- Based on its mechanism of action, Ceritinib may cause fetal harm when administered to a pregnant woman. In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures below the recommended human dose of 750 mg daily caused increases in skeletal anomalies in rats and rabbits. Apprise women of reproductive potential of the potential hazard to a fetus . Advise females of reproductive potential to use effective contraception during treatment with Ceritinib and for at least 2 weeks following completion of therapy
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Severe or Persistent Gastrointestinal Toxicity
- Hepatotoxicity
- Interstitial Lung Disease/Pneumonitis
- QT Interval Prolongation
- Hyperglycemia
- Bradycardia
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety evaluation of Ceritinib is based on 255 ALK-positive patients in Study 1 (246 patients with NSCLC and 9 patients with other cancers who received Ceritinib at a dose of 750 mg daily). The median duration of exposure to Ceritinib was 6 months. The study population characteristics were: median age 53 years, age less than 65 (84%), female (53%), Caucasian (63%), Asian (34%), NSCLC adenocarcinoma histology (90%), never or former smoker (97%), ECOG PS 0 or 1 (89%), brain metastasis (49%), and number of prior therapies 2 or more (67%).
- Dose reductions due to adverse reactions occurred in 59% of patients treated with Ceritinib . The most frequent adverse reactions, reported in at least 10% of patients, that led to dose reductions or interruptions were: increased ALT (29%), nausea (20%), increased AST (16%), diarrhea (16%), and vomiting (16%). Serious adverse drug reactions reported in 2% or more of patients in Study 1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Fatal adverse reactions in patients treated with Ceritinib occurred in 5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis (1 patient each). Discontinuation of therapy due to adverse reactions occurred in 10% of patients treated with Ceritinib . The most frequent adverse drug reactions that led to discontinuation in 1% or more of patients in Study 1 were pneumonia, ILD/pneumonitis, and decreased appetite.
- Tables 2 and 3 summarize the common adverse reactions and laboratory abnormalities observed in Ceritinib -treated patients.
- Additional clinically significant adverse reactions occurring in 2% or more of patients treated with Ceritinib included neuropathy (17%; comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy), vision disorder (9%; comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity), prolonged QT interval (4%), and bradycardia (3%).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ceritinib in the drug label.
# Drug Interactions
- Ceritinib is primarily metabolized by CYP3A4 and is a substrate of the efflux transporter P-glycoprotein (P-gp).
- Ketoconazole (a strong CYP3A4/P-gp inhibitor) increased the systemic exposure of ceritinib . Avoid concurrent use of strong CYP3A inhibitors during treatment with Ceritinib . If concomitant use of strong CYP3A inhibitors including certain antivirals (e.g., ritonavir), macrolide antibiotics (e.g., telithromycin), antifungals (e.g., ketoconazole), and nefazodone is unavoidable, reduce the Ceritinib dose by approximately one-third, rounded to the nearest 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the Ceritinib dose that was taken prior to initiating the strong CYP3A4 inhibitor.
- Do not consume grapefruit and grapefruit juice as they may inhibit CYP3A.
- Rifampin (a strong CYP3A4/P-gp inducer) decreased the systemic exposure of ceritinib . Avoid concurrent use of strong CYP3A inducers(e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) during treatment with Ceritinib .
- Ceritinib may inhibit CYP3A and CYP2C9 at clinical concentrations. Avoid concurrent use of CYP3A and CYP2C9 substrates known to have narrow therapeutic indices or substrates primarily metabolized by CYP3A and CYP2C9 during treatment with Ceritinib . If use of these medications is unavoidable, consider dose reduction of CYP3A substrates with narrow therapeutic indices (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) and CYP2C9 substrates with narrow therapeutic indices (e.g., phenytoin, warfarin).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on its mechanism of action, Ceritinib may cause fetal harm when administered to a pregnant woman. In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
- In an embryo-fetal development study in which pregnant rats were administered daily doses of ceritinib during organogenesis, dose-related skeletal anomalies were observed at doses as low as 50 mg/kg (less than 0.5-fold the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations.
- In pregnant rabbits administered ceritinib daily during organogenesis, dose-related skeletal anomalies, including incomplete ossification, were observed at doses equal to or greater than 2 mg/kg/day (approximately 0.015-fold the human exposure by AUC at the recommended dose). A low incidence of visceral anomalies, including absent or malpositioned gallbladder and retroesophageal subclavian cardiac artery, was observed at doses equal to or greater than 10 mg/kg/day (approximately 0.13-fold the human exposure by AUC at the recommended dose). Maternal toxicity and abortion occurred in rabbits at doses of 35 mg/kg or greater. In addition, embryolethality was observed in rabbits at a dose of 50 mg/kg.Risk Summary
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceritinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ceritinib during labor and delivery.
### Nursing Mothers
- It is not known whether ceritinib or its metabolites are present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from ceritinib, advise mothers to discontinue nursing.
### Pediatric Use
- The safety and effectiveness of Ceritinib in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of Ceritinib did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 255 patients in Study 1 who received Ceritinib at the recommended dose, 40 (16%) were 65 years or older.
### Gender
There is no FDA guidance on the use of Ceritinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ceritinib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ceritinib in patients with renal impairment.
### Hepatic Impairment
- As ceritinib is eliminated primarily via the liver, patients with hepatic impairment may have increased exposure. Dose adjustment is not recommended for patients with |mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin greater than 1.0 to 1.5 times ULN and any AST) based on results of the population pharmacokinetic analysis . A recommended dose has not been determined for patients with moderate to severe hepatic impairment
### Females of Reproductive Potential and Males
- Based on its mechanism of action, Ceritinib may cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment with Ceritinib and for at least 2 weeks following completion of therapy.
### Immunocompromised Patients
There is no FDA guidance one the use of Ceritinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold Ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose of Ceritinib .
- Monitor serum glucose levels as clinically indicated.
# IV Compatibility
There is limited information regarding IV Compatibility of Ceritinib in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Ceritinib in the drug label.
# Pharmacology
## Mechanism of Action
- Ceritinib is a kinase inhibitor. Targets of ceritinib inhibition identified in either biochemical or cellular assays at clinically relevant concentrations include ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Among these, ceritinib is most active against ALK. Ceritinib inhibited autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays.
- Ceritinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. Ceritinib exhibited dose-dependent anti-tumor activity in mice bearing EML4-ALK-positive NSCLC xenografts with demonstrated resistance to crizotinib, at concentrations within a clinically relevant range.
## Structure
- Ceritinib (ceritinib) is a tyrosine kinase inhibitor for oral administration. The molecular formula for ceritinib is C28H36N5O3ClS. The molecular weight is 558.14 g/mole. Ceritinib is described chemically as 5-Chloro-N4-phenyl]-N2--2,4-pyrimidinediamine.
- The chemical structure of ceritinib is shown below:
- Ceritinib is a white to almost white or light yellow or light brown powder with a pKa of 9.7 and 4.1.
- Ceritinib is supplied as printed hard-gelatin capsules containing 150 mg of ceritinib and the following inactive ingredients: colloidal anhydrous silica, L-hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and hard gelatin capsule shells. The capsule shell is composed of gelatin, indiogotine, and titanium dioxide.
## Pharmacodynamics
- Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of ceritinib on the QT interval in an open-label, dose-escalation, and expansion study. A total of 304 patients were treated with Ceritinib doses ranging from 50 to 750 mg with 255 patients treated with Ceritinib 750 mg. One of 304 patients (less than 1%) was found to have a QTc greater than 500 msec and 10 patients (3%) had an increase from baseline QTc greater than 60 msec. A central tendency analysis of the QTc data at average steady-state concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 16 msec at Ceritinib 750 mg. A pharmacokinetic/pharmacodynamic analysis suggested concentration-dependent QTc interval prolongation .
- Based on central review of ECG data, 2 of 304 patients (0.7%) had bradycardia defined as less than 50 beats per minute. Bradycardia was reported as an adverse drug reaction in 3% of patients in Study 1.
## Pharmacokinetics
- After single oral administration of Ceritinib in patients, peak plasma levels (Cmax) of ceritinib were achieved at approximately 4 to 6 hours, and area under the curve (AUC) and Cmax increased dose proportionally over 50 to 750 mg. The absolute bioavailability of Ceritinib has not been determined.
- Following Ceritinib 750 mg once daily dosing, steady-state was reached by approximately 15 days with a geometric mean accumulation ratio of 6.2 after 3 weeks. Systemic exposure increased in a greater than dose proportional manner after repeat doses of 50 to 750 mg once daily.
- Systemic exposure of ceritinib was increased when administered with a meal. A food effect study conducted in healthy subjects with a single 500 mg ceritinib dose showed that a high‐fat meal (containing approximately 1000 calories and 58 grams of fat) increased ceritinib AUC by 73% and Cmaxby 41% and a low-fat meal (containing approximately 330 calories and 9 grams of fat) increased ceritinib AUC by 58% and Cmax by 43% as compared with the fasted state. A 400 mg or higher Ceritinib dose taken with a meal is expected to result in systemic exposure exceeding that of a 750 mg Ceritinib dose taken in the fasted state, and may increase adverse drug reactions.
- Ceritinib is 97% bound to human plasma proteins, independent of drug concentration. The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg Ceritinib dose in patients. Ceritinib also has a slight preferential distribution to red blood cells, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35.
- Following a single 750 mg Ceritinib dose, the geometric mean apparent plasma terminal half-life (t1/2) of ceritinib was 41 hours in patients. Ceritinib demonstrates nonlinear PK over time. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h).
- Metabolism: In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma.
- Excretion: Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.
- Age, Gender, Race, and Body Weight: Age, gender, race, and body weight had no clinically important effect on the systemic exposure of ceritinib based on population pharmacokinetic analyses.
- Hepatic Impairment: As ceritinib is eliminated primarily via the liver, patients with hepatic impairment may have increased exposure. A pharmacokinetic trial in patients with hepatic impairment has not been conducted. Based on a population pharmacokinetic analysis of 48 patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin greater than 1.0 to 1.5 times ULN and any AST) and 254 patients with normal hepatic function (total bilirubin less than or equal to ULN and AST less than or equal to ULN), ceritinib exposures were similar in patients with mild hepatic impairment and normal hepatic function. The pharmacokinetics of ceritinib has not been studied in patients with moderate to severe hepatic impairment .
- Renal Impairment: A pharmacokinetic trial in patients with renal impairment has not been conducted as ceritinib elimination via the kidney is low (1.3% of a single oral administered dose). Based on a population pharmacokinetic analysis of 97 patients with mild renal impairment (CLcr 60 to less than 90 mL/min), 22 patients with moderate renal impairment (CLcr 30 to less than 60 mL/min) and 183 patients with normal renal function (greater than or equal to 90 mL/min), ceritinib exposures were similar in patients with mild and moderate renal impairment and normal renal function. Patients with severe renal impairment (CLcr less than 30 mL/min) were not included in the clinical trial.
- Pediatrics: No trials have been conducted to evaluate the pharmacokinetics of ceritinib in pediatric patients.
- Effect of Strong CYP3A Inhibitors on Ceritinib: In vitro studies show that ceritinib is a substrate of CYP3A. Coadministration of a single 450 mg Ceritinib dose with ketoconazole (a strong CYP3A inhibitor) 200 mg twice daily for 14 days increased ceritinib AUC (90% CI) by 2.9-fold (2.5, 3.3) and Cmax (90% CI) by 22% (7%, 39%) in 19 healthy subjects . The steady-state AUC of ceritinib at reduced doses after coadministration with ketoconazole 200 mg twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib alone .
- Effect of Strong CYP3A Inducers on Ceritinib: Coadministration of a single 750 mg Ceritinib dose with rifampin (a strong CYP3A inducer) 400 mg daily for 14 days decreased ceritinib AUC (90% CI) by 70% (61%, 77%) and Cmax (90% CI) by 44% (24%, 59%) in 19 healthy subjects.
- Effect of Ceritinib on CYP Substrates: Based on in vitro data, ceritinib may inhibit CYP3A and CYP2C9 at clinical concentrations. Time-dependent inhibition of CYP3A was also observed.
- Effect of Transporters on Ceritinib Disposition: Ceritinib is a substrate of efflux transporter P-gp, but is not a substrate of Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Protein (MRP2), Organic Cation Transporter (OCT1), Organic Anion Transporter (OAT2), or Organic Anion Transporting Polypeptide (OATP1B1) in vitro. Drugs that inhibit P-gp may increase ceritinib concentrations.
- Effect of Ceritinib on Transporters: Based on in vitro data, ceritinib does not inhibit apical efflux transporters, P-gp, BCRP, or MRP2, hepatic uptake transporters OATP1B1 and OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or organic cation uptake transporters OCT1 and OCT2 at clinical concentrations.
- Effect of Gastric Acid Reducing Agents on Ceritinib: Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of ceritinib and reduce its bioavailability as ceritinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. A dedicated study has not been conducted to evaluate the effect of gastric acid reducing agents on the bioavailability of ceritinib.
## Nonclinical Toxicology
- Carcinogenicity studies have not been performed with ceritinib.
- Ceritinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced numerical aberrations (aneugenic) in the in vitro cytogenetic assay using human lymphocytes, and micronuclei in the in vitro micronucleus test using TK6 cells. Ceritinib was not clastogenic in the in vivo rat micronucleus assay.
- There are no data on the effect of ceritinib on human fertility. Fertility/early embryonic development studies were not conducted with ceritinib. There were no adverse effects on male or female reproductive organs in general toxicology studies conducted in monkeys and rats at exposures equal to or greater than 0.5- and 1.5-fold, respectively, of the human exposure by AUC at the recommended dose of 750 mg.
- Target organs in nonclinical animal models included, but were not limited to, the pancreas, biliopancreatic/bile ducts, gastrointestinal tract, and liver. Pancreatic focal acinar cell atrophy was observed in rats at 1.5-fold the human exposure by AUC at the recommended dose. Biliopancreatic duct and bile duct necrosis was observed in rats at exposures equal to or greater than 5% of the human exposure by AUC at the recommended dose. Bile duct inflammation and vacuolation were also noted in monkeys at exposures equal to or greater than 0.5-fold the human exposure by AUC at the recommended dose. Frequent minimal necrosis and hemorrhage of the duodenum was exhibited in monkeys at 0.5-fold the human exposure by AUC, and in rats at an exposure similar to that observed clinically.
- Ceritinib crossed the blood brain barrier in rats with a brain-to-blood exposure (AUCinf) ratio of approximately 15%.
# Clinical Studies
- The efficacy of Ceritinib was established in a multicenter, single-arm, open-label clinical trial (Study 1). A total of 163 patients with metastatic ALK-positive NSCLC who progressed while receiving or were intolerant to crizotinib were enrolled. All patients received Ceritinib at a dose of 750 mg once daily. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.0 as evaluated by both investigators and a Blinded Independent Central Review Committee (BIRC). Duration of response (DOR) was an additional outcome measure.
- The study population characteristics were: median age 52 years, age less than 65 (87%), female (54%), Caucasian (66%), Asian (29%), never or former smoker (97%), ECOG PS 0 or 1 (87%), progression on previous crizotinib (91%), number of prior therapies 2 or more (84%), and adenocarcinoma histology (93%). Sites of extra-thoracic metastasis included brain (60%), liver (42%), and bone (42%). ALK-positivity was verified retrospectively by review of local test results for 99% of patients.
- Efficacy results from Study 1 are summarized in Table 4.
# How Supplied
- Ceritinib 150 mg capsules
- Hard gelatin capsule with opaque blue cap and opaque white body; opaque blue cap marked in black ink with “LDK 150MG”, opaque white body marked in black ink with “NVR”. Available in:
- Bottles of 70 capsules NDC 0078-0640-70
## Storage
- Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Inform patients that diarrhea, nausea, vomiting, and abdominal pain are the most commonly reported adverse reactions in patients treated with Ceritinib . Inform patients of supportive care options such as anti-emetic and anti-diarrheal medications. Advise patients to contact their healthcare provider for severe or persistent gastrointestinal symptoms
- Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity
- Inform patients of the risks of severe or fatal ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms
- Inform patients of the risks of QTc interval prolongation and bradycardia. Advise patients to contact their healthcare provider immediately to report new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, fainting, and changes in or new use of heart or blood pressure medications
- Inform patients of the signs and symptoms of hyperglycemia. Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperglycemia
- Advise females to inform their healthcare provider if they are pregnant. Inform females of reproductive potential of the risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Ceritinib and for at least 2 weeks following completion of therapy
- Advise females not to breastfeed during treatment with Ceritinib
- Inform patients not to consume grapefruit and grapefruit juice during treatment with Ceritinib .
- Take Ceritinib on an empty stomach (i.e., do not take within 2 hours of a meal) .
- Advise patients to make up a missed dose of Ceritinib unless the next dose is due within 12 hours
# Precautions with Alcohol
- Alcohol-Ceritinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zykadia®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Ceritinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
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# Overview
Ceritinib is an antineoplastic agent that is FDA approved for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Common adverse reactions include increased ALT, nausea, increased AST, diarrhea , and vomiting and serious adverse drug reactions are convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ceritinib is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
- This indication is approved under accelerated approval based on tumor response rate and duration of response . An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- The recommended dose of Ceritinib is 750 mg orally once daily until disease progression or unacceptable toxicity. Administer Ceritinib on an empty stomach (i.e., do not administer within 2 hours of a meal) .
- A recommended dose has not been determined for patients with moderate to severe hepatic impairment.
- If a dose of Ceritinib is missed, make up that dose unless the next dose is due within 12 hours.
- Recommendations for dose modifications of Ceritinib for adverse reactions are provided in Table 1.
- Approximately 60% of patients initiating treatment at the recommended dose required at least one dose reduction and the median time to first dose reduction was 7 weeks.
- Discontinue Ceritinib for patients unable to tolerate 300 mg daily.
- Avoid concurrent use of strong CYP3A inhibitors during treatment with Ceritinib
- If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the Ceritinib dose by approximately one-third, rounded to the nearest 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the Ceritinib dose that was taken prior to initiating the strong CYP3A4 inhibitor.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceritinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceritinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of Ceritinib in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- The safety and effectiveness of Ceritinib in pediatric patients have not been established.
### Non–Guideline-Supported Use
- The safety and effectiveness of Ceritinib in pediatric patients have not been established.
# Contraindications
- None
# Warnings
- Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients treated with Ceritinib in Study 1. Dose modification due to diarrhea, nausea, vomiting, or abdominal pain occurred in 38% of patients.
- Monitor and manage patients using standards of care, including anti-diarrheals, anti-emetics, or fluid replacement, as indicated. Based on the severity of the adverse drug reaction, withhold Ceritinib with resumption at a reduced dose as described in Table 1 .
- Drug-induced hepatotoxicity occurred in patients treated with Ceritinib . Elevations in alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (ULN) occurred in 27% of 255 patients in Study 1. One patient (0.4%) required permanent discontinuation due to elevated transaminases and jaundice.
- Monitor with liver laboratory tests including ALT, aspartate aminotransferase (AST), and total bilirubin once a month and as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Based on the severity of the adverse drug reaction, withhold Ceritinib with resumption at a reduced dose, or permanently discontinue Ceritinib as described in Table 1
- Severe, life-threatening, or fatal ILD/pneumonitis can occur in patients treated with Ceritinib . In Study 1, pneumonitis was reported in 4% of 255 patients treated with Ceritinib . CTCAE Grade 3 or 4 ILD/pneumonitis was reported in 3% of patients, and fatal ILD/pneumonitis was reported in 1 patient (0.4%) in Study 1. One percent (1%) of patients discontinued Ceritinib in Study 1 due to ILD/pneumonitis.
- Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue Ceritinib in patients diagnosed with treatment-related ILD/pneumonitis
- QTc interval prolongation occurs in patients treated with Ceritinib . Three percent (3%) of 255 patients experienced a QTc interval increase over baseline greater than 60 msec in Study 1. Across the development program of Ceritinib , one of 304 patients (less than 1%) treated with Ceritinib doses ranging from 50 to 750 mg was found to have a QTc greater than 500 msec and 3% of patients had an increase from baseline QTc greater than 60 msec. A pharmacokinetic analysis suggested that Ceritinib causes concentration-dependent increases in the QT interval.
- When possible, avoid use of Ceritinib in patients with congenital long QT syndrome. Conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications that are known to prolong the QTc interval. Withhold Ceritinib in patients who develop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec, then resume Ceritinib at a reduced dose as described in Table 1. Permanently discontinue Ceritinib in patients who develop QTc interval prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia.
- Hyperglycemia can occur in patients receiving Ceritinib . In Study 1, CTCAE Grade 3–4 hyperglycemia, based on laboratory values, occurred in 13% of 255 patients. There was a 6-fold increase in the risk of CTCAE Grade 3–4 hyperglycemia in patients with diabetes or glucose intolerance and a 2-fold increase in patients taking corticosteroids.
- Monitor serum glucose levels as clinically indicated. Initiate or optimize anti-hyperglycemic medications as indicated. Based on the severity of the adverse drug reaction, withhold Ceritinib until hyperglycemia is adequately controlled, then resume Ceritinib at a reduced dose as described in Table 1. If adequate hyperglycemic control cannot be achieved with optimal medical management, permanently discontinue Ceritinib .
- Bradycardia can occur in patients receiving Ceritinib . In Study 1, sinus bradycardia, defined as a heart rate of less than 50 beats per minute, was noted as a new finding in 1% of 255 patients. Bradycardia was reported as an adverse drug reaction in 3% of patients in Study 1.
- Avoid using Ceritinib in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold Ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose of Ceritinib . Permanently discontinue Ceritinib for life-threatening bradycardia if no contributing concomitant medication is identified; however, if associated with a concomitant medication known to cause bradycardia or hypotension, withhold Ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if the concomitant medication can be adjusted or discontinued, resume Ceritinib at a reduced dose as described in Table 1 upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring .
- Based on its mechanism of action, Ceritinib may cause fetal harm when administered to a pregnant woman. In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures below the recommended human dose of 750 mg daily caused increases in skeletal anomalies in rats and rabbits. Apprise women of reproductive potential of the potential hazard to a fetus . Advise females of reproductive potential to use effective contraception during treatment with Ceritinib and for at least 2 weeks following completion of therapy
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Severe or Persistent Gastrointestinal Toxicity
- Hepatotoxicity
- Interstitial Lung Disease/Pneumonitis
- QT Interval Prolongation
- Hyperglycemia
- Bradycardia
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety evaluation of Ceritinib is based on 255 ALK-positive patients in Study 1 (246 patients with NSCLC and 9 patients with other cancers who received Ceritinib at a dose of 750 mg daily). The median duration of exposure to Ceritinib was 6 months. The study population characteristics were: median age 53 years, age less than 65 (84%), female (53%), Caucasian (63%), Asian (34%), NSCLC adenocarcinoma histology (90%), never or former smoker (97%), ECOG PS 0 or 1 (89%), brain metastasis (49%), and number of prior therapies 2 or more (67%).
- Dose reductions due to adverse reactions occurred in 59% of patients treated with Ceritinib . The most frequent adverse reactions, reported in at least 10% of patients, that led to dose reductions or interruptions were: increased ALT (29%), nausea (20%), increased AST (16%), diarrhea (16%), and vomiting (16%). Serious adverse drug reactions reported in 2% or more of patients in Study 1 were convulsion, pneumonia, ILD/pneumonitis, dyspnea, dehydration, hyperglycemia, and nausea. Fatal adverse reactions in patients treated with Ceritinib occurred in 5% of patients, consisting of: pneumonia (4 patients), respiratory failure, ILD/pneumonitis, pneumothorax, gastric hemorrhage, general physical health deterioration, pulmonary tuberculosis, cardiac tamponade, and sepsis (1 patient each). Discontinuation of therapy due to adverse reactions occurred in 10% of patients treated with Ceritinib . The most frequent adverse drug reactions that led to discontinuation in 1% or more of patients in Study 1 were pneumonia, ILD/pneumonitis, and decreased appetite.
- Tables 2 and 3 summarize the common adverse reactions and laboratory abnormalities observed in Ceritinib -treated patients.
- Additional clinically significant adverse reactions occurring in 2% or more of patients treated with Ceritinib included neuropathy (17%; comprised of paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, or polyneuropathy), vision disorder (9%; comprised of vision impairment, blurred vision, photopsia, accommodation disorder, presbyopia, or reduced visual acuity), prolonged QT interval (4%), and bradycardia (3%).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ceritinib in the drug label.
# Drug Interactions
- Ceritinib is primarily metabolized by CYP3A4 and is a substrate of the efflux transporter P-glycoprotein (P-gp).
- Ketoconazole (a strong CYP3A4/P-gp inhibitor) increased the systemic exposure of ceritinib . Avoid concurrent use of strong CYP3A inhibitors during treatment with Ceritinib . If concomitant use of strong CYP3A inhibitors including certain antivirals (e.g., ritonavir), macrolide antibiotics (e.g., telithromycin), antifungals (e.g., ketoconazole), and nefazodone is unavoidable, reduce the Ceritinib dose by approximately one-third, rounded to the nearest 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the Ceritinib dose that was taken prior to initiating the strong CYP3A4 inhibitor.
- Do not consume grapefruit and grapefruit juice as they may inhibit CYP3A.
- Rifampin (a strong CYP3A4/P-gp inducer) decreased the systemic exposure of ceritinib . Avoid concurrent use of strong CYP3A inducers(e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) during treatment with Ceritinib .
- Ceritinib may inhibit CYP3A and CYP2C9 at clinical concentrations. Avoid concurrent use of CYP3A and CYP2C9 substrates known to have narrow therapeutic indices or substrates primarily metabolized by CYP3A and CYP2C9 during treatment with Ceritinib . If use of these medications is unavoidable, consider dose reduction of CYP3A substrates with narrow therapeutic indices (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) and CYP2C9 substrates with narrow therapeutic indices (e.g., phenytoin, warfarin).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on its mechanism of action, Ceritinib may cause fetal harm when administered to a pregnant woman. In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
- In an embryo-fetal development study in which pregnant rats were administered daily doses of ceritinib during organogenesis, dose-related skeletal anomalies were observed at doses as low as 50 mg/kg (less than 0.5-fold the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations.
- In pregnant rabbits administered ceritinib daily during organogenesis, dose-related skeletal anomalies, including incomplete ossification, were observed at doses equal to or greater than 2 mg/kg/day (approximately 0.015-fold the human exposure by AUC at the recommended dose). A low incidence of visceral anomalies, including absent or malpositioned gallbladder and retroesophageal subclavian cardiac artery, was observed at doses equal to or greater than 10 mg/kg/day (approximately 0.13-fold the human exposure by AUC at the recommended dose). Maternal toxicity and abortion occurred in rabbits at doses of 35 mg/kg or greater. In addition, embryolethality was observed in rabbits at a dose of 50 mg/kg.Risk Summary
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ceritinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ceritinib during labor and delivery.
### Nursing Mothers
- It is not known whether ceritinib or its metabolites are present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from ceritinib, advise mothers to discontinue nursing.
### Pediatric Use
- The safety and effectiveness of Ceritinib in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of Ceritinib did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 255 patients in Study 1 who received Ceritinib at the recommended dose, 40 (16%) were 65 years or older.
### Gender
There is no FDA guidance on the use of Ceritinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ceritinib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ceritinib in patients with renal impairment.
### Hepatic Impairment
- As ceritinib is eliminated primarily via the liver, patients with hepatic impairment may have increased exposure. Dose adjustment is not recommended for patients with |mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin greater than 1.0 to 1.5 times ULN and any AST) based on results of the population pharmacokinetic analysis . A recommended dose has not been determined for patients with moderate to severe hepatic impairment
### Females of Reproductive Potential and Males
- Based on its mechanism of action, Ceritinib may cause fetal harm when administered to a pregnant woman . Advise females of reproductive potential to use effective contraception during treatment with Ceritinib and for at least 2 weeks following completion of therapy.
### Immunocompromised Patients
There is no FDA guidance one the use of Ceritinib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, withhold Ceritinib until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, evaluate the use of concomitant medications, and adjust the dose of Ceritinib .
- Monitor serum glucose levels as clinically indicated.
# IV Compatibility
There is limited information regarding IV Compatibility of Ceritinib in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Ceritinib in the drug label.
# Pharmacology
## Mechanism of Action
- Ceritinib is a kinase inhibitor. Targets of ceritinib inhibition identified in either biochemical or cellular assays at clinically relevant concentrations include ALK, insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Among these, ceritinib is most active against ALK. Ceritinib inhibited autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells in in vitro and in vivo assays.
- Ceritinib inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. Ceritinib exhibited dose-dependent anti-tumor activity in mice bearing EML4-ALK-positive NSCLC xenografts with demonstrated resistance to crizotinib, at concentrations within a clinically relevant range.
## Structure
- Ceritinib (ceritinib) is a tyrosine kinase inhibitor for oral administration. The molecular formula for ceritinib is C28H36N5O3ClS. The molecular weight is 558.14 g/mole. Ceritinib is described chemically as 5-Chloro-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-2,4-pyrimidinediamine.
- The chemical structure of ceritinib is shown below:
- Ceritinib is a white to almost white or light yellow or light brown powder with a pKa of 9.7 and 4.1.
- Ceritinib is supplied as printed hard-gelatin capsules containing 150 mg of ceritinib and the following inactive ingredients: colloidal anhydrous silica, L-hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and hard gelatin capsule shells. The capsule shell is composed of gelatin, indiogotine, and titanium dioxide.
## Pharmacodynamics
- Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of ceritinib on the QT interval in an open-label, dose-escalation, and expansion study. A total of 304 patients were treated with Ceritinib doses ranging from 50 to 750 mg with 255 patients treated with Ceritinib 750 mg. One of 304 patients (less than 1%) was found to have a QTc greater than 500 msec and 10 patients (3%) had an increase from baseline QTc greater than 60 msec. A central tendency analysis of the QTc data at average steady-state concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 16 msec at Ceritinib 750 mg. A pharmacokinetic/pharmacodynamic analysis suggested concentration-dependent QTc interval prolongation .
- Based on central review of ECG data, 2 of 304 patients (0.7%) had bradycardia defined as less than 50 beats per minute. Bradycardia was reported as an adverse drug reaction in 3% of patients in Study 1.
## Pharmacokinetics
- After single oral administration of Ceritinib in patients, peak plasma levels (Cmax) of ceritinib were achieved at approximately 4 to 6 hours, and area under the curve (AUC) and Cmax increased dose proportionally over 50 to 750 mg. The absolute bioavailability of Ceritinib has not been determined.
- Following Ceritinib 750 mg once daily dosing, steady-state was reached by approximately 15 days with a geometric mean accumulation ratio of 6.2 after 3 weeks. Systemic exposure increased in a greater than dose proportional manner after repeat doses of 50 to 750 mg once daily.
- Systemic exposure of ceritinib was increased when administered with a meal. A food effect study conducted in healthy subjects with a single 500 mg ceritinib dose showed that a high‐fat meal (containing approximately 1000 calories and 58 grams of fat) increased ceritinib AUC by 73% and Cmaxby 41% and a low-fat meal (containing approximately 330 calories and 9 grams of fat) increased ceritinib AUC by 58% and Cmax by 43% as compared with the fasted state. A 400 mg or higher Ceritinib dose taken with a meal is expected to result in systemic exposure exceeding that of a 750 mg Ceritinib dose taken in the fasted state, and may increase adverse drug reactions.
- Ceritinib is 97% bound to human plasma proteins, independent of drug concentration. The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg Ceritinib dose in patients. Ceritinib also has a slight preferential distribution to red blood cells, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35.
- Following a single 750 mg Ceritinib dose, the geometric mean apparent plasma terminal half-life (t1/2) of ceritinib was 41 hours in patients. Ceritinib demonstrates nonlinear PK over time. The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h).
- Metabolism: In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma.
- Excretion: Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.
- Age, Gender, Race, and Body Weight: Age, gender, race, and body weight had no clinically important effect on the systemic exposure of ceritinib based on population pharmacokinetic analyses.
- Hepatic Impairment: As ceritinib is eliminated primarily via the liver, patients with hepatic impairment may have increased exposure. A pharmacokinetic trial in patients with hepatic impairment has not been conducted. Based on a population pharmacokinetic analysis of 48 patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin greater than 1.0 to 1.5 times ULN and any AST) and 254 patients with normal hepatic function (total bilirubin less than or equal to ULN and AST less than or equal to ULN), ceritinib exposures were similar in patients with mild hepatic impairment and normal hepatic function. The pharmacokinetics of ceritinib has not been studied in patients with moderate to severe hepatic impairment .
- Renal Impairment: A pharmacokinetic trial in patients with renal impairment has not been conducted as ceritinib elimination via the kidney is low (1.3% of a single oral administered dose). Based on a population pharmacokinetic analysis of 97 patients with mild renal impairment (CLcr 60 to less than 90 mL/min), 22 patients with moderate renal impairment (CLcr 30 to less than 60 mL/min) and 183 patients with normal renal function (greater than or equal to 90 mL/min), ceritinib exposures were similar in patients with mild and moderate renal impairment and normal renal function. Patients with severe renal impairment (CLcr less than 30 mL/min) were not included in the clinical trial.
- Pediatrics: No trials have been conducted to evaluate the pharmacokinetics of ceritinib in pediatric patients.
- Effect of Strong CYP3A Inhibitors on Ceritinib: In vitro studies show that ceritinib is a substrate of CYP3A. Coadministration of a single 450 mg Ceritinib dose with ketoconazole (a strong CYP3A inhibitor) 200 mg twice daily for 14 days increased ceritinib AUC (90% CI) by 2.9-fold (2.5, 3.3) and Cmax (90% CI) by 22% (7%, 39%) in 19 healthy subjects . The steady-state AUC of ceritinib at reduced doses after coadministration with ketoconazole 200 mg twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib alone .
- Effect of Strong CYP3A Inducers on Ceritinib: Coadministration of a single 750 mg Ceritinib dose with rifampin (a strong CYP3A inducer) 400 mg daily for 14 days decreased ceritinib AUC (90% CI) by 70% (61%, 77%) and Cmax (90% CI) by 44% (24%, 59%) in 19 healthy subjects.
- Effect of Ceritinib on CYP Substrates: Based on in vitro data, ceritinib may inhibit CYP3A and CYP2C9 at clinical concentrations. Time-dependent inhibition of CYP3A was also observed.
- Effect of Transporters on Ceritinib Disposition: Ceritinib is a substrate of efflux transporter P-gp, but is not a substrate of Breast Cancer Resistance Protein (BCRP), Multidrug Resistance Protein (MRP2), Organic Cation Transporter (OCT1), Organic Anion Transporter (OAT2), or Organic Anion Transporting Polypeptide (OATP1B1) in vitro. Drugs that inhibit P-gp may increase ceritinib concentrations.
- Effect of Ceritinib on Transporters: Based on in vitro data, ceritinib does not inhibit apical efflux transporters, P-gp, BCRP, or MRP2, hepatic uptake transporters OATP1B1 and OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or organic cation uptake transporters OCT1 and OCT2 at clinical concentrations.
- Effect of Gastric Acid Reducing Agents on Ceritinib: Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of ceritinib and reduce its bioavailability as ceritinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. A dedicated study has not been conducted to evaluate the effect of gastric acid reducing agents on the bioavailability of ceritinib.
## Nonclinical Toxicology
- Carcinogenicity studies have not been performed with ceritinib.
- Ceritinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay but induced numerical aberrations (aneugenic) in the in vitro cytogenetic assay using human lymphocytes, and micronuclei in the in vitro micronucleus test using TK6 cells. Ceritinib was not clastogenic in the in vivo rat micronucleus assay.
- There are no data on the effect of ceritinib on human fertility. Fertility/early embryonic development studies were not conducted with ceritinib. There were no adverse effects on male or female reproductive organs in general toxicology studies conducted in monkeys and rats at exposures equal to or greater than 0.5- and 1.5-fold, respectively, of the human exposure by AUC at the recommended dose of 750 mg.
- Target organs in nonclinical animal models included, but were not limited to, the pancreas, biliopancreatic/bile ducts, gastrointestinal tract, and liver. Pancreatic focal acinar cell atrophy was observed in rats at 1.5-fold the human exposure by AUC at the recommended dose. Biliopancreatic duct and bile duct necrosis was observed in rats at exposures equal to or greater than 5% of the human exposure by AUC at the recommended dose. Bile duct inflammation and vacuolation were also noted in monkeys at exposures equal to or greater than 0.5-fold the human exposure by AUC at the recommended dose. Frequent minimal necrosis and hemorrhage of the duodenum was exhibited in monkeys at 0.5-fold the human exposure by AUC, and in rats at an exposure similar to that observed clinically.
- Ceritinib crossed the blood brain barrier in rats with a brain-to-blood exposure (AUCinf) ratio of approximately 15%.
# Clinical Studies
- The efficacy of Ceritinib was established in a multicenter, single-arm, open-label clinical trial (Study 1). A total of 163 patients with metastatic ALK-positive NSCLC who progressed while receiving or were intolerant to crizotinib were enrolled. All patients received Ceritinib at a dose of 750 mg once daily. The major efficacy outcome measure was objective response rate (ORR) according to RECIST v1.0 as evaluated by both investigators and a Blinded Independent Central Review Committee (BIRC). Duration of response (DOR) was an additional outcome measure.
- The study population characteristics were: median age 52 years, age less than 65 (87%), female (54%), Caucasian (66%), Asian (29%), never or former smoker (97%), ECOG PS 0 or 1 (87%), progression on previous crizotinib (91%), number of prior therapies 2 or more (84%), and adenocarcinoma histology (93%). Sites of extra-thoracic metastasis included brain (60%), liver (42%), and bone (42%). ALK-positivity was verified retrospectively by review of local test results for 99% of patients.
- Efficacy results from Study 1 are summarized in Table 4.
# How Supplied
- Ceritinib 150 mg capsules
- Hard gelatin capsule with opaque blue cap and opaque white body; opaque blue cap marked in black ink with “LDK 150MG”, opaque white body marked in black ink with “NVR”. Available in:
- Bottles of 70 capsules NDC 0078-0640-70
## Storage
- Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Inform patients that diarrhea, nausea, vomiting, and abdominal pain are the most commonly reported adverse reactions in patients treated with Ceritinib . Inform patients of supportive care options such as anti-emetic and anti-diarrheal medications. Advise patients to contact their healthcare provider for severe or persistent gastrointestinal symptoms
- Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity
- Inform patients of the risks of severe or fatal ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms
- Inform patients of the risks of QTc interval prolongation and bradycardia. Advise patients to contact their healthcare provider immediately to report new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, fainting, and changes in or new use of heart or blood pressure medications
- Inform patients of the signs and symptoms of hyperglycemia. Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperglycemia
- Advise females to inform their healthcare provider if they are pregnant. Inform females of reproductive potential of the risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Ceritinib and for at least 2 weeks following completion of therapy
- Advise females not to breastfeed during treatment with Ceritinib
- Inform patients not to consume grapefruit and grapefruit juice during treatment with Ceritinib .
- Take Ceritinib on an empty stomach (i.e., do not take within 2 hours of a meal) .
- Advise patients to make up a missed dose of Ceritinib unless the next dose is due within 12 hours
# Precautions with Alcohol
- Alcohol-Ceritinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zykadia®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ceritinib | |
2256876ba521815b2292b89d4356e88b06dd95e4 | wikidoc | Cetuximab | Cetuximab
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# Black Box Warning
# Overview
Cetuximab is a monoclonal antibody that is FDA approved for the treatment of squamous cell carcinoma of the head and neck (SCCHN), and K-Ras Mutation-negative,EGFR-expressing colorectal cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include acneiform eruption, dry skin, pruritus, radiation dermatitis, rash, hypomagnesemia, weight decreasing, constipation, diarrhea, nausea, neutropenia, infectious disease, asthenia, headache, sensory neuropathy, dyspnea, fatigue, late effect of radiation and pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Head and neck cancer
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Cetuximab in adult patients.
### Non–Guideline-Supported Use
# Gastric cancer
Dosing information
- 400 mg/m(2) IV over 2 hours (loading dose) then 250 mg/m(2) IV over 1 hour (maintenance dose) every week’‘’
- 400 mg/m(2) IV (loading dose) then 250 mg/m(2) IV (maintenance dose) every week
# Malignant neoplasm of cardio-esophageal junction of stomach
Dosing information
- 400 mg/m(2) IV over 2 hours (loading dose) then 250 mg/m(2) IV over 1 hour (maintenance dose) every week ‘’‘，
- 400 mg/m(2) IV (loading dose) then 250 mg/m(2) IV (maintenance dose) every week
# Non-small cell lung cancer
Dosing information
- Not applicable
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Cetuximab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Cetuximab in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Cetuximab in pediatric patients.
# Contraindications
- None.
# Warnings
### Infusion Reactions
Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Cetuximab include:
- Rapid onset of airway obstruction (bronchospasm, stridor, hoarseness)
- Hypotension
- Shock
- Loss of consciousness
- Myocardial infarction, and/or
- Cardiac arrest.
- Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Cetuximab, with fatal outcome in 1 patient.
- Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.
- Monitor patients for 1 hour following Cetuximab infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.
- Immediately and permanently discontinue Cetuximab in patients with serious infusion reactions.
### Cardiopulmonary Arrest
- Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Cetuximab as compared to none of 212 patients treated with radiation therapy alone in Study 1. *Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death.
- One of these patients had arrhythmia and one had congestive heart failure.
- Death occurred 27, 32, and 43 days after the last dose of Cetuximab.
- One patient with no prior history of coronary artery disease died one day after the last dose of Cetuximab.
- In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone.
- Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin.
- All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Cetuximab in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks.
- Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Cetuximab.
### Pulmonary Toxicity
- Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Cetuximab in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer.
- Interrupt Cetuximab for acute onset or worsening of pulmonary symptoms.
- Permanently discontinue Cetuximab for confirmed ILD.
### Dermatologic Toxicity
Dermatologic toxicities, including
- Acneiform rash,
- skin drying and fissuring,
- paronychial inflammation,
- Infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis)
- Hypertrichosis occurred in patients receiving Cetuximab therapy.
- Acneiform rash occurred in 76–88% of 1373 patients receiving Cetuximab in Studies 1, 3, 5, and 6.
- Severe acneiform rash occurred in 1–17% of patients.
- Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days.
- Monitor patients receiving Cetuximab for dermatologic toxicities and infectious sequelae.
- Instruct patients to limit sun exposure during Cetuximab therapy.
### Use of Cetuximab in Combination With Radiation and Cisplatin
- In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Cetuximab in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone.
- The addition of Cetuximab resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone.
- Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Cetuximab combination arm and 14 patients (3.0%) in the control arm.
- Nine patients in the Cetuximab arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm.
- The main efficacy outcome of the study was progression-free survival (PFS).
- The addition of Cetuximab to radiation and cisplatin did not improve PFS.
### Hypomagnesemia and Electrolyte Abnormalities
- In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Cetuximab in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%.
- In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone.
- In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%).
- No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.
- The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Cetuximab.
- Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Cetuximab. Replete electrolytes as necessary.
### K-Ras Testing in Metastatic or Advanced colorectal cancer Patients
- Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Cetuximab.
- Cetuximab is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC.
- Cetuximab is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2).
- Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Cetuximab treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type).
- Cetuximab is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use.
- Perform the assesment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized.
- Improper assay performance can lead to unreliable test results.
Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Cetuximab.
### Epidermal Growth Factor Receptor (EGFR) Expression and Response
- Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.
- Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression.
- Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDxTM test kit.
- Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong).
- Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data below reflect exposure to Cetuximab in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks.
Infusion reactions:
- Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.
Infections:
- The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.
Renal:
- Renal failure occurred in 1% of patients with colorectal cancer.
Squamous Cell Carcinoma of the Head and Neck
Cetuximab in Combination with Radiation Therapy
- Table 2 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Cetuximab for locally or regionally advanced SCCHN in Study 1. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).
- The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.
Late Radiation Toxicity
- The overall incidence of late radiation toxicities (any grade) was higher in Cetuximab in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Cetuximab plus radiation treatment groups.
Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-fluorouracil
- Study 2 used EU-approved cetuximab. Since U.S.-licensed Cetuximab provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Cetuximab for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Cetuximab .
Table 3 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89).
- For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm.
Colorectal Cancer
Study 4: EU-Approved Cetuximab in Combination with FOLFIRI
- Study 4 used EU-approved cetuximab. U.S.-licensed Cetuximab provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Cetuximab in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Cetuximab.
Table 4 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224).
Cetuximab in Combination with irinotecan
- The most frequently reported adverse reactions in 354 patients treated with Cetuximab plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).
### Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity. - Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay.
- Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Cetuximab has not been adequately determined.
- Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Cetuximab.
- The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.
- Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
- For these reasons, comparison of the incidence of antibodies to Cetuximab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of Cetuximab. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Aseptic meningitis
- Mucosal inflammation
# Drug Interactions
- A drug interaction study was performed in which Cetuximab was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Cetuximab and irinotecan.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of Cetuximab in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Cetuximab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Cetuximab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cetuximab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cetuximab during labor and delivery.
### Nursing Mothers
- It is not known whether Cetuximab is secreted in human milk. IgG antibodies, such as Cetuximab, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cetuximab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of Cetuximab.
### Pediatric Use
- The safety and effectiveness of Cetuximab in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Cetuximab was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mgh/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mgh/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.
### Geriatic Use
- Of the 1662 patients who received Cetuximab with irinotecan, FOLFIRI or Cetuximab monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.
- Clinical studies of Cetuximab conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Cetuximab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cetuximab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cetuximab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cetuximab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cetuximab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cetuximab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous infusion
### Monitoring
- FDA Package Insert for Cetuximab contains no information regarding Adverse Reactions.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- The maximum single dose of Cetuximab administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.
# Pharmacology
## Mechanism of Action
- The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4.
- The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum.
- Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha.
- In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production.
- Signal transduction through the EGFR results in activation of wild-type K-Ras protein. However, in cells with activating K-Ras somatic mutations, the mutant K-Ras protein is continuously active and appears independent of EGFR regulation.
- In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types.
- In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR.
- No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression.
- The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone.
## Structure
Cetuximab® (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions and has an approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian (murine myeloma) cell culture.
Cetuximab is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous cetuximab particulates. Cetuximab is supplied at a concentration of 2 mg/mL in either 100 mg (50 mL) or 200 mg (100 mL), single-use vials. Cetuximab is formulated in a solution with no preservatives, which contains 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium phosphate monobasic monohydrate, and Water for Injection, USP.
## Pharmacodynamics
Effects on Electrocardiogram (ECG)
The effect of cetuximab on QT interval was evaluated in an open-label, single-arm, monotherapy trial in 37 subjects with advanced malignancies who received an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2 for a total of 5 weeks. No large changes in the mean QT interval of >20 ms from baseline were detected in the trial based on the Fridericia correction method. A small increase in the mean QTc interval of <10 ms cannot be excluded because of the limitations in the trial design.
## Pharmacokinetics
Cetuximab administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses >200 mg/m2, it appeared to plateau. The volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2–3 L/m2.
Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 to 235 and 41 to 85 µg/mL, respectively. The mean half-life of cetuximab was approximately 112 hours (range 63–230 hours). The pharmacokinetics of cetuximab were similar in patients with SCCHN and those with colorectal cancer.
Cetuximab had an approximately 22% (90% confidence interval; 6%, 38%) higher systemic exposure relative to the EU-approved cetuximab used in Studies 2 and 4 based on a population pharmacokinetic analysis.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.
### Animal Pharmacology and/or Toxicology
In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.
# Clinical Studies
Studies 2 and 4 were conducted outside the U.S. using an EU-approved cetuximab as the clinical trial material. Cetuximab provides approximately 22% higher exposure relative to the EU-approved cetuximab used in Studies 2 and 4; these pharmacokinetic data, together with the results of Studies 2, 4, and other clinical trial data establish the efficacy of Cetuximab at the recommended dose in SCCHN and mCRC .
### Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Study 1 was a randomized, multicenter, controlled trial of 424 patients with locally or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) to receive either Cetuximab plus radiation therapy or radiation therapy alone. Stratification factors were Karnofsky performance status (60–80 versus 90–100), nodal stage (N0 versus N+), tumor stage (T1–3 versus T4 using American Joint Committee on Cancer 1998 staging criteria), and radiation therapy fractionation (concomitant boost versus once-daily versus twice-daily). Radiation therapy was administered for 6–7 weeks as once-daily, twice-daily, or concomitant boost. Cetuximab was administered as a 400 mg/m2 initial dose beginning one week prior to initiation of radiation therapy, followed by 250 mg/m2 weekly administered 1 hour prior to radiation therapy for the duration of radiation therapy (6–7 weeks).
Of the 424 randomized patients, the median age was 57 years, 80% were male, 83% were Caucasian, and 90% had baseline Karnofsky performance status ≥80. There were 258 patients enrolled in U.S. sites (61%). Sixty percent of patients had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen.
The main outcome measure of this trial was duration of locoregional control. Overall survival was also assessed. Results are presented in Table 6.
Study 2 was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN.
Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive EU-approved cetuximab plus cisplatin or carboplatin and 5-FU, or cisplatin or carboplatin and 5-FU alone. Choice of cisplatin or carboplatin was at the discretion of the treating physician. Stratification factors were Karnofsky performance status (<80 versus ≥80) and previous chemotherapy. cisplatin (100 mg/m2, Day 1) or carboplatin (AUC 5, Day 1) plus intravenous 5-FU (1000 mg/m2/day, Days 1–4) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Cetuximab was administered at a 400 mg/m2 initial dose, followed by a 250 mg/m2 weekly dose in combination with chemotherapy. Patients demonstrating at least stable disease on cetuximab in combination with chemotherapy were to continue cetuximab monotherapy at 250 mg/m2 weekly, in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy. For patients where treatment was delayed because of the toxic effects of chemotherapy, weekly cetuximab was continued. If chemotherapy was discontinued for toxicity, cetuximab could be continued as monotherapy until disease progression or unacceptable toxicity.
Of the 442 randomized patients, the median age was 57 years, 90% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status ≥80. Thirty-four percent of patients had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyngeal primary tumors. Fifty-three percent of patients had recurrent locoregional disease only and 47% had metastatic disease. Fifty-eight percent had AJCC Stage IV disease and 21% had Stage III disease. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately fifteen percent of the patients in the cisplatin alone arm switched to carboplatin during the treatment period.
The main outcome measure of this trial was overall survival. Results are presented in Table 7 and Figure 1.
Figure 1: Kaplan-Meier Curve for Overall Survival in Patients with Recurrent Locoregional Disease or Metastatic Squamous Cell Carcinoma of the Head and Neck
In exploratory subgroup analyses of Study 2 by initial platinum therapy (cisplatin or carboplatin), for patients (N=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 versus 7.3 months, respectively; HR 0.71; 95% CI 0.54, 0.93). The difference in median progression-free survival was 2.1 months (5.6 versus 3.5 months, respectively; HR 0.55; 95% CI 0.41, 0.73). The objective response rate was 39% and 23% respectively (OR 2.18; 95% CI 1.29, 3.69). For patients (N=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 versus 8.3 months; HR 0.99; 95% CI 0.69, 1.43). The difference in median progression-free survival was 1.7 months (4.8 versus 3.1 months, respectively; HR 0.61; 95% CI 0.42, 0.89). The objective response rate was 30% and 15% respectively (OR 2.45; 95% CI 1.10, 5.46).
Study 3 was a single-arm, multicenter clinical trial in 103 patients with recurrent or metastatic SCCHN. All patients had documented disease progression within 30 days of a platinum-based chemotherapy regimen. Patients received a 20-mg test dose of Cetuximab on Day 1, followed by a 400 mg/m2 initial dose, and 250 mg/m2 weekly until disease progression or unacceptable toxicity.
The median age was 57 years, 82% were male, 100% Caucasian, and 62% had a Karnofsky performance status of ≥80.
The objective response rate was 13% (95% confidence interval 7%–21%). Median duration of response was 5.8 months (range 1.2–5.8 months).
### colorectal cancer
Cetuximab Clinical Trials in K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic colorectal cancer
Study 4 was a randomized, open-label, multicenter, study of 1217 patients with EGFR-expressing metastatic colorectal cancer. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI or FOLFIRI alone as first-line treatment. Stratification factors were Eastern Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and region (sites in Western Europe versus Eastern Europe versus other).
FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 administered intravenously on Day 1), folinic acid (400 mg/m2 or 200 mg/m2 administered intravenously on Day 1), and 5-FU (400 mg/m2 bolus on Day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion). Cetuximab was administered as a 400 mg/m2 initial dose on Day 1, Week 1, followed by 250 mg/m2 weekly administered 1 hour prior to chemotherapy. Study treatment continued until disease progression or unacceptable toxicity occurred.
Of the 1217 randomized patients, the median age was 61 years, 60% were male, 86% were Caucasian, and 96% had a baseline ECOG performance status 0–1, 60% had primary tumor localized in colon, 84% had 1–2 metastatic sites and 20% had received prior adjuvant and/or neoadjuvant chemotherapy. Demographics and baseline characteristics were similar between study arms.
K-Ras mutation status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had K-Ras mutation-negative (wild-type) tumors and 403 (37%) patients had K-Ras mutation-positive tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D .
Baseline characteristics and demographics in the K-Ras mutation-negative (wild-type) subset were similar to that seen in the overall population .
The main outcome measure of this trial was progression-free survival assesed by an independent review committee (IRC). Overall survival and response rate were also assessed. A statistically significant improvement in PFS was observed for the cetuximab plus FOLFIRI arm compared with the FOLFIRI arm (median PFS 8.9 vs 8.1 months, HR 0.85 , p-value=0.036). Overall survival was not significantly different at the planned, final analysis based on 838 events .
Results of the planned PFS and ORR analysis in all randomized patients and post-hoc PFS and ORR analysis in subgroups of patients defined by K-Ras mutation status, and post-hoc analysis of updated OS based on additional follow-up (1000 events) in all randomized patients and in subgroups of patients defined by K-Ras mutation status are presented in Table 8 and Figure 2. The treatment effect in the all-randomized population for PFS was driven by treatment effects limited to patients who have K-Ras mutation-negative (wild-type) tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutation-positive tumors.
Figure 2: Kaplan-Meier Curve for Overall Survival in the K-Ras Mutation-negative (Wild-type) Population in Study 4
Study 5 was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent mCRC. Patients were randomized (1:1) to receive either Cetuximab plus best supportive care (BSC) or BSC alone. Cetuximab was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity.
Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were Caucasian, and 77% had baseline ECOG performance status of 0–1. Demographics and baseline characteristics were similar between study arms. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen.
K-Ras status was available for 453/572 (79%) of the patients: 245 (54%) patients had K-Ras mutation-negative (wild-type) tumors and 208 (46%) patients had K-Ras mutation-positive tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D .
The main outcome measure of the study was overall survival. Results are presented in Table 9 and Figure 3.
Figure 3: Kaplan-Meier Curve for Overall Survival in Patients with K-Ras Mutation-negative (Wild-type) Metastatic colorectal cancer in Study 5
Study 6 was a multicenter, clinical trial conducted in 329 patients with EGFR-expressing recurrent mCRC. Tumor specimens were not available for testing for K-Ras mutation status. Patients were randomized (2:1) to receive either Cetuximab plus irinotecan (218 patients) or Cetuximab monotherapy (111 patients). Cetuximab was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. In the Cetuximab plus irinotecan arm, irinotecan was added to Cetuximab using the same dose and schedule for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 350 mg/m2 every 3 weeks, 180 mg/m2 every 2 weeks, or 125 mg/m2 weekly times four doses every 6 weeks. Of the 329 patients, the median age was 59 years, 63% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status ≥80. Approximately two-thirds had previously failed oxaliplatin treatment.
The efficacy of Cetuximab plus irinotecan or Cetuximab monotherapy, based on durable objective responses, was evaluated in all randomized patients and in two pre-specified subpopulations: irinotecan refractory patients, and irinotecan and oxaliplatin failures. In patients receiving Cetuximab plus irinotecan, the objective response rate was 23% (95% confidence interval 18%–29%), median duration of response was 5.7 months, and median time to progression was 4.1 months. In patients receiving Cetuximab monotherapy, the objective response rate was 11% (95% confidence interval 6%–18%), median duration of response was 4.2 months, and median time to progression was 1.5 months. Similar response rates were observed in the pre-defined subsets in both the combination arm and monotherapy arm of the study.
# How Supplied
Cetuximab® (cetuximab) is supplied at a concentration of 2 mg/mL as a 100 mg/50 mL, single-use vial or as a 200 mg/100 mL, single-use vial as a sterile, injectable liquid containing no preservatives.
NDC 66733-948-23 100 mg/50 mL, single-use vial, individually packaged in a carton
NDC 66733-958-23 200 mg/100 mL, single-use vial, individually packaged in a carton
## Storage
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). Do not freeze. Increased particulate formation may occur at temperatures at or below 0° C. This product contains no preservatives. Preparations of Cetuximab in infusion containers are chemically and physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° F) and up to 8 hours at controlled room temperature (20° C to 25° C; 68° F to 77° F). Discard any remaining solution in the infusion container after 8 hours at controlled room temperature or after 12 hours at 2° C to 8° C. Discard any unused portion of the vial.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise patients:
- To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.
- Of the potential risks of using Cetuximab during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Cetuximab therapy.
- That nursing is not recommended during, and for 2 months following the last dose of Cetuximab therapy.
- To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Cetuximab.
# Precautions with Alcohol
Alcohol-Cetuximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Erbitux
# Look-Alike Drug Names
cetuximab - rituximab
# Drug Shortage Status
# Price | Cetuximab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Sree Teja Yelamanchili, MBBS [3]
# Disclaimer
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# Black Box Warning
# Overview
Cetuximab is a monoclonal antibody that is FDA approved for the treatment of squamous cell carcinoma of the head and neck (SCCHN), and K-Ras Mutation-negative,EGFR-expressing colorectal cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include acneiform eruption, dry skin, pruritus, radiation dermatitis, rash, hypomagnesemia, weight decreasing, constipation, diarrhea, nausea, neutropenia, infectious disease, asthenia, headache, sensory neuropathy, dyspnea, fatigue, late effect of radiation and pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Head and neck cancer
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Cetuximab in adult patients.
### Non–Guideline-Supported Use
# Gastric cancer
Dosing information
- 400 mg/m(2) IV over 2 hours (loading dose) then 250 mg/m(2) IV over 1 hour (maintenance dose) every week’‘’[1]
- 400 mg/m(2) IV (loading dose) then 250 mg/m(2) IV (maintenance dose) every week [2]
# Malignant neoplasm of cardio-esophageal junction of stomach
Dosing information
- 400 mg/m(2) IV over 2 hours (loading dose) then 250 mg/m(2) IV over 1 hour (maintenance dose) every week ‘’‘[1]，[3]
- 400 mg/m(2) IV (loading dose) then 250 mg/m(2) IV (maintenance dose) every week[2]
# Non-small cell lung cancer
Dosing information
- Not applicable
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Cetuximab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Cetuximab in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Cetuximab in pediatric patients.
# Contraindications
- None.
# Warnings
### Infusion Reactions
Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Cetuximab include:
- Rapid onset of airway obstruction (bronchospasm, stridor, hoarseness)
- Hypotension
- Shock
- Loss of consciousness
- Myocardial infarction, and/or
- Cardiac arrest.
- Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Cetuximab, with fatal outcome in 1 patient.
- Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.
- Monitor patients for 1 hour following Cetuximab infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.
- Immediately and permanently discontinue Cetuximab in patients with serious infusion reactions.
### Cardiopulmonary Arrest
- Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Cetuximab as compared to none of 212 patients treated with radiation therapy alone in Study 1. *Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death.
- One of these patients had arrhythmia and one had congestive heart failure.
- Death occurred 27, 32, and 43 days after the last dose of Cetuximab.
- One patient with no prior history of coronary artery disease died one day after the last dose of Cetuximab.
- In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone.
- Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin.
- All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Cetuximab in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks.
- Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Cetuximab.
### Pulmonary Toxicity
- Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Cetuximab in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer.
- Interrupt Cetuximab for acute onset or worsening of pulmonary symptoms.
- Permanently discontinue Cetuximab for confirmed ILD.
### Dermatologic Toxicity
Dermatologic toxicities, including
- Acneiform rash,
- skin drying and fissuring,
- paronychial inflammation,
- Infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis)
- Hypertrichosis occurred in patients receiving Cetuximab therapy.
- Acneiform rash occurred in 76–88% of 1373 patients receiving Cetuximab in Studies 1, 3, 5, and 6.
- Severe acneiform rash occurred in 1–17% of patients.
- Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days.
- Monitor patients receiving Cetuximab for dermatologic toxicities and infectious sequelae.
- Instruct patients to limit sun exposure during Cetuximab therapy.
### Use of Cetuximab in Combination With Radiation and Cisplatin
- In a controlled study, 940 patients with locally advanced SCCHN were randomized 1:1 to receive either Cetuximab in combination with radiation therapy and cisplatin or radiation therapy and cisplatin alone.
- The addition of Cetuximab resulted in an increase in the incidence of Grade 3–4 mucositis, radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances compared to radiation and cisplatin alone.
- Adverse reactions with fatal outcome were reported in 20 patients (4.4%) in the Cetuximab combination arm and 14 patients (3.0%) in the control arm.
- Nine patients in the Cetuximab arm (2.0%) experienced myocardial ischemia compared to 4 patients (0.9%) in the control arm.
- The main efficacy outcome of the study was progression-free survival (PFS).
- The addition of Cetuximab to radiation and cisplatin did not improve PFS.
### Hypomagnesemia and Electrolyte Abnormalities
- In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Cetuximab in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%.
- In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone.
- In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%).
- No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.
- The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Cetuximab.
- Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Cetuximab. Replete electrolytes as necessary.
### K-Ras Testing in Metastatic or Advanced colorectal cancer Patients
- Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Cetuximab.
- Cetuximab is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC.
- Cetuximab is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2).
- Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Cetuximab treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type).
- Cetuximab is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use.
- Perform the assesment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized.
- Improper assay performance can lead to unreliable test results.
Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Cetuximab.
### Epidermal Growth Factor Receptor (EGFR) Expression and Response
- Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.
- Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression.
- Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDxTM test kit.
- Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong).
- Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data below reflect exposure to Cetuximab in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks.
Infusion reactions:
- Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.
Infections:
- The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.
Renal:
- Renal failure occurred in 1% of patients with colorectal cancer.
Squamous Cell Carcinoma of the Head and Neck
Cetuximab in Combination with Radiation Therapy
- Table 2 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Cetuximab for locally or regionally advanced SCCHN in Study 1. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).
- The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.
Late Radiation Toxicity
- The overall incidence of late radiation toxicities (any grade) was higher in Cetuximab in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Cetuximab plus radiation treatment groups.
Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-fluorouracil
- Study 2 used EU-approved cetuximab. Since U.S.-licensed Cetuximab provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Cetuximab for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Cetuximab .
Table 3 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89).
- For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm.
Colorectal Cancer
Study 4: EU-Approved Cetuximab in Combination with FOLFIRI
- Study 4 used EU-approved cetuximab. U.S.-licensed Cetuximab provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Cetuximab in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Cetuximab.
Table 4 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224).
Cetuximab in Combination with irinotecan
- The most frequently reported adverse reactions in 354 patients treated with Cetuximab plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%).
### Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity. * Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay.
- Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Cetuximab has not been adequately determined.
- Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Cetuximab.
- The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.
- Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
- For these reasons, comparison of the incidence of antibodies to Cetuximab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of Cetuximab. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Aseptic meningitis
- Mucosal inflammation
# Drug Interactions
- A drug interaction study was performed in which Cetuximab was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Cetuximab and irinotecan.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of Cetuximab in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Cetuximab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Cetuximab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cetuximab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cetuximab during labor and delivery.
### Nursing Mothers
- It is not known whether Cetuximab is secreted in human milk. IgG antibodies, such as Cetuximab, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cetuximab, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of Cetuximab.
### Pediatric Use
- The safety and effectiveness of Cetuximab in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Cetuximab was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.
### Geriatic Use
- Of the 1662 patients who received Cetuximab with irinotecan, FOLFIRI or Cetuximab monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.
- Clinical studies of Cetuximab conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Cetuximab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cetuximab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cetuximab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cetuximab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cetuximab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cetuximab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous infusion
### Monitoring
- FDA Package Insert for Cetuximab contains no information regarding Adverse Reactions.
# IV Compatibility
- There is limited information about the IV Compatibility.
# Overdosage
- The maximum single dose of Cetuximab administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.
# Pharmacology
## Mechanism of Action
- The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4.
- The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum.
- Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha.
- In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production.
- Signal transduction through the EGFR results in activation of wild-type K-Ras protein. However, in cells with activating K-Ras somatic mutations, the mutant K-Ras protein is continuously active and appears independent of EGFR regulation.
- In vitro, cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types.
- In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR.
- No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression.
- The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone.
## Structure
Cetuximab® (cetuximab) is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions and has an approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian (murine myeloma) cell culture.
Cetuximab is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous cetuximab particulates. Cetuximab is supplied at a concentration of 2 mg/mL in either 100 mg (50 mL) or 200 mg (100 mL), single-use vials. Cetuximab is formulated in a solution with no preservatives, which contains 8.48 mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.41 mg/mL sodium phosphate monobasic monohydrate, and Water for Injection, USP.
## Pharmacodynamics
Effects on Electrocardiogram (ECG)
The effect of cetuximab on QT interval was evaluated in an open-label, single-arm, monotherapy trial in 37 subjects with advanced malignancies who received an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2 for a total of 5 weeks. No large changes in the mean QT interval of >20 ms from baseline were detected in the trial based on the Fridericia correction method. A small increase in the mean QTc interval of <10 ms cannot be excluded because of the limitations in the trial design.
## Pharmacokinetics
Cetuximab administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from 0.08 to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses >200 mg/m2, it appeared to plateau. The volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2–3 L/m2.
Following the recommended dose regimen (400 mg/m2 initial dose; 250 mg/m2 weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 to 235 and 41 to 85 µg/mL, respectively. The mean half-life of cetuximab was approximately 112 hours (range 63–230 hours). The pharmacokinetics of cetuximab were similar in patients with SCCHN and those with colorectal cancer.
Cetuximab had an approximately 22% (90% confidence interval; 6%, 38%) higher systemic exposure relative to the EU-approved cetuximab used in Studies 2 and 4 based on a population pharmacokinetic analysis.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.
### Animal Pharmacology and/or Toxicology
In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.
# Clinical Studies
Studies 2 and 4 were conducted outside the U.S. using an EU-approved cetuximab as the clinical trial material. Cetuximab provides approximately 22% higher exposure relative to the EU-approved cetuximab used in Studies 2 and 4; these pharmacokinetic data, together with the results of Studies 2, 4, and other clinical trial data establish the efficacy of Cetuximab at the recommended dose in SCCHN and mCRC [see Clinical Pharmacology (12.3)].
### Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Study 1 was a randomized, multicenter, controlled trial of 424 patients with locally or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) to receive either Cetuximab plus radiation therapy or radiation therapy alone. Stratification factors were Karnofsky performance status (60–80 versus 90–100), nodal stage (N0 versus N+), tumor stage (T1–3 versus T4 using American Joint Committee on Cancer 1998 staging criteria), and radiation therapy fractionation (concomitant boost versus once-daily versus twice-daily). Radiation therapy was administered for 6–7 weeks as once-daily, twice-daily, or concomitant boost. Cetuximab was administered as a 400 mg/m2 initial dose beginning one week prior to initiation of radiation therapy, followed by 250 mg/m2 weekly administered 1 hour prior to radiation therapy for the duration of radiation therapy (6–7 weeks).
Of the 424 randomized patients, the median age was 57 years, 80% were male, 83% were Caucasian, and 90% had baseline Karnofsky performance status ≥80. There were 258 patients enrolled in U.S. sites (61%). Sixty percent of patients had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen.
The main outcome measure of this trial was duration of locoregional control. Overall survival was also assessed. Results are presented in Table 6.
Study 2 was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN.
Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive EU-approved cetuximab plus cisplatin or carboplatin and 5-FU, or cisplatin or carboplatin and 5-FU alone. Choice of cisplatin or carboplatin was at the discretion of the treating physician. Stratification factors were Karnofsky performance status (<80 versus ≥80) and previous chemotherapy. cisplatin (100 mg/m2, Day 1) or carboplatin (AUC 5, Day 1) plus intravenous 5-FU (1000 mg/m2/day, Days 1–4) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Cetuximab was administered at a 400 mg/m2 initial dose, followed by a 250 mg/m2 weekly dose in combination with chemotherapy. Patients demonstrating at least stable disease on cetuximab in combination with chemotherapy were to continue cetuximab monotherapy at 250 mg/m2 weekly, in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy. For patients where treatment was delayed because of the toxic effects of chemotherapy, weekly cetuximab was continued. If chemotherapy was discontinued for toxicity, cetuximab could be continued as monotherapy until disease progression or unacceptable toxicity.
Of the 442 randomized patients, the median age was 57 years, 90% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status ≥80. Thirty-four percent of patients had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyngeal primary tumors. Fifty-three percent of patients had recurrent locoregional disease only and 47% had metastatic disease. Fifty-eight percent had AJCC Stage IV disease and 21% had Stage III disease. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately fifteen percent of the patients in the cisplatin alone arm switched to carboplatin during the treatment period.
The main outcome measure of this trial was overall survival. Results are presented in Table 7 and Figure 1.
Figure 1: Kaplan-Meier Curve for Overall Survival in Patients with Recurrent Locoregional Disease or Metastatic Squamous Cell Carcinoma of the Head and Neck
In exploratory subgroup analyses of Study 2 by initial platinum therapy (cisplatin or carboplatin), for patients (N=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 versus 7.3 months, respectively; HR 0.71; 95% CI 0.54, 0.93). The difference in median progression-free survival was 2.1 months (5.6 versus 3.5 months, respectively; HR 0.55; 95% CI 0.41, 0.73). The objective response rate was 39% and 23% respectively (OR 2.18; 95% CI 1.29, 3.69). For patients (N=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 versus 8.3 months; HR 0.99; 95% CI 0.69, 1.43). The difference in median progression-free survival was 1.7 months (4.8 versus 3.1 months, respectively; HR 0.61; 95% CI 0.42, 0.89). The objective response rate was 30% and 15% respectively (OR 2.45; 95% CI 1.10, 5.46).
Study 3 was a single-arm, multicenter clinical trial in 103 patients with recurrent or metastatic SCCHN. All patients had documented disease progression within 30 days of a platinum-based chemotherapy regimen. Patients received a 20-mg test dose of Cetuximab on Day 1, followed by a 400 mg/m2 initial dose, and 250 mg/m2 weekly until disease progression or unacceptable toxicity.
The median age was 57 years, 82% were male, 100% Caucasian, and 62% had a Karnofsky performance status of ≥80.
The objective response rate was 13% (95% confidence interval 7%–21%). Median duration of response was 5.8 months (range 1.2–5.8 months).
### colorectal cancer
Cetuximab Clinical Trials in K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic colorectal cancer
Study 4 was a randomized, open-label, multicenter, study of 1217 patients with EGFR-expressing metastatic colorectal cancer. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI or FOLFIRI alone as first-line treatment. Stratification factors were Eastern Cooperative Oncology Group (ECOG) performance status (0 and 1 versus 2) and region (sites in Western Europe versus Eastern Europe versus other).
FOLFIRI regimen included 14-day cycles of irinotecan (180 mg/m2 administered intravenously on Day 1), folinic acid (400 mg/m2 [racemic] or 200 mg/m2 [L-form] administered intravenously on Day 1), and 5-FU (400 mg/m2 bolus on Day 1 followed by 2400 mg/m2 as a 46-hour continuous infusion). Cetuximab was administered as a 400 mg/m2 initial dose on Day 1, Week 1, followed by 250 mg/m2 weekly administered 1 hour prior to chemotherapy. Study treatment continued until disease progression or unacceptable toxicity occurred.
Of the 1217 randomized patients, the median age was 61 years, 60% were male, 86% were Caucasian, and 96% had a baseline ECOG performance status 0–1, 60% had primary tumor localized in colon, 84% had 1–2 metastatic sites and 20% had received prior adjuvant and/or neoadjuvant chemotherapy. Demographics and baseline characteristics were similar between study arms.
K-Ras mutation status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had K-Ras mutation-negative (wild-type) tumors and 403 (37%) patients had K-Ras mutation-positive tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D [see Warnings and Precautions (5.7)].
Baseline characteristics and demographics in the K-Ras mutation-negative (wild-type) subset were similar to that seen in the overall population [see Warnings and Precautions (5.7)].
The main outcome measure of this trial was progression-free survival assesed by an independent review committee (IRC). Overall survival and response rate were also assessed. A statistically significant improvement in PFS was observed for the cetuximab plus FOLFIRI arm compared with the FOLFIRI arm (median PFS 8.9 vs 8.1 months, HR 0.85 [95% CI 0.74, 0.99], p-value=0.036). Overall survival was not significantly different at the planned, final analysis based on 838 events [HR=0.93, 95% CI (0.8, 1.1), p-value 0.327].
Results of the planned PFS and ORR analysis in all randomized patients and post-hoc PFS and ORR analysis in subgroups of patients defined by K-Ras mutation status, and post-hoc analysis of updated OS based on additional follow-up (1000 events) in all randomized patients and in subgroups of patients defined by K-Ras mutation status are presented in Table 8 and Figure 2. The treatment effect in the all-randomized population for PFS was driven by treatment effects limited to patients who have K-Ras mutation-negative (wild-type) tumors. There is no evidence of effectiveness in the subgroup of patients with K-Ras mutation-positive tumors.
Figure 2: Kaplan-Meier Curve for Overall Survival in the K-Ras Mutation-negative (Wild-type) Population in Study 4
Study 5 was a multicenter, open-label, randomized, clinical trial conducted in 572 patients with EGFR-expressing, previously treated, recurrent mCRC. Patients were randomized (1:1) to receive either Cetuximab plus best supportive care (BSC) or BSC alone. Cetuximab was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity.
Of the 572 randomized patients, the median age was 63 years, 64% were male, 89% were Caucasian, and 77% had baseline ECOG performance status of 0–1. Demographics and baseline characteristics were similar between study arms. All patients were to have received and progressed on prior therapy including an irinotecan-containing regimen and an oxaliplatin-containing regimen.
K-Ras status was available for 453/572 (79%) of the patients: 245 (54%) patients had K-Ras mutation-negative (wild-type) tumors and 208 (46%) patients had K-Ras mutation-positive tumors where testing assessed for the following somatic mutations in codons 12 and 13 (exon 2): G12A, G12D, G12R, G12C, G12S, G12V, G13D [see Warnings and Precautions (5.7)].
The main outcome measure of the study was overall survival. Results are presented in Table 9 and Figure 3.
Figure 3: Kaplan-Meier Curve for Overall Survival in Patients with K-Ras Mutation-negative (Wild-type) Metastatic colorectal cancer in Study 5
Study 6 was a multicenter, clinical trial conducted in 329 patients with EGFR-expressing recurrent mCRC. Tumor specimens were not available for testing for K-Ras mutation status. Patients were randomized (2:1) to receive either Cetuximab plus irinotecan (218 patients) or Cetuximab monotherapy (111 patients). Cetuximab was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicity. In the Cetuximab plus irinotecan arm, irinotecan was added to Cetuximab using the same dose and schedule for irinotecan as the patient had previously failed. Acceptable irinotecan schedules were 350 mg/m2 every 3 weeks, 180 mg/m2 every 2 weeks, or 125 mg/m2 weekly times four doses every 6 weeks. Of the 329 patients, the median age was 59 years, 63% were male, 98% were Caucasian, and 88% had baseline Karnofsky performance status ≥80. Approximately two-thirds had previously failed oxaliplatin treatment.
The efficacy of Cetuximab plus irinotecan or Cetuximab monotherapy, based on durable objective responses, was evaluated in all randomized patients and in two pre-specified subpopulations: irinotecan refractory patients, and irinotecan and oxaliplatin failures. In patients receiving Cetuximab plus irinotecan, the objective response rate was 23% (95% confidence interval 18%–29%), median duration of response was 5.7 months, and median time to progression was 4.1 months. In patients receiving Cetuximab monotherapy, the objective response rate was 11% (95% confidence interval 6%–18%), median duration of response was 4.2 months, and median time to progression was 1.5 months. Similar response rates were observed in the pre-defined subsets in both the combination arm and monotherapy arm of the study.
# How Supplied
Cetuximab® (cetuximab) is supplied at a concentration of 2 mg/mL as a 100 mg/50 mL, single-use vial or as a 200 mg/100 mL, single-use vial as a sterile, injectable liquid containing no preservatives.
NDC 66733-948-23 100 mg/50 mL, single-use vial, individually packaged in a carton
NDC 66733-958-23 200 mg/100 mL, single-use vial, individually packaged in a carton
## Storage
Store vials under refrigeration at 2° C to 8° C (36° F to 46° F). Do not freeze. Increased particulate formation may occur at temperatures at or below 0° C. This product contains no preservatives. Preparations of Cetuximab in infusion containers are chemically and physically stable for up to 12 hours at 2° C to 8° C (36° F to 46° F) and up to 8 hours at controlled room temperature (20° C to 25° C; 68° F to 77° F). Discard any remaining solution in the infusion container after 8 hours at controlled room temperature or after 12 hours at 2° C to 8° C. Discard any unused portion of the vial.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise patients:
- To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.
- Of the potential risks of using Cetuximab during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Cetuximab therapy.
- That nursing is not recommended during, and for 2 months following the last dose of Cetuximab therapy.
- To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Cetuximab.
# Precautions with Alcohol
Alcohol-Cetuximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Erbitux
# Look-Alike Drug Names
cetuximab - rituximab[4]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cetuximab | |
1eafe1bf204f0dec7503065e291c37c3833d53de | wikidoc | Chalazion | Chalazion
Synonyms and keywords: Meibomian gland lipogranuloma
# Overview
A chalazion is a cyst in the eyelid that is caused by inflammation of a blocked meibomian gland, usually on the upper eyelid. Chalazions differ from styes (hordeolums) in that they are usually painless apart from the tenderness caused when they swell up. A chalazion may eventually disappear on its own after a few months, though more often than not, some treatment is necessary.
# Natural History, Complications and Prognosis
A large chalazion can cause astigmatism due to pressure on the cornea. This will resolve with resolution of the chalazion.
Complications including, but not limited to hypopigmentation may occur with corticosteroid injection.
The presence of a recurring chalazion in the same area sometimes leads to a consideration of sebaceous cell carcinoma.
The minor operation is quite painless, the eyelid is injected with a local anesthetic a clamp is put on the eyelid, then the eyelid is turned over and the chalazion is scraped out.
# Diagnosis
## History and Symptoms
- Swelling on the eyelid
- Eyelid tenderness
- Sensitivity to light
- Increased tearing
## Physical Examination
### Eyes
# Treatment
## Medical Therapy
The primary treatment is application of warm compresses for 10 to 20 minutes at least 4 times a day. This may soften the hardened oils blocking the duct and promote drainage and healing.
Topical antibiotic eye drops or ointment (eg chloramphenicol or fusidic acid) are sometimes used for the initial acute infection, but are otherwise of little value in treating a chalazion. Chalazia will often disappear without further treatment within a few months and virtually all will resorb within two years.
## Surgery
If they continue to enlarge or fail to settle within a few months, then smaller lesions may be injected with a corticosteroid or larger ones may be surgically removed using local anesthesia.
This is usually done from underneath the eyelid to avoid a scar on the skin. Rarely chalazia may reoccur and these will be biopsied to help rule out tumors.
## Primary Prevention
Proper cleansing of the eyelid may prevent recurrences in people prone to chalazia. Cleaning the eyelash area with diluted baby shampoo will help reduce clogging of the ducts.
# Related Chapters
- Blepharitis
- Stye | Chalazion
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Meibomian gland lipogranuloma
# Overview
A chalazion is a cyst in the eyelid that is caused by inflammation of a blocked meibomian gland, usually on the upper eyelid. Chalazions differ from styes (hordeolums) in that they are usually painless apart from the tenderness caused when they swell up. A chalazion may eventually disappear on its own after a few months, though more often than not, some treatment is necessary.
# Natural History, Complications and Prognosis
A large chalazion can cause astigmatism due to pressure on the cornea. This will resolve with resolution of the chalazion.
Complications including, but not limited to hypopigmentation may occur with corticosteroid injection.
The presence of a recurring chalazion in the same area sometimes leads to a consideration of sebaceous cell carcinoma.
The minor operation is quite painless, the eyelid is injected with a local anesthetic a clamp is put on the eyelid, then the eyelid is turned over and the chalazion is scraped out.
# Diagnosis
## History and Symptoms
- Swelling on the eyelid
- Eyelid tenderness
- Sensitivity to light
- Increased tearing
## Physical Examination
### Eyes
# Treatment
## Medical Therapy
The primary treatment is application of warm compresses for 10 to 20 minutes at least 4 times a day. This may soften the hardened oils blocking the duct and promote drainage and healing.
Topical antibiotic eye drops or ointment (eg chloramphenicol or fusidic acid) are sometimes used for the initial acute infection, but are otherwise of little value in treating a chalazion. Chalazia will often disappear without further treatment within a few months and virtually all will resorb within two years.[2]
## Surgery
If they continue to enlarge or fail to settle within a few months, then smaller lesions may be injected with a corticosteroid or larger ones may be surgically removed using local anesthesia.[3][4]
This is usually done from underneath the eyelid to avoid a scar on the skin. Rarely chalazia may reoccur and these will be biopsied to help rule out tumors.
## Primary Prevention
Proper cleansing of the eyelid may prevent recurrences in people prone to chalazia. Cleaning the eyelash area with diluted baby shampoo will help reduce clogging of the ducts.[5]
# Related Chapters
- Blepharitis
- Stye | https://www.wikidoc.org/index.php/Chalazion | |
38f1bbc79a5463618e97e7915222c3a3c65769f8 | wikidoc | Chalcogen | Chalcogen
# Overview
The chalcogens (with the "ch" pronounced like a k) are the name for the periodic table group 16 (old-style: VIB or VIA) in the periodic table. It is sometimes known as the oxygen family. It consists of the elements oxygen (O), sulfur (S), selenium (Se), tellurium (Te), the radioactive polonium (Po), and the synthetic ununhexium (Uuh). The compounds of the heavier chalcogens (particularly the sulfides, selenides, and tellurides) are collectively known as chalcogenides. Unless grouped with a heavier chalcogen, oxides are not considered chalcogenides.
The name is generally considered to mean "ore former" from the Greek chalcos "ore" and -gen "formation".
Oxygen and sulfur are nonmetals, and polonium, selenium and tellurium are metalloid semiconductors (i.e., their electrical properties are between those of a metal and an insulator). Nevertheless, tellurium, as well as selenium, is often referred to as a metal when in elemental form.
Chalcogens are quite common as minerals. For example, pyrite (FeS2) is an iron ore and AuTe2 gave its name to the gold rush town of Telluride, Colorado in the United States.
The formal oxidation number of the chalcogen is generally -2 in a chalcogenide but other values, such as -1 in pyrite, can be attained.
The highest formal oxidation number +6 is found in sulfates, selenates and tellurates, such as in sodium selenate (Na2SeO4). Modern chemical understanding based on quantum theory somewhat outdates the use of formal oxidation numbers in favour of a many-electron wavefunction approach allowing detailed computer simulation, though the concept, while flawed, is still useful in thought experiments. | Chalcogen
# Overview
The chalcogens (with the "ch" pronounced like a k) are the name for the periodic table group 16 (old-style: VIB or VIA) in the periodic table. It is sometimes known as the oxygen family. It consists of the elements oxygen (O), sulfur (S), selenium (Se), tellurium (Te), the radioactive polonium (Po), and the synthetic ununhexium (Uuh). The compounds of the heavier chalcogens (particularly the sulfides, selenides, and tellurides) are collectively known as chalcogenides. Unless grouped with a heavier chalcogen, oxides are not considered chalcogenides.
The name is generally considered to mean "ore former" from the Greek chalcos "ore" and -gen "formation". [1]
Oxygen and sulfur are nonmetals, and polonium, selenium and tellurium are metalloid semiconductors (i.e., their electrical properties are between those of a metal and an insulator). Nevertheless, tellurium, as well as selenium, is often referred to as a metal when in elemental form.
Chalcogens are quite common as minerals. For example, pyrite (FeS2) is an iron ore and AuTe2 gave its name to the gold rush town of Telluride, Colorado in the United States.
The formal oxidation number of the chalcogen is generally -2 in a chalcogenide but other values, such as -1 in pyrite, can be attained.
The highest formal oxidation number +6 is found in sulfates, selenates and tellurates, such as in sodium selenate (Na2SeO4). Modern chemical understanding based on quantum theory somewhat outdates the use of formal oxidation numbers in favour of a many-electron wavefunction approach allowing detailed computer simulation, though the concept, while flawed, is still useful in thought experiments.
Template:PeriodicTablesFooter | https://www.wikidoc.org/index.php/Chalcogen | |
199f64f7d19a67321cc068ebe96ffdcba19e0f53 | wikidoc | ChapStick | ChapStick
ChapStick is the brand name adopted in the United States, Australia, Canada, and United Kingdom by Wyeth Consumer Healthcare for its range of lip balms produced to be used on chapped lips. Due to ChapStick's popularity, the term has become a genericized trademark, used to refer to any lip balm contained in a lipstick-style tube and applied in the same manner as lipstick; however, the term is still a registered trademark, with rights exclusively owned by Wyeth.
ChapStick comes in several different varieties, each with its own flavor and stylized applicators. Various formulations include the Classics, Moisturizers, Medicated, Flava-Craze, Overnight, and All-Natural.
Chapstick is sometimes available in special flavors developed in connection with marketing partners such as Disney (as in cross-promotions with Winnie the Pooh or the movie Cars) or with causes, such as Breast Cancer Awareness (as in the "Susan G. Komen Pink Pack"). The "Flava-Craze" line is marketed to children, with colorful applicators and "fun" flavors such as "Grape Craze," "Blue Crazeberry," and "Watermelon Splash."
Any given ChapStick may contain camphor, beeswax, menthol, petrolatum, phenol, Vitamin E, and aloe. However, there are hundreds of variants of ChapStick, each with its own composition. Hundreds of generic lipbalms also exist, each with their own varieties and flavors, meaning there are several thousand Chapstick and Chapstick-like products available to consumers.
# Uses
ChapStick functions as both a sunscreen, available with SPFs as high as 30, and a skin moisturizer and lubricant to help prevent and protect chafed, chapped, sunburned, cracked, and windburned lips.
"Medicated" varieties also contain analgesics to relieve sore lips.
# History of ChapStick
In the early 1870s, Dr. Charles Browne Fleet , a physician and pharmacological tinkerer from Lynchburg, Virginia, invented ChapStick as a lip balm. The handmade product, which resembled a wickless candle wrapped in tin foil, was sold locally, but did not have much success.
In 1912, John Morton, also a Lynchburg resident, bought the rights to the product for five dollars. In their family kitchen, Mrs. Morton melted the pink ChapStick mixture, cooled it, and cut in into sticks. Their lucrative sales were used to found the Morton Manufacturing Corporation.
In 1963, The A. H. Robins Company acquired ChapStick from Morton Manufacturing Corporation. At that time, only ChapStick Lip Balm regular stick was being marketed to consumers; subsequently, many more varieties have been introduced. This includes ChapStick flavored sticks in 1971, ChapStick Sunblock 15 in 1981, ChapStick Petroleum Jelly Plus in 1981, and ChapStick Medicated in 1992. Picabo Street is commonly seen on television commercials as one of the company's endorsers.
# Trivia
- ChapStick tubes with hidden microphones played a role in the Watergate Scandal of the early 1970s.
- US Olympic skier Suzy Chaffee starred in ChapStick commercials on television in which she dubbed herself "Suzy ChapStick."
- ChapStick is part of the Breast Cancer Awareness program. ChapStick will donate 20¢ to the Susan G. Komen for the Cure for every ChapStick pink pack sold.
- The slang term "ChapStick lesbian" refers to a lesbian who wears little makeup (as opposed to a "lipstick lesbian"). | ChapStick
ChapStick is the brand name adopted in the United States, Australia, Canada, and United Kingdom by Wyeth Consumer Healthcare for its range of lip balms produced to be used on chapped lips. Due to ChapStick's popularity, the term has become a genericized trademark, used to refer to any lip balm contained in a lipstick-style tube and applied in the same manner as lipstick; however, the term is still a registered trademark, with rights exclusively owned by Wyeth.
ChapStick comes in several different varieties, each with its own flavor and stylized applicators. Various formulations include the Classics, Moisturizers, Medicated, Flava-Craze, Overnight, and All-Natural.
Chapstick is sometimes available in special flavors developed in connection with marketing partners such as Disney (as in cross-promotions with Winnie the Pooh or the movie Cars) or with causes, such as Breast Cancer Awareness (as in the "Susan G. Komen Pink Pack"). The "Flava-Craze" line is marketed to children, with colorful applicators and "fun" flavors such as "Grape Craze," "Blue Crazeberry," and "Watermelon Splash."
Any given ChapStick may contain camphor, beeswax, menthol, petrolatum, phenol, Vitamin E, and aloe. However, there are hundreds of variants of ChapStick, each with its own composition. Hundreds of generic lipbalms also exist, each with their own varieties and flavors, meaning there are several thousand Chapstick and Chapstick-like products available to consumers.
# Uses
ChapStick functions as both a sunscreen, available with SPFs as high as 30, and a skin moisturizer and lubricant to help prevent and protect chafed, chapped, sunburned, cracked, and windburned lips.
"Medicated" varieties also contain analgesics to relieve sore lips.
# History of ChapStick
In the early 1870s, Dr. Charles Browne Fleet [1], a physician and pharmacological tinkerer from Lynchburg, Virginia, invented ChapStick as a lip balm. The handmade product, which resembled a wickless candle wrapped in tin foil, was sold locally, but did not have much success.
In 1912, John Morton, also a Lynchburg resident, bought the rights to the product for five dollars. In their family kitchen, Mrs. Morton melted the pink ChapStick mixture, cooled it, and cut in into sticks. Their lucrative sales were used to found the Morton Manufacturing Corporation.
In 1963, The A. H. Robins Company acquired ChapStick from Morton Manufacturing Corporation. At that time, only ChapStick Lip Balm regular stick was being marketed to consumers; subsequently, many more varieties have been introduced. This includes ChapStick flavored sticks in 1971, ChapStick Sunblock 15 in 1981, ChapStick Petroleum Jelly Plus in 1981, and ChapStick Medicated in 1992. Picabo Street is commonly seen on television commercials as one of the company's endorsers.
# Trivia
Template:Trivia
- ChapStick tubes with hidden microphones played a role in the Watergate Scandal of the early 1970s.[2]
- US Olympic skier Suzy Chaffee starred in ChapStick commercials on television in which she dubbed herself "Suzy ChapStick." [3]
- ChapStick is part of the Breast Cancer Awareness program. ChapStick will donate 20¢ to the Susan G. Komen for the Cure for every ChapStick pink pack sold. [4]
- The slang term "ChapStick lesbian" refers to a lesbian who wears little makeup (as opposed to a "lipstick lesbian").[citation needed] | https://www.wikidoc.org/index.php/ChapStick | |
f752df9006ac92a7304780671b42c33044d49185 | wikidoc | Chelation | Chelation
To read more about chelation therapy click here.
To read more about chelation therapy for cardiovascular disease click here.
# Overview
Chelation (from Greek χηλή, chelè, meaning claw; pronounced Template:IPA) is the binding or complexation of a bi- or multidentate ligand. These ligands, which are often organic compounds, are called chelants, chelators, chelating agents, or sequestering agent. The ligand forms a chelate complex with the substrate. The term is reserved for complexes in which the metal ion is bound to two or more atoms of the chelating agent, although the bonds may be any combination of coordination or ionic bonds.
# History
The term chelate was first applied in 1920 by Sir Gilbert T. Morgan and H. D. K. Drew, who stated: "The adjective chelate, derived from the great claw or chele (Greek) of the lobster or other crustaceans, is suggested for the caliperlike groups which function as two associating units and fasten to the central atom so as to produce heterocyclic rings."
# General
Relative to the aqua complexes, e.g. 2+, the increased stability of a chelated complex, e.g. 2- is called the chelate effect. Because chelating agents bind to metals through more than one coordination site, such ligands bind more tenaciously than unidentate ligands (like water). If a chelate were replaced by several monodentate ligands (such as water or ammonia), the total number of molecules would decrease, whereas if several monodentate ligands were replaced by a chelate, the number of free molecules increases. The effect is therefore entropic in that more sites are used by fewer ligands and this leaves more unbonded molecules: a total increase in the number of molecules in solution and a corresponding increase in entropy.
# Chelation in nature
Virtually all biochemicals exhibit the ability to dissolve metal cations. Thus proteins, polysaccharides, and polynucleic acids are excellent polydentate ligands for many of the metal ions. In addition to these adventitious chelators, several are produced to specifically bind certain metals. Such chelating agents include the porphyrin rings in hemoglobin or chlorophyll and the Fe3+-chelating siderophores secreted by microorganisms. Histidine, malate and phytochelatin are typical chelators used by plants to avoid having poisonous metal ions in a free form.
## In geology
In earth science, chemical weathering is attributed to organic chelating agents, e.g. peptides and sugars, that have the ability to solubilize the metal ions in minerals and rocks. Most metal complexes in the environment and in nature are bound in some form of chelate ring, e.g. with "humic acid" or a protein. Thus, metal chelates are relevant to the mobilization of metals in the soil, the uptake and the accumulation of metals into plants and micro-organisms. Selective chelation of heavy metals is relevant to bioremediation, e.g. removal of 137Cs from radioactive waste.
# Uses
Chelators are used in chemical analysis, as water softeners, and are ingredients in many commercial products such as shampoos and food preservatives. A commonly used synthetic chelator is EDTA. The term is used in water treatment programs and specifically in steam engineering, to describe a boiler water treatment system: Chelant Water Treatment system.
## In medicine
Antibiotic drugs of the tetracycline family are chelators of Ca2+ and Mg2+ ions. Chelation therapy describes the use of chelating agents to detoxify poisonous metal agents such as mercury, arsenic, and lead by converting them to a chemically inert form that can be excreted without further interaction with the body. Chelation is also used as a scientifically unverified treatment for autism or other conditions. There are no published peer review publications regarding the efficacy of chelation agents for the treatment of autism.
In addition to its use for the treatment of metal poisoning, chelation therapy has been considered an alternative medicine for the treatment of atherosclerotic disease. Many mechanisms have been postulated, including decalcification of atherosclerotic vessels. Other potential mechanisms, more accepted in the modern era, center around metal detoxification. Opinions regarding the use of chelation therapy for cardiovascular diseases (CVD) have long been controversial, as, until recently, there was not enough high-quality evidence for or against its use. Most recently, the Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled, 2x2 factorial trial, investigated the effect of EDTA-based infusions among stable post-myocardial infarction patients more than 50 years of age and with fairly normal kidney function. TACT revealed a modest decrease in major adverse cardiovascular events among enrolled patients randomized to EDTA-based infusions. When the pre-specified subgroup of patients with diabetes was analyzed, the decrease in adverse cardiovascular outcomes was even more robust.
EDTA chelation can be a dangerous practice, especially when Na2EDTA is prescribed rather than CaEDTA. The CDC reports that use of Na2EDTA has resulted in fatalities due to hypocalcemia.
EDTA is also used in root canal treatment as a way to irrigate the canal. EDTA is used as a chelating agent to either soften the dentin facilitating access to the entire canal length and to remove the smear layer formed during instrumentation. | Chelation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
To read more about chelation therapy click here.
To read more about chelation therapy for cardiovascular disease click here.
# Overview
Chelation (from Greek χηλή, chelè, meaning claw; pronounced Template:IPA) is the binding or complexation of a bi- or multidentate ligand. These ligands, which are often organic compounds, are called chelants, chelators, chelating agents, or sequestering agent. The ligand forms a chelate complex with the substrate. The term is reserved for complexes in which the metal ion is bound to two or more atoms of the chelating agent, although the bonds may be any combination of coordination or ionic bonds.
# History
The term chelate was first applied in 1920 by Sir Gilbert T. Morgan and H. D. K. Drew, who stated: "The adjective chelate, derived from the great claw or chele (Greek) of the lobster or other crustaceans, is suggested for the caliperlike groups which function as two associating units and fasten to the central atom so as to produce heterocyclic rings."[1]
# General
Relative to the aqua complexes, e.g. [M(H2O)6]2+, the increased stability of a chelated complex, e.g. [M(EDTA]2- is called the chelate effect. Because chelating agents bind to metals through more than one coordination site, such ligands bind more tenaciously than unidentate ligands (like water). If a chelate were replaced by several monodentate ligands (such as water or ammonia), the total number of molecules would decrease, whereas if several monodentate ligands were replaced by a chelate, the number of free molecules increases. The effect is therefore entropic in that more sites are used by fewer ligands and this leaves more unbonded molecules: a total increase in the number of molecules in solution and a corresponding increase in entropy.
# Chelation in nature
Virtually all biochemicals exhibit the ability to dissolve metal cations. Thus proteins, polysaccharides, and polynucleic acids are excellent polydentate ligands for many of the metal ions. In addition to these adventitious chelators, several are produced to specifically bind certain metals. Such chelating agents include the porphyrin rings in hemoglobin or chlorophyll and the Fe3+-chelating siderophores secreted by microorganisms. Histidine, malate and phytochelatin are typical chelators used by plants to avoid having poisonous metal ions in a free form.[2][3][4]
## In geology
In earth science, chemical weathering is attributed to organic chelating agents, e.g. peptides and sugars, that have the ability to solubilize the metal ions in minerals and rocks.[5] Most metal complexes in the environment and in nature are bound in some form of chelate ring, e.g. with "humic acid" or a protein. Thus, metal chelates are relevant to the mobilization of metals in the soil, the uptake and the accumulation of metals into plants and micro-organisms. Selective chelation of heavy metals is relevant to bioremediation, e.g. removal of 137Cs from radioactive waste.[6]
# Uses
Chelators are used in chemical analysis, as water softeners, and are ingredients in many commercial products such as shampoos and food preservatives. A commonly used synthetic chelator is EDTA. The term is used in water treatment programs and specifically in steam engineering, to describe a boiler water treatment system: Chelant Water Treatment system.
## In medicine
Antibiotic drugs of the tetracycline family are chelators of Ca2+ and Mg2+ ions. Chelation therapy describes the use of chelating agents to detoxify poisonous metal agents such as mercury, arsenic, and lead by converting them to a chemically inert form that can be excreted without further interaction with the body. Chelation is also used as a scientifically unverified treatment for autism or other conditions. There are no published peer review publications regarding the efficacy of chelation agents for the treatment of autism.[7]
In addition to its use for the treatment of metal poisoning, chelation therapy has been considered an alternative medicine for the treatment of atherosclerotic disease. Many mechanisms have been postulated, including decalcification of atherosclerotic vessels. Other potential mechanisms, more accepted in the modern era, center around metal detoxification. Opinions regarding the use of chelation therapy for cardiovascular diseases (CVD) have long been controversial, as, until recently, there was not enough high-quality evidence for or against its use. Most recently, the Trial to Assess Chelation Therapy (TACT), a randomized, double blind, placebo controlled, 2x2 factorial trial, investigated the effect of EDTA-based infusions among stable post-myocardial infarction patients more than 50 years of age and with fairly normal kidney function. TACT revealed a modest decrease in major adverse cardiovascular events among enrolled patients randomized to EDTA-based infusions. When the pre-specified subgroup of patients with diabetes was analyzed, the decrease in adverse cardiovascular outcomes was even more robust.
EDTA chelation can be a dangerous practice, especially when Na2EDTA is prescribed rather than CaEDTA. The CDC reports that use of Na2EDTA has resulted in fatalities due to hypocalcemia.[8]
EDTA is also used in root canal treatment as a way to irrigate the canal. EDTA is used as a chelating agent to either soften the dentin facilitating access to the entire canal length and to remove the smear layer formed during instrumentation. | https://www.wikidoc.org/index.php/Chelate | |
9fba8b32ff39ae0a660bc34ae05de7250e38cdcf | wikidoc | Chemistry | Chemistry
# Overview
Chemistry (from Egyptian kēme (chem), meaning "earth") is the science concerned with the composition, structure, and properties of matter, as well as the changes it undergoes during chemical reactions. Chemistry is a physical science related to studies of various atoms, molecules, crystals and other aggregrates of matter whether in isolation or combination, which incorporates the concepts of energy and entropy in relation to the spontaneity of chemical processes.
Disciplines within chemistry are traditionally grouped by the type of matter being studied or the kind of study. These include inorganic chemistry, the study of inorganic matter; organic chemistry, the study of organic matter; biochemistry, the study of substances found in biological organisms; physical chemistry, the energy related studies of chemical systems at macro, molecular and submolecular scales; analytical chemistry, the analysis of material samples to gain an understanding of their chemical composition and structure. Many more specialized disciplines have emerged in recent years, e.g. neurochemistry the chemical study of the mind (see subdisciplines).
Historically, modern chemistry evolved out of alchemy following the chemical revolution (1773) (see History).
# Overview
Chemistry is the scientific study of interaction of substances called chemical substances that are constituted of atoms or the subatomic components that make up atoms: protons, electrons and neutrons. Atoms combine to produce ions, molecules or crystals. Chemistry can be called "the central science" because it connects the other natural sciences, such as astronomy, physics, material science, biology, and geology.
The genesis of chemistry can be traced to certain practices, known as alchemy, which had been practiced for several millennia in various parts of the world, particularly the middle east.
The structure of objects we commonly use and the properties of the matter we commonly interact with, are a consequence of the properties of chemical substances and their interactions. For example, steel is harder than iron because its atoms are bound together in a more rigid crystalline lattice; wood burns or undergoes rapid oxidation because it can react spontaneously with oxygen in a chemical reaction above a certain temperature; sugar and salt dissolve in water because their molecular/ionic properties are such that dissolution is preferred under the ambient conditions.
The transformations that are studied in chemistry are a result of interaction either between different chemical substances or between matter and energy. Traditional chemistry involves study of interactions between substances in a chemistry laboratory using various forms of laboratory glassware.
A chemical reaction is a transformation of some such substances into one or more other such substances. It can be symbolically depicted through a chemical equation. The number of atoms on the left and the right in the equation for a chemical transformation is most often equal. The nature of chemical reactions a substance may undergo and the energy changes that may accompany it are constrained by certain basic rules, known as chemical laws.
Energy and entropy considerations are invariably important in almost all chemical studies. Chemical substances are classified in terms of their structure, phase as well as their chemical compositions. They can be analysed using the tools of chemical analysis, e.g. spectroscopy and chromatography.
Chemistry is an integral part of the science curriculum both at the high school as well as the early college level. At these levels, it is often called 'general chemistry' which is an introduction to a wide variety of fundamental concepts that enable the student to acquire tools and skills useful at the advanced levels, whereby chemistry is invariably studied in any of its various sub-disciplines. Scientists, engaged in chemical research are known as chemists. Most chemists specialize in one or more sub-disciplines.
# History
The genesis of chemistry can be traced to the widely observed phenomenon of burning that led to metallurgy- the art and science of processing ores to get metals (e.g. metallurgy in ancient India). The greed for gold led to the discovery of the process for its purification, even though, the underlying principles were not well understood -- it was thought to be a transformation rather than purification. Many scholars in those days thought it reasonable to believe that there exist means for transforming cheaper (base) metals into gold. This gave way to alchemy, and the search for the Philosopher's Stone, which was believed to bring about such a transformation by mere touch.
Some consider medieval Muslims to be the earliest chemists, who introduced precise observation and controlled experimentation into the field, and discovered numerous chemical substances. The most influential Muslim chemists were Geber (d. 815), al-Kindi (d. 873), al-Razi (d. 925), and al-Biruni (d. 1048). The works of Geber became more widely known in Europe through Latin translations by a pseudo-Geber in 14th century Spain, who also wrote some of his own books under the pen name "Geber". The contribution of Indian alchemists and metallurgists in the development of chemistry was also quite significant.
The emergence of chemistry in Europe was primarily due to the recurrent incidence of the plague and blights there during the so called Dark Ages. This gave rise to a need for medicines. It was thought that there exists a universal medicine called the Elixir of Life that can cure all diseases, but like the Philosopher's Stone, it was never found.
For some practitioners, alchemy was an intellectual pursuit, over time, they got better at it. Paracelsus (1493-1541), for example, rejected the 4-elemental theory and with only a vague understanding of his chemicals and medicines, formed a hybrid of alchemy and science in what was to be called iatrochemistry. Similarly, the influences of philosophers such as Sir Francis Bacon (1561-1626) and René Descartes (1596-1650), who demanded more rigor in mathematics and in removing bias from scientific observations, led to a scientific revolution. In chemistry, this began with Robert Boyle (1627-1691), who came up with an equations known as the Boyle's Law about the characteristics of gaseous state. Chemistry indeed came of age when Antoine Lavoisier (1743-1794), developed the theory of Conservation of mass in 1783; and the development of the Atomic Theory by John Dalton around 1800. The Law of Conservation of Mass resulted in the reformulation of chemistry based on this law and the oxygen theory of combustion, which was largely based on the work of Lavoisier. Lavoisier's fundamental contributions to chemistry were a result of a conscious effort to fit all experiments into the framework of a single theory. He established the consistent use of the chemical balance, used oxygen to overthrow the phlogiston theory, and developed a new system of chemical nomenclature and made contibution to the modern metric system. Lavoisier also worked to translate the archaic and technical language of chemistry into something that could be easily understood by the largely uneducated masses, leading to an increased public interest in chemistry. All these advances in chemistry led to what is usually called the chemical revolution. The contributions of Lavoisier led to what is now called modern chemistry - the chemistry that is studied in educational institutions all over the world. It is because of these and other contribtuions that Antoine Lavoisier is often celebrated as the "Father of Modern Chemistry". The later discovery of Friedrich Wöhler that many natural substances, organic compounds, can indeed be synthesized in a chemistry laboratory also helped the modern chemistry to mature from its infancy.
The discoveries of the chemical elements has a long history from the days of alchemy and culminating in the creation of the periodic table of the chemical elements by Dmitri Mendeleev (1834-1907) and later discoveries of some synthetic elements.
# Etymology
The word chemistry comes from the earlier study of alchemy, which is basically the quest to make gold from earthen starting materials. As to the origin of the word "alchemy" the question is a debatable one; it certainly can be traced back to the Greeks, and some, following E. Wallis Budge, have also asserted Egyptian origins. Alchemy, generally, derives from the old French alkemie from the Arabic al-kimia - "the art of transformation". The Arabs borrowed the word "kimia" from the Greeks when they conquered Alexandria in the year 642 AD. A tentative outline is as follows:
- Egyptian alchemy , formulate early "element" theories such as the Ogdoad.
- Greek alchemy , the Greek king Alexander the Great conquers Egypt and founds Alexandria, having the world's largest library, where scholars and wise men gather to study.
- Arabian alchemy , the Arabs take over Alexandria; Jabir is the main chemist
- European alchemy , Pseudo-Geber builds on Arabic chemistry
- Chemistry , Boyle writes his classic chemistry text The Sceptical Chymist
- Chemistry , Lavoisier writes his classic Elements of Chemistry
- Chemistry , Dalton publishes his Atomic Theory
Thus, an alchemist was called a 'chemist' in popular speech, and later the suffix "-ry" was added to this to describe the art of the chemist as "chemistry".
# Definitions
In retrospect, the definition of chemistry seems to invariably change per decade, as new discoveries and theories add to the functionality of the science. Shown below are some of the standard definitions used by various noted chemists:
- Alchemy (330) – the study of the composition of waters, movement, growth, embodying and disembodying, drawing the spirits from bodies and bonding the spirits within bodies (Zosimos).
- Chymistry (1661) – the subject of the material principles of mixt bodies (Boyle).
- Chymistry (1663) – a scientific art, by which one learns to dissolve bodies, and draw from them the different substances on their composition, and how to unite them again, and exalt them to an higher perfection (Glaser).
- Chemistry (1730) – the art of resolving mixt, compound, or aggregate bodies into their principles; and of composing such bodies from those principles (Stahl).
- Chemistry (1837) – the science concerned with the laws and effects of molecular forces (Dumas).
- Chemistry (1947) – the science of substances: their structure, their properties, and the reactions that change them into other substances (Pauling).
- Chemistry (1998) – the study of matter and the changes it undergoes (Chang).
# Basic concepts
Several concepts are essential for the study of chemistry, some of them are:
## Atom
An atom is the basic unit of an element. It is a collection of matter consisting of a positively charged core (the atomic nucleus) which contains protons and neutrons, and which maintains a number of electrons to balance the positive charge in the nucleus. Atom is also the smallest entity that can be envisaged to retain some of the chemical properties of the element, viz. Electronegativity, Ionization potential, Preferred oxidation state(s), Coordination number, Preferred types of bonds to form e.g., metallic, ionic, covalent.
## Element
The concept of chemical element is related to that of chemical substance. A chemical element is characterized by a particular number of protons in the nuclei of its atoms. This number is known as the atomic number of the element. For example, all atoms with 6 protons in their nuclei are atoms of the chemical element carbon, and all atoms with 92 protons in their nuclei are atoms of the element uranium. However, several isotopes of an element, that differ from one another in the number of neutrons present in the nucleus, may exist.
The most convenient presentation of the chemical elements is in the periodic table of the chemical elements, which groups elements by atomic number. Due to its ingenious arrangement, groups, or columns, and periods, or rows, of elements in the table either share several chemical properties, or follow a certain trend in characteristics such as atomic radius, electronegativity, etc. Lists of the elements by name, by symbol, and by atomic number are also available.
## Compound
A compound is a substance with a particular ratio of atoms of particular chemical elements which determines its composition, and a particular organization which determines chemical properties. For example, water is a compound containing hydrogen and oxygen in the ratio of two to one, with the oxygen between the hydrogens, and an angle of 104.5° between them. Compounds are formed and interconverted by chemical reactions.
## Substance
A chemical substance is a kind of matter with a definite composition and set of properties. Strictly speaking, a mixture of compounds, elements or compounds and elements is not a chemical substance, but it may be called a chemical. Most of the substances we encounter in our daily life are some kind of mixture, e.g. air, alloys, biomass etc.
Nomenclature of substances is a critical part of the language of chemistry. Generally it refers to a system for naming chemical compounds. Earlier in the history of chemistry substances were given name by their discoverer, which often led to some confusion and difficulty. However, today the IUPAC system of chemical nomenclature allows chemists to specify by name specific compounds amongst the infinite variety of possible chemicals. The standard nomenclature of chemical substances is set by the International Union of Pure and Applied Chemistry (IUPAC). There are well-defined systems in place for naming chemical species. Organic compounds are named according to the organic nomenclature system. Inorganic compounds are named according to the inorganic nomenclature system. In addition the Chemical Abstracts Service has devised a method to index chemical substance. In this scheme each chemical substance is identifiable by a numeric number known as CAS registry number.
## Molecule
A molecule is the smallest indivisible portion, beside an atom, of a pure chemical substance that has its unique set of chemical properties, that is, its potential to undergo a certain set of chemical reactions with other substances. Molecules can exist as electrically neutral units unlike ions. Molecules are typically a set of atoms bound together by covalent bonds, such that the structure is electrically neutral and all valence electrons are paired with other electrons either in bonds or in lone pairs.
One of the main characteristic of a molecule is its geometry often called its structure. While the structure of diatomic, triatomic or tetra atomic molecules may be trivial, (linear, angular pyramidal etc.) the structure of polyatomic molecules, that are constituted of more than six atoms (of several elements) can be crucial for its chemical nature.
## Mole
A mole is the amount of a substance that contains as many elementary entities (atoms, molecules or ions) as there are atoms in 0.012 kilogram (or 12 grams) of carbon-12, where the carbon-12 atoms are unbound, at rest and in their ground state. This number is known as the Avogadro constant, and is determined empirically. The currently accepted value is 6.02214179(30)Template:E mol-1 (2007 CODATA). It is much like the term "a dozen" in that it is an absolute number (having no units) and can describe any type of elementary object, although the mole's use is usually limited to measurement of subatomic, atomic, and molecular structures.
The number of moles of a substance in one liter of a solution is known as its molarity. Molarity is the common unit used to express the concentration of a solution in physical chemistry.
## Ions and salts
An ion is a charged species, an atom or a molecule, that has lost or gained one or more electrons. Positively charged cations (e.g. sodium cation Na+) and negatively charged anions (e.g. chloride Cl−) can form a crystalline lattice of neutral salts (e.g. sodium chloride NaCl). Examples of polyatomic ions that do not split up during acid-base reactions are hydroxide (OH−) and phosphate (PO43−).
Ions in the gaseous phase is often known as plasma.
## Phase
In addition to the specific chemical properties that distinguish different chemical classifications chemicals can exist in several phases. For the most part, the chemical classifications are independent of these bulk phase classifications; however, some more exotic phases are incompatible with certain chemical properties. A phase is a set of states of a chemical system that have similar bulk structural properties, over a range of conditions, such as pressure or temperature. Physical properties, such as density and refractive index tend to fall within values characteristic of the phase. The phase of matter is defined by the phase transition, which is when energy put into or taken out of the system goes into rearranging the structure of the system, instead of changing the bulk conditions.
Sometimes the distinction between phases can be continuous instead of having a discrete boundary, in this case the matter is considered to be in a supercritical state. When three states meet based on the conditions, it is known as a triple point and since this is invariant, it is a convenient way to define a set of conditions.
The most familiar examples of phases are solids, liquids, and gases. Many substances exhibit multiple solid phases. For example, there are three phases of solid iron (alpha, gamma, and delta) that vary based on temperature and pressure. A principal difference between solid phases is the crystal structure, or arrangement, of the atoms. Less familiar phases include plasmas, Bose-Einstein condensates and fermionic condensates and the paramagnetic and ferromagnetic phases of magnetic materials. While most familiar phases deal with three-dimensional systems, it is also possible to define analogs in two-dimensional systems, which has received attention for its relevance to systems in biology.
## Chemical bond
A chemical bond is a concept for understanding how atoms stick together in molecules. It may be visualized as the multipole balance between the positive charges in the nuclei and the negative charges oscillating about them. More than simple attraction and repulsion, the energies and distributions characterize the availability of an electron to bond to another atom. These potentials create the interactions which holds together atoms in molecules or crystals. In many simple compounds, Valence Bond Theory, the Valence Shell Electron Pair Repulsion model (VSEPR), and the concept of oxidation number can be used to predict molecular structure and composition. Similarly, theories from classical physics can be used to predict many ionic structures. With more complicated compounds, such as metal complexes, valence bond theory fails and alternative approaches, primarily based on principles of quantum chemistry such as the molecular orbital theory, are necessary. See diagram on electronic orbitals.
## Chemical reaction
Chemical reaction is a concept related to the transformation of a chemical substance through its interaction with another, or as a result of its interaction with some form of energy. A chemical reaction may occur naturally or carried out in a laboratory by chemists in specially designed vessels which are often laboratory glassware. It can result in the formation or dissociation of molecules, that is, molecules breaking apart to form two or more smaller molecules, or rearrangement of atoms within or across molecules. Chemical reactions usually involve the making or breaking of chemical bonds. Oxidation, reduction, dissociation, acid-base neutralization and molecular rearrangement are some of the commonly used kinds of chemical reactions.
A chemical reaction can be symbolically depicted through a chemical equation. While in a non-nuclear chemical reaction the number and kind of atoms on both sides of the equation are equal, for a nuclear reaction this holds true only for the nuclear particles viz. protons and neutrons.
The sequence of steps in which the reorganization of chemical bonds may be taking place in the course of a chemical reaction is called its mechanism. A chemical reaction can be envisioned to take place in a number of steps, each of which may have a different speed. Many reaction intermediates with variable stability can thus be envisaged during the course of a reaction. Reaction mechanisms are proposed to explain the kinetics and the relative product mix of a reaction. Many physical chemists specialize in exploring and proposing the mechanisms of various chemical reactions. Several empirical rules, like the Woodward-Hoffmann rules often come handy while proposing a mechanism for a chemical reaction.
A stricter definition is that "a chemical reaction is a process that results in the interconversion of chemical species". Under this definition, a chemical reaction may be an elementary reaction or a stepwise reaction. An additional caveat is made, in that this definition includes cases where the interconversion of conformers is experimentally observable. Such detectable chemical reactions normally involve sets of molecular entities as indicated by this definition, but it is often conceptually convenient to use the term also for changes involving single molecular entities (i.e. 'microscopic chemical events').
## Energy
A chemical reaction is invariably accompanied by an increase or decrease of energy of the substances involved. Some energy is transferred between the surroundings and the reactants of the reaction in the form of heat or light, thus the products of a reaction may have more or less energy than the reactants. A reaction is said to be exothermic if the final state is lower on the energy scale than the initial state; in case of endothermic reactions the situation is otherwise.
Chemical reactions are invariably not possible unless the reactants surmount an energy barrier known as the activation energy. The speed of a chemical reaction (at given temperature T) is related to the activation energy E, by the Boltzmann's population factor e^{-E/kT} - that is the probability of molecule to have energy greater than or equal to E at the given temperature T. This exponential dependence of a reaction rate on temperature is known as the Arrhenius equation.
The activation energy necessary for a chemical reaction can be in the form of heat, light, electricity or mechanical force in the form of ultrasound.
A related concept Free energy, which incorporates entropy considerations too, is a very useful means for predicting the feasibility of a reaction and determining the state of equilibrium of a chemical reaction, in chemical thermodynamics. A reaction is feasible only if the total change in the Gibbs free energy is negative, \Delta G \le 0 \,; if it is equal to zero the chemical reaction is said to be at equilibrium.
There are only a limited possible states of energy for electrons, atoms and molecules. These are determined by the rules of quantum mechanics, which require quantization of energy of a bound system. The atoms/molecules in an higher energy state are said to be excited. The molecules/atoms of substance in an excited energy state are often much more reactive, that is amenable to chemical reactions.
The phase of a substance is invariably determined by its energy and those of its surroundings. When the intermolecular forces of a substance are such that energy of the surroundings is not sufficient to overcome them, it occurs in a more ordered phase like liquid or solid as is the case with water (H2O), a liquid at room temperature because its molecules are bound by hydrogen bonds. Whereas hydrogen sulfide (H2S) is a gas at room temperature and standard pressure, as its molecules are bound by weaker dipole-dipole interactions.
The transfer of energy from one chemical substance to other depend on the size of energy quanta emitted from one substance. However, heat energy is easily transferred from almost any substance to another mainly because the vibrational and rotational energy levels in a substance are very closely placed. Because, the electronic energy levels are not so closely spaced, ultraviolet electromagnetic radiation is not transferred with equal felicity, as is also the case with electrical energy.
The existence of characteristic energy levels for different chemical substances is useful for their identification by the analysis of spectral lines of different kinds of spectra often used in chemical spectroscopy e.g. IR, microwave, NMR, ESR etc. This is used to identify the composition of remote objects - like stars and far galaxies - by analyzing their radiation (see spectroscopy).
The term chemical energy is often used to indicate the potential of a chemical substance to undergo a transformation through a chemical reaction or transform other chemical substances.
## Chemical laws
Chemical reactions are governed by certain laws, which have become fundamental concepts in chemistry. Some of them are:
- Law of conservation of mass, according to the modern physics it is actually energy that is conserved, and that energy and mass are related; a concept which becomes important in nuclear chemistry.
- Law of conservation of Energy leads to the important concepts of equilibrium, thermodynamics, and kinetics.
- Law of definite composition, although in many systems (notably biomacromolecules and minerals) the ratios tend to require large numbers, and are frequently represented as a fraction.
- Law of multiple proportions
- Hess's Law
- Beer-Lambert law
- Fick's law of diffusion
- Raoult's Law
- Henry's law
- Boyle's law (1662, relating pressure and volume)
- Charles's law (1787, relating volume and temperature)
- Gay-Lussac's law (1809, relating pressure and temperature)
- Avogadro's law
# Subdisciplines
Chemistry is typically divided into several major sub-disciplines. There are also several main cross-disciplinary and more specialized fields of chemistry.
- Analytical chemistry is the analysis of material samples to gain an understanding of their chemical composition and structure. Analytical chemistry incorporates standardized experimental methods in chemistry. These methods may be used in all subdisciplines of chemistry, excluding purely theoretical chemistry.
- Biochemistry is the study of the chemicals, chemical reactions and chemical interactions that take place in living organisms. Biochemistry and organic chemistry are closely related, as in medicinal chemistry or neurochemistry. Biochemistry is also associated with molecular biology and genetics.
- Inorganic chemistry is the study of the properties and reactions of inorganic compounds. The distinction between organic and inorganic disciplines is not absolute and there is much overlap, most importantly in the sub-discipline of organometallic chemistry.
- Materials chemistry is the preparation, characterization, and understanding of substances with a useful function. The field is a new breadth of study in graduate programs, and it integrates elements from all classical areas of chemistry with a focus on fundamental issues that are unique to materials. Primary systems of study include the chemistry of condensed phases (solids, liquids, polymers) and interfaces between different phases.
- Nuclear chemistry is the study of how subatomic particles come together and make nuclei. Modern Transmutation is a large component of nuclear chemistry, and the table of nuclides is an important result and tool for this field.
- Organic chemistry is the study of the structure, properties, composition, mechanisms, and reactions of organic compounds. An organic compound is defined as any compound based on a carbon skeleton.
- Physical chemistry is the study of the physical and fundamental basis of chemical systems and processes. In particular, the energetics and dynamics of such systems and processes are of interest to physical chemists. Important areas of study include chemical thermodynamics, chemical kinetics, electrochemistry, statistical mechanics, and spectroscopy. Physical chemistry has large overlap with molecular physics. Physical chemistry involves the use of calculus in deriving equations. It is usually associated with quantum chemistry and theoretical chemistry. Physical chemistry is a distinct discipline from chemical physics.
- Theoretical chemistry is the study of chemistry via fundamental theoretical reasoning (usually within mathematics or physics). In particular the application of quantum mechanics to chemistry is called quantum chemistry. Since the end of the Second World War, the development of computers has allowed a systematic development of computational chemistry, which is the art of developing and applying computer programs for solving chemical problems. Theoretical chemistry has large overlap with (theoretical and experimental) condensed matter physics and molecular physics.
Other fields include Astrochemistry, Atmospheric chemistry, Chemical Engineering, Chemical biology, Chemo-informatics, Electrochemistry, Environmental chemistry, Flow chemistry, Geochemistry, Green chemistry, History of chemistry, Materials science, Medicinal chemistry, Molecular Biology, Nanotechnology, Organometallic chemistry, Petrochemistry, Pharmacology, Photochemistry, Phytochemistry, Polymer chemistry, Solid-state chemistry, Sonochemistry, Supramolecular chemistry, Surface chemistry, Immunochemistry and Thermochemistry.
# Chemical industry
The chemical industry represents an important economic activity. The global top 50 chemical producers in 2004 had sales of 587 billion US dollars with a profit margin of 8.1% and research and development spending of 2.1% of total chemical sales.
# Further reading
## Popular reading
- Atkins, P.W. Galileo's Finger (Oxford University Press) ISBN 0198609418
- Atkins, P.W. Atkins' Molecules (Cambridge University Press) ISBN 0521823978
- Stwertka, A. A Guide to the Elements (Oxford University Press) ISBN 0195150279
## Introductory undergraduate text books
- Chang, Raymond. Chemistry 6th ed. Boston: James M. Smith, 1998. ISBN 0-07-115221-0.
- Atkins, P.W., Overton, T., Rourke, J., Weller, M. and Armstrong, F. Shriver and Atkins inorganic chemistry (4th edition) 2006 (Oxford University Press) ISBN 0-19-926463-5
- Clayden, J., Greeves, N., Warren, S., Wothers, P. Organic Chemistry 2000 (Oxford University Press) ISBN 0-19-850346-6
- Voet and Voet Biochemistry (Wiley) ISBN 0-471-58651-X
## Advanced undergraduate-level or graduate text books
- Atkins, P.W. Physical Chemistry (Oxford University Press) ISBN 0-19-879285-9
- Atkins, P.W. et al. Molecular Quantum Mechanics (Oxford University Press)
- McWeeny, R. Coulson's Valence (Oxford Science Publications) ISBN 0-19-855144-4
- Pauling, L. The Nature of the chemical bond (Cornell University Press) ISBN 0-8014-0333-2
- Pauling, L., and Wilson, E. B. Introduction to Quantum Mechanics with Applications to Chemistry (Dover Publications) ISBN 0-486-64871-0
- Stephenson, G. Mathematical Methods for Science Students (Longman)ISBN 0-582-44416-0
- Smart and Moore Solid State Chemistry: An Introduction (Chapman and Hall) ISBN 0-412-40040-5
# Professional societies
- American Chemical Society
- Chemical Institute of Canada
- Chemical Society of Peru
- International Union of Pure and Applied Chemistry
- Royal Australian Chemical Institute
- Royal Society of Chemistry
- Society of Chemical Industry
- World Association of Theoretical and Computational Chemists | Chemistry
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [9]
# Overview
Chemistry (from Egyptian kēme (chem), meaning "earth"[1]) is the science concerned with the composition, structure, and properties of matter, as well as the changes it undergoes during chemical reactions.[2] Chemistry is a physical science related to studies of various atoms, molecules, crystals and other aggregrates of matter whether in isolation or combination, which incorporates the concepts of energy and entropy in relation to the spontaneity of chemical processes.
Disciplines within chemistry are traditionally grouped by the type of matter being studied or the kind of study. These include inorganic chemistry, the study of inorganic matter; organic chemistry, the study of organic matter; biochemistry, the study of substances found in biological organisms; physical chemistry, the energy related studies of chemical systems at macro, molecular and submolecular scales; analytical chemistry, the analysis of material samples to gain an understanding of their chemical composition and structure. Many more specialized disciplines have emerged in recent years, e.g. neurochemistry the chemical study of the mind (see subdisciplines).
Historically, modern chemistry evolved out of alchemy following the chemical revolution (1773) (see History).
# Overview
Chemistry is the scientific study of interaction of substances called chemical substances[3] that are constituted of atoms or the subatomic components that make up atoms: protons, electrons and neutrons.[4] Atoms combine to produce ions, molecules or crystals. Chemistry can be called "the central science" because it connects the other natural sciences, such as astronomy, physics, material science, biology, and geology.[5][6]
The genesis of chemistry can be traced to certain practices, known as alchemy, which had been practiced for several millennia in various parts of the world, particularly the middle east.[7]
The structure of objects we commonly use and the properties of the matter we commonly interact with, are a consequence of the properties of chemical substances and their interactions. For example, steel is harder than iron because its atoms are bound together in a more rigid crystalline lattice; wood burns or undergoes rapid oxidation because it can react spontaneously with oxygen in a chemical reaction above a certain temperature; sugar and salt dissolve in water because their molecular/ionic properties are such that dissolution is preferred under the ambient conditions.
The transformations that are studied in chemistry are a result of interaction either between different chemical substances or between matter and energy. Traditional chemistry involves study of interactions between substances in a chemistry laboratory using various forms of laboratory glassware.
A chemical reaction is a transformation of some such substances into one or more other such substances.[8] It can be symbolically depicted through a chemical equation. The number of atoms on the left and the right in the equation for a chemical transformation is most often equal. The nature of chemical reactions a substance may undergo and the energy changes that may accompany it are constrained by certain basic rules, known as chemical laws.
Energy and entropy considerations are invariably important in almost all chemical studies. Chemical substances are classified in terms of their structure, phase as well as their chemical compositions. They can be analysed using the tools of chemical analysis, e.g. spectroscopy and chromatography.
Chemistry is an integral part of the science curriculum both at the high school as well as the early college level. At these levels, it is often called 'general chemistry' which is an introduction to a wide variety of fundamental concepts that enable the student to acquire tools and skills useful at the advanced levels, whereby chemistry is invariably studied in any of its various sub-disciplines. Scientists, engaged in chemical research are known as chemists.[9] Most chemists specialize in one or more sub-disciplines.
# History
The genesis of chemistry can be traced to the widely observed phenomenon of burning that led to metallurgy- the art and science of processing ores to get metals (e.g. metallurgy in ancient India). The greed for gold led to the discovery of the process for its purification, even though, the underlying principles were not well understood -- it was thought to be a transformation rather than purification. Many scholars in those days thought it reasonable to believe that there exist means for transforming cheaper (base) metals into gold. This gave way to alchemy, and the search for the Philosopher's Stone, which was believed to bring about such a transformation by mere touch.[10]
Some consider medieval Muslims to be the earliest chemists, who introduced precise observation and controlled experimentation into the field, and discovered numerous chemical substances.[11] The most influential Muslim chemists were Geber (d. 815), al-Kindi (d. 873), al-Razi (d. 925), and al-Biruni (d. 1048).[12] The works of Geber became more widely known in Europe through Latin translations by a pseudo-Geber in 14th century Spain, who also wrote some of his own books under the pen name "Geber". The contribution of Indian alchemists and metallurgists in the development of chemistry was also quite significant.[13]
The emergence of chemistry in Europe was primarily due to the recurrent incidence of the plague and blights there during the so called Dark Ages. This gave rise to a need for medicines. It was thought that there exists a universal medicine called the Elixir of Life that can cure all diseases, but like the Philosopher's Stone, it was never found.
For some practitioners, alchemy was an intellectual pursuit, over time, they got better at it. Paracelsus (1493-1541), for example, rejected the 4-elemental theory and with only a vague understanding of his chemicals and medicines, formed a hybrid of alchemy and science in what was to be called iatrochemistry. Similarly, the influences of philosophers such as Sir Francis Bacon (1561-1626) and René Descartes (1596-1650), who demanded more rigor in mathematics and in removing bias from scientific observations, led to a scientific revolution. In chemistry, this began with Robert Boyle (1627-1691), who came up with an equations known as the Boyle's Law about the characteristics of gaseous state.[14] Chemistry indeed came of age when Antoine Lavoisier (1743-1794), developed the theory of Conservation of mass in 1783; and the development of the Atomic Theory by John Dalton around 1800. The Law of Conservation of Mass resulted in the reformulation of chemistry based on this law and the oxygen theory of combustion, which was largely based on the work of Lavoisier. Lavoisier's fundamental contributions to chemistry were a result of a conscious effort to fit all experiments into the framework of a single theory. He established the consistent use of the chemical balance, used oxygen to overthrow the phlogiston theory, and developed a new system of chemical nomenclature and made contibution to the modern metric system. Lavoisier also worked to translate the archaic and technical language of chemistry into something that could be easily understood by the largely uneducated masses, leading to an increased public interest in chemistry. All these advances in chemistry led to what is usually called the chemical revolution. The contributions of Lavoisier led to what is now called modern chemistry - the chemistry that is studied in educational institutions all over the world. It is because of these and other contribtuions that Antoine Lavoisier is often celebrated as the "Father of Modern Chemistry". The later discovery of Friedrich Wöhler that many natural substances, organic compounds, can indeed be synthesized in a chemistry laboratory also helped the modern chemistry to mature from its infancy.
The discoveries of the chemical elements has a long history from the days of alchemy and culminating in the creation of the periodic table of the chemical elements by Dmitri Mendeleev (1834-1907)[15] and later discoveries of some synthetic elements.
# Etymology
The word chemistry comes from the earlier study of alchemy, which is basically the quest to make gold from earthen starting materials.[16] As to the origin of the word "alchemy" the question is a debatable one; it certainly can be traced back to the Greeks, and some, following E. Wallis Budge, have also asserted Egyptian origins. Alchemy, generally, derives from the old French alkemie from the Arabic al-kimia - "the art of transformation". The Arabs borrowed the word "kimia" from the Greeks when they conquered Alexandria in the year 642 AD. A tentative outline is as follows:
- Egyptian alchemy [5,000 BCE – 400 BCE], formulate early "element" theories such as the Ogdoad.
- Greek alchemy [332 BCE – 642 CE], the Greek king Alexander the Great conquers Egypt and founds Alexandria, having the world's largest library, where scholars and wise men gather to study.
- Arabian alchemy [642 CE – 1200], the Arabs take over Alexandria; Jabir is the main chemist
- European alchemy [1300 – present], Pseudo-Geber builds on Arabic chemistry
- Chemistry [1661], Boyle writes his classic chemistry text The Sceptical Chymist
- Chemistry [1787], Lavoisier writes his classic Elements of Chemistry
- Chemistry [1803], Dalton publishes his Atomic Theory
Thus, an alchemist was called a 'chemist' in popular speech, and later the suffix "-ry" was added to this to describe the art of the chemist as "chemistry".
# Definitions
In retrospect, the definition of chemistry seems to invariably change per decade, as new discoveries and theories add to the functionality of the science. Shown below are some of the standard definitions used by various noted chemists:
- Alchemy (330) – the study of the composition of waters, movement, growth, embodying and disembodying, drawing the spirits from bodies and bonding the spirits within bodies (Zosimos).[17]
- Chymistry (1661) – the subject of the material principles of mixt bodies (Boyle).[18]
- Chymistry (1663) – a scientific art, by which one learns to dissolve bodies, and draw from them the different substances on their composition, and how to unite them again, and exalt them to an higher perfection (Glaser).[19]
- Chemistry (1730) – the art of resolving mixt, compound, or aggregate bodies into their principles; and of composing such bodies from those principles (Stahl).[20]
- Chemistry (1837) – the science concerned with the laws and effects of molecular forces (Dumas).[21]
- Chemistry (1947) – the science of substances: their structure, their properties, and the reactions that change them into other substances (Pauling).[22]
- Chemistry (1998) – the study of matter and the changes it undergoes (Chang).[23]
# Basic concepts
Several concepts are essential for the study of chemistry, some of them are:[24]
## Atom
An atom is the basic unit of an element. It is a collection of matter consisting of a positively charged core (the atomic nucleus) which contains protons and neutrons, and which maintains a number of electrons to balance the positive charge in the nucleus. Atom is also the smallest entity that can be envisaged to retain some of the chemical properties of the element, viz. Electronegativity, Ionization potential, Preferred oxidation state(s), Coordination number, Preferred types of bonds to form e.g., metallic, ionic, covalent.
## Element
The concept of chemical element is related to that of chemical substance. A chemical element is characterized by a particular number of protons in the nuclei of its atoms. This number is known as the atomic number of the element. For example, all atoms with 6 protons in their nuclei are atoms of the chemical element carbon, and all atoms with 92 protons in their nuclei are atoms of the element uranium. However, several isotopes of an element, that differ from one another in the number of neutrons present in the nucleus, may exist.
The most convenient presentation of the chemical elements is in the periodic table of the chemical elements, which groups elements by atomic number. Due to its ingenious arrangement, groups, or columns, and periods, or rows, of elements in the table either share several chemical properties, or follow a certain trend in characteristics such as atomic radius, electronegativity, etc. Lists of the elements by name, by symbol, and by atomic number are also available.
## Compound
A compound is a substance with a particular ratio of atoms of particular chemical elements which determines its composition, and a particular organization which determines chemical properties. For example, water is a compound containing hydrogen and oxygen in the ratio of two to one, with the oxygen between the hydrogens, and an angle of 104.5° between them. Compounds are formed and interconverted by chemical reactions.
## Substance
A chemical substance is a kind of matter with a definite composition and set of properties. Strictly speaking, a mixture of compounds, elements or compounds and elements is not a chemical substance, but it may be called a chemical. Most of the substances we encounter in our daily life are some kind of mixture, e.g. air, alloys, biomass etc.
Nomenclature of substances is a critical part of the language of chemistry. Generally it refers to a system for naming chemical compounds. Earlier in the history of chemistry substances were given name by their discoverer, which often led to some confusion and difficulty. However, today the IUPAC system of chemical nomenclature allows chemists to specify by name specific compounds amongst the infinite variety of possible chemicals. The standard nomenclature of chemical substances is set by the International Union of Pure and Applied Chemistry (IUPAC). There are well-defined systems in place for naming chemical species. Organic compounds are named according to the organic nomenclature system.[25] Inorganic compounds are named according to the inorganic nomenclature system.[26] In addition the Chemical Abstracts Service has devised a method to index chemical substance. In this scheme each chemical substance is identifiable by a numeric number known as CAS registry number.
## Molecule
A molecule is the smallest indivisible portion, beside an atom, of a pure chemical substance that has its unique set of chemical properties, that is, its potential to undergo a certain set of chemical reactions with other substances. Molecules can exist as electrically neutral units unlike ions. Molecules are typically a set of atoms bound together by covalent bonds, such that the structure is electrically neutral and all valence electrons are paired with other electrons either in bonds or in lone pairs.
One of the main characteristic of a molecule is its geometry often called its structure. While the structure of diatomic, triatomic or tetra atomic molecules may be trivial, (linear, angular pyramidal etc.) the structure of polyatomic molecules, that are constituted of more than six atoms (of several elements) can be crucial for its chemical nature.
## Mole
A mole is the amount of a substance that contains as many elementary entities (atoms, molecules or ions) as there are atoms in 0.012 kilogram (or 12 grams) of carbon-12, where the carbon-12 atoms are unbound, at rest and in their ground state.[27] This number is known as the Avogadro constant, and is determined empirically. The currently accepted value is 6.02214179(30)Template:E mol-1 (2007 CODATA). It is much like the term "a dozen" in that it is an absolute number (having no units) and can describe any type of elementary object, although the mole's use is usually limited to measurement of subatomic, atomic, and molecular structures.
The number of moles of a substance in one liter of a solution is known as its molarity. Molarity is the common unit used to express the concentration of a solution in physical chemistry.
## Ions and salts
An ion is a charged species, an atom or a molecule, that has lost or gained one or more electrons. Positively charged cations (e.g. sodium cation Na+) and negatively charged anions (e.g. chloride Cl−) can form a crystalline lattice of neutral salts (e.g. sodium chloride NaCl). Examples of polyatomic ions that do not split up during acid-base reactions are hydroxide (OH−) and phosphate (PO43−).
Ions in the gaseous phase is often known as plasma.
## Phase
In addition to the specific chemical properties that distinguish different chemical classifications chemicals can exist in several phases. For the most part, the chemical classifications are independent of these bulk phase classifications; however, some more exotic phases are incompatible with certain chemical properties. A phase is a set of states of a chemical system that have similar bulk structural properties, over a range of conditions, such as pressure or temperature. Physical properties, such as density and refractive index tend to fall within values characteristic of the phase. The phase of matter is defined by the phase transition, which is when energy put into or taken out of the system goes into rearranging the structure of the system, instead of changing the bulk conditions.
Sometimes the distinction between phases can be continuous instead of having a discrete boundary, in this case the matter is considered to be in a supercritical state. When three states meet based on the conditions, it is known as a triple point and since this is invariant, it is a convenient way to define a set of conditions.
The most familiar examples of phases are solids, liquids, and gases. Many substances exhibit multiple solid phases. For example, there are three phases of solid iron (alpha, gamma, and delta) that vary based on temperature and pressure. A principal difference between solid phases is the crystal structure, or arrangement, of the atoms. Less familiar phases include plasmas, Bose-Einstein condensates and fermionic condensates and the paramagnetic and ferromagnetic phases of magnetic materials. While most familiar phases deal with three-dimensional systems, it is also possible to define analogs in two-dimensional systems, which has received attention for its relevance to systems in biology.
## Chemical bond
A chemical bond is a concept for understanding how atoms stick together in molecules. It may be visualized as the multipole balance between the positive charges in the nuclei and the negative charges oscillating about them.[28] More than simple attraction and repulsion, the energies and distributions characterize the availability of an electron to bond to another atom. These potentials create the interactions which holds together atoms in molecules or crystals. In many simple compounds, Valence Bond Theory, the Valence Shell Electron Pair Repulsion model (VSEPR), and the concept of oxidation number can be used to predict molecular structure and composition. Similarly, theories from classical physics can be used to predict many ionic structures. With more complicated compounds, such as metal complexes, valence bond theory fails and alternative approaches, primarily based on principles of quantum chemistry such as the molecular orbital theory, are necessary. See diagram on electronic orbitals.
## Chemical reaction
Chemical reaction is a concept related to the transformation of a chemical substance through its interaction with another, or as a result of its interaction with some form of energy. A chemical reaction may occur naturally or carried out in a laboratory by chemists in specially designed vessels which are often laboratory glassware. It can result in the formation or dissociation of molecules, that is, molecules breaking apart to form two or more smaller molecules, or rearrangement of atoms within or across molecules. Chemical reactions usually involve the making or breaking of chemical bonds. Oxidation, reduction, dissociation, acid-base neutralization and molecular rearrangement are some of the commonly used kinds of chemical reactions.
A chemical reaction can be symbolically depicted through a chemical equation. While in a non-nuclear chemical reaction the number and kind of atoms on both sides of the equation are equal, for a nuclear reaction this holds true only for the nuclear particles viz. protons and neutrons.[29]
The sequence of steps in which the reorganization of chemical bonds may be taking place in the course of a chemical reaction is called its mechanism. A chemical reaction can be envisioned to take place in a number of steps, each of which may have a different speed. Many reaction intermediates with variable stability can thus be envisaged during the course of a reaction. Reaction mechanisms are proposed to explain the kinetics and the relative product mix of a reaction. Many physical chemists specialize in exploring and proposing the mechanisms of various chemical reactions. Several empirical rules, like the Woodward-Hoffmann rules often come handy while proposing a mechanism for a chemical reaction.
A stricter definition is that "a chemical reaction is a process that results in the interconversion of chemical species".[30] Under this definition, a chemical reaction may be an elementary reaction or a stepwise reaction. An additional caveat is made, in that this definition includes cases where the interconversion of conformers is experimentally observable. Such detectable chemical reactions normally involve sets of molecular entities as indicated by this definition, but it is often conceptually convenient to use the term also for changes involving single molecular entities (i.e. 'microscopic chemical events').
## Energy
A chemical reaction is invariably accompanied by an increase or decrease of energy of the substances involved. Some energy is transferred between the surroundings and the reactants of the reaction in the form of heat or light, thus the products of a reaction may have more or less energy than the reactants. A reaction is said to be exothermic if the final state is lower on the energy scale than the initial state; in case of endothermic reactions the situation is otherwise.
Chemical reactions are invariably not possible unless the reactants surmount an energy barrier known as the activation energy. The speed of a chemical reaction (at given temperature T) is related to the activation energy E, by the Boltzmann's population factor <math>e^{-E/kT} </math> - that is the probability of molecule to have energy greater than or equal to E at the given temperature T. This exponential dependence of a reaction rate on temperature is known as the Arrhenius equation.
The activation energy necessary for a chemical reaction can be in the form of heat, light, electricity or mechanical force in the form of ultrasound.[31]
A related concept Free energy, which incorporates entropy considerations too, is a very useful means for predicting the feasibility of a reaction and determining the state of equilibrium of a chemical reaction, in chemical thermodynamics. A reaction is feasible only if the total change in the Gibbs free energy is negative, <math> \Delta G \le 0 \,</math>; if it is equal to zero the chemical reaction is said to be at equilibrium.
There are only a limited possible states of energy for electrons, atoms and molecules. These are determined by the rules of quantum mechanics, which require quantization of energy of a bound system. The atoms/molecules in an higher energy state are said to be excited. The molecules/atoms of substance in an excited energy state are often much more reactive, that is amenable to chemical reactions.
The phase of a substance is invariably determined by its energy and those of its surroundings. When the intermolecular forces of a substance are such that energy of the surroundings is not sufficient to overcome them, it occurs in a more ordered phase like liquid or solid as is the case with water (H2O), a liquid at room temperature because its molecules are bound by hydrogen bonds.[32] Whereas hydrogen sulfide (H2S) is a gas at room temperature and standard pressure, as its molecules are bound by weaker dipole-dipole interactions.
The transfer of energy from one chemical substance to other depend on the size of energy quanta emitted from one substance. However, heat energy is easily transferred from almost any substance to another mainly because the vibrational and rotational energy levels in a substance are very closely placed. Because, the electronic energy levels are not so closely spaced, ultraviolet electromagnetic radiation is not transferred with equal felicity, as is also the case with electrical energy.
The existence of characteristic energy levels for different chemical substances is useful for their identification by the analysis of spectral lines of different kinds of spectra often used in chemical spectroscopy e.g. IR, microwave, NMR, ESR etc. This is used to identify the composition of remote objects - like stars and far galaxies - by analyzing their radiation (see spectroscopy).
The term chemical energy is often used to indicate the potential of a chemical substance to undergo a transformation through a chemical reaction or transform other chemical substances.
## Chemical laws
Chemical reactions are governed by certain laws, which have become fundamental concepts in chemistry. Some of them are:
- Law of conservation of mass, according to the modern physics it is actually energy that is conserved, and that energy and mass are related; a concept which becomes important in nuclear chemistry.
- Law of conservation of Energy leads to the important concepts of equilibrium, thermodynamics, and kinetics.
- Law of definite composition, although in many systems (notably biomacromolecules and minerals) the ratios tend to require large numbers, and are frequently represented as a fraction.
- Law of multiple proportions
- Hess's Law
- Beer-Lambert law
- Fick's law of diffusion
- Raoult's Law
- Henry's law
- Boyle's law (1662, relating pressure and volume)
- Charles's law (1787, relating volume and temperature)
- Gay-Lussac's law (1809, relating pressure and temperature)
- Avogadro's law
# Subdisciplines
Chemistry is typically divided into several major sub-disciplines. There are also several main cross-disciplinary and more specialized fields of chemistry.[33]
- Analytical chemistry is the analysis of material samples to gain an understanding of their chemical composition and structure. Analytical chemistry incorporates standardized experimental methods in chemistry. These methods may be used in all subdisciplines of chemistry, excluding purely theoretical chemistry.
- Biochemistry is the study of the chemicals, chemical reactions and chemical interactions that take place in living organisms. Biochemistry and organic chemistry are closely related, as in medicinal chemistry or neurochemistry. Biochemistry is also associated with molecular biology and genetics.
- Inorganic chemistry is the study of the properties and reactions of inorganic compounds. The distinction between organic and inorganic disciplines is not absolute and there is much overlap, most importantly in the sub-discipline of organometallic chemistry.
- Materials chemistry is the preparation, characterization, and understanding of substances with a useful function. The field is a new breadth of study in graduate programs, and it integrates elements from all classical areas of chemistry with a focus on fundamental issues that are unique to materials. Primary systems of study include the chemistry of condensed phases (solids, liquids, polymers) and interfaces between different phases.
- Nuclear chemistry is the study of how subatomic particles come together and make nuclei. Modern Transmutation is a large component of nuclear chemistry, and the table of nuclides is an important result and tool for this field.
- Organic chemistry is the study of the structure, properties, composition, mechanisms, and reactions of organic compounds. An organic compound is defined as any compound based on a carbon skeleton.
- Physical chemistry is the study of the physical and fundamental basis of chemical systems and processes. In particular, the energetics and dynamics of such systems and processes are of interest to physical chemists. Important areas of study include chemical thermodynamics, chemical kinetics, electrochemistry, statistical mechanics, and spectroscopy. Physical chemistry has large overlap with molecular physics. Physical chemistry involves the use of calculus in deriving equations. It is usually associated with quantum chemistry and theoretical chemistry. Physical chemistry is a distinct discipline from chemical physics.
- Theoretical chemistry is the study of chemistry via fundamental theoretical reasoning (usually within mathematics or physics). In particular the application of quantum mechanics to chemistry is called quantum chemistry. Since the end of the Second World War, the development of computers has allowed a systematic development of computational chemistry, which is the art of developing and applying computer programs for solving chemical problems. Theoretical chemistry has large overlap with (theoretical and experimental) condensed matter physics and molecular physics.
Other fields include Astrochemistry, Atmospheric chemistry, Chemical Engineering, Chemical biology, Chemo-informatics, Electrochemistry, Environmental chemistry, Flow chemistry, Geochemistry, Green chemistry, History of chemistry, Materials science, Medicinal chemistry, Molecular Biology, Nanotechnology, Organometallic chemistry, Petrochemistry, Pharmacology, Photochemistry, Phytochemistry, Polymer chemistry, Solid-state chemistry, Sonochemistry, Supramolecular chemistry, Surface chemistry, Immunochemistry and Thermochemistry.
# Chemical industry
The chemical industry represents an important economic activity. The global top 50 chemical producers in 2004 had sales of 587 billion US dollars with a profit margin of 8.1% and research and development spending of 2.1% of total chemical sales.[34]
# Further reading
## Popular reading
- Atkins, P.W. Galileo's Finger (Oxford University Press) ISBN 0198609418
- Atkins, P.W. Atkins' Molecules (Cambridge University Press) ISBN 0521823978
- Stwertka, A. A Guide to the Elements (Oxford University Press) ISBN 0195150279
## Introductory undergraduate text books
- Chang, Raymond. Chemistry 6th ed. Boston: James M. Smith, 1998. ISBN 0-07-115221-0.
- Atkins, P.W., Overton, T., Rourke, J., Weller, M. and Armstrong, F. Shriver and Atkins inorganic chemistry (4th edition) 2006 (Oxford University Press) ISBN 0-19-926463-5
- Clayden, J., Greeves, N., Warren, S., Wothers, P. Organic Chemistry 2000 (Oxford University Press) ISBN 0-19-850346-6
- Voet and Voet Biochemistry (Wiley) ISBN 0-471-58651-X
## Advanced undergraduate-level or graduate text books
- Atkins, P.W. Physical Chemistry (Oxford University Press) ISBN 0-19-879285-9
- Atkins, P.W. et al. Molecular Quantum Mechanics (Oxford University Press)
- McWeeny, R. Coulson's Valence (Oxford Science Publications) ISBN 0-19-855144-4
- Pauling, L. The Nature of the chemical bond (Cornell University Press) ISBN 0-8014-0333-2
- Pauling, L., and Wilson, E. B. Introduction to Quantum Mechanics with Applications to Chemistry (Dover Publications) ISBN 0-486-64871-0
- Stephenson, G. Mathematical Methods for Science Students (Longman)ISBN 0-582-44416-0
- Smart and Moore Solid State Chemistry: An Introduction (Chapman and Hall) ISBN 0-412-40040-5
# Professional societies
- American Chemical Society
- Chemical Institute of Canada
- Chemical Society of Peru
- International Union of Pure and Applied Chemistry
- Royal Australian Chemical Institute
- Royal Society of Chemistry
- Society of Chemical Industry
- World Association of Theoretical and Computational Chemists | https://www.wikidoc.org/index.php/Chemistry | |
c7c6bc22b53ff4e17b72e96fc2a04b23203a4071 | wikidoc | Chemokine | Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Proteins are classified as chemokines according to shared structural characteristics such as small size (they are all approximately 8-10 kilodaltons in size), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. However, these proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines. Some chemokines are considered pro-inflammatory and can be induced during an immune response to promote cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development. Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been described for other invertebrates. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.
# Function
The major role of chemokines is to guide the migration of cells. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine. Some chemokines control cells of the immune system during processes of immune surveillance, such as directing lymphocytes to the lymph nodes so they can screen for invasion of pathogens by interacting with antigen-presenting cells residing in these tissues. These are known as homeostatic chemokines and are produced and secreted without any need to stimulate their source cell(s). Some chemokines have roles in development; they promote angiogenesis (the growth of new blood vessels), or guide cells to tissues that provide specific signals critical for cellular maturation. Other chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage such as silica or the urate crystals that occur in gout. Their release is often stimulated by pro-inflammatory cytokines such as interleukin 1. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system.
# Structural characteristics
Proteins are classified into the chemokine family based on their structural characteristics, not just their ability to attract cells. All chemokines are small, with a molecular mass of between 8 and 10 kDa. They are approximately 20-50% identical to each other; that is, they share gene sequence and amino acid sequence homology. They all also possess conserved amino acids that are important for creating their 3-dimensional or tertiary structure, such as (in most cases) four cysteines that interact with each other in pairs to create a Greek key shape that is a characteristic of chemokines. Intramolecular disulphide bonds typically join the first to third, and the second to fourth cysteine residues, numbered as they appear in the protein sequence of the chemokine. Typical chemokine proteins are produced as pro-peptides, beginning with a signal peptide of approximately 20 amino acids that gets cleaved from the active (mature) portion of the molecule during the process of its secretion from the cell. The first two cysteines, in a chemokine, are situated close together near the N-terminal end of the mature protein, with the third cysteine residing in the centre of the molecule and the fourth close to the C-terminal end. A loop of approximately ten amino acids follows the first two cysteines and is known as the N-loop. This is followed by a single-turn helix, called a 310-helix, three β-strands and a C-terminal α-helix. These helices and strands are connected by turns called 30s, 40s and 50s loops; the third and fourth cysteines are located in the 30s and 50s loops.
# Types
Members of the chemokine family are categorized into four groups depending on the spacing of their first two cysteine residues.
## CC chemokines
The CC chemokines (or β-chemokines) have two adjacent cysteines near their amino terminus. There have been at least 27 distinct members of this subgroup reported for mammals, called CC chemokine ligands (CCL)-1 to -28; CCL10 is the same as CCL9. Chemokines of this subfamily usually contain four cysteines (C4-CC chemokines), but a small number of CC chemokines possess six cysteines (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23 and CCL28. CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells. An example of a CC chemokine is monocyte chemoattractant protein-1 (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissue macrophages.
CC chemokines induce cellular migration by binding to and activating CC chemokine receptors, ten of which have been discovered to date and called CCR1-10. These receptors are expressed on the surface of different cell types allowing their specific attraction by the chemokines. A CC chemokine that attracts lymphocytes is CCL28, which is chemoattractant to T cells and B cells that express the chemokine receptor CCR10. This chemokine can also attract eosinophils that express CCR3. CCL5 (or RANTES) attracts cells such as T cells, eosinophils and basophils that express the receptor CCR5.
## CXC chemokines
The two N-terminal cysteines of CXC chemokines (or α-chemokines) are separated by one amino acid, represented in this name with an "X". There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with a specific amino acid sequence (or motif) of Glutamic acid-Leucine-Arginine (or ELR for short) immediately before the first cysteine of the CXC motif (ELR-positive), and those without an ELR motif (ELR-negative). ELR-positive CXC chemokines specifically induce the migration of neutrophils, and interact with chemokine receptors CXCR1 and CXCR2. An example of an ELR-positive CXC chemokine is interleukin-8 (IL-8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors, of which seven have been discovered to date, designated CXCR1-7.
## C chemokines
The third group of chemokines is known as the C chemokines (or γ chemokines), and is unlike all other chemokines in that it has only two cysteines; one N-terminal cysteine and one cysteine downstream. Two chemokines have been described for this subgroup and are called XCL1 (lymphotactin-α) and XCL2 (lymphotactin-β). These chemokines attract T cell precursors to the thymus.
## CX3C chemokines
A fourth group has also been discovered and members have three amino acids between the two cysteines and is termed CX3C chemokine (or δ-chemokines). The only CX3C chemokine discovered to date is called fractalkine (or CX3CL1). It is both secreted and tethered to the surface of the cell that expresses it, thereby serving as both a chemoattractant and as an adhesion molecule.
# Receptors
## Structure and Features
Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains that are found on the surface of leukocytes. Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on the type of chemokine they bind; CXCR that bind CXC chemokines, CCR that bind CC chemokines, CX3CR1 that binds the sole CX3C chemokine (CX3CL1), and XCR1 that binds the two XC chemokines (XCL1 and XCL2). They share many structural features; they are similar in size (with about 350 amino acids), have a short, acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has a conserved cysteine residue that allow formation of a disulphide bridge between these loops. G proteins are coupled to the C-terminal end of the chemokine receptor to allow intracellular signaling after receptor activation, while the N-terminal domain of the chemokine receptor determines ligand binding specificity.
## Signal Transduction
Chemokine receptors associate with G-proteins to transmit cell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of an enzyme known as phospholipase C (PLC). PLC cleaves a molecule called Phosphatidylinositol (4,5)-bisphosphate (PIP2) into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor.
# Infection control
The discovery that the β chemokines RANTES, MIP (Macrophage Inflammatory Proteins) 1α and 1β (now known as CCL5, CCL3 and CCL4 respectively) suppress HIV-1 provided the initial connection and indicated that these molecules might control infection as part of immune responses in vivo. The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in HIV infection, as well as with an uninfected status in subjects at risk for infection suggests a positive role for these molecules in controlling the natural course of HIV infection. | Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Proteins are classified as chemokines according to shared structural characteristics such as small size (they are all approximately 8-10 kilodaltons in size), and the presence of four cysteine residues in conserved locations that are key to forming their 3-dimensional shape. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. However, these proteins have historically been known under several other names including the SIS family of cytokines, SIG family of cytokines, SCY family of cytokines, Platelet factor-4 superfamily or intercrines. Some chemokines are considered pro-inflammatory and can be induced during an immune response to promote cells of the immune system to a site of infection, while others are considered homeostatic and are involved in controlling the migration of cells during normal processes of tissue maintenance or development. Chemokines are found in all vertebrates, some viruses and some bacteria, but none have been described for other invertebrates. These proteins exert their biological effects by interacting with G protein-linked transmembrane receptors called chemokine receptors, that are selectively found on the surfaces of their target cells.
# Function
The major role of chemokines is to guide the migration of cells. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration towards the source of the chemokine. Some chemokines control cells of the immune system during processes of immune surveillance, such as directing lymphocytes to the lymph nodes so they can screen for invasion of pathogens by interacting with antigen-presenting cells residing in these tissues. These are known as homeostatic chemokines and are produced and secreted without any need to stimulate their source cell(s). Some chemokines have roles in development; they promote angiogenesis (the growth of new blood vessels), or guide cells to tissues that provide specific signals critical for cellular maturation. Other chemokines are inflammatory and are released from a wide variety of cells in response to bacterial infection, viruses and agents that cause physical damage such as silica or the urate crystals that occur in gout. Their release is often stimulated by pro-inflammatory cytokines such as interleukin 1. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils and other effector cells from the blood to sites of infection or tissue damage. Certain inflammatory chemokines activate cells to initiate an immune response or promote wound healing. They are released by many different cell types and serve to guide cells of both innate immune system and adaptive immune system.
# Structural characteristics
Proteins are classified into the chemokine family based on their structural characteristics, not just their ability to attract cells. All chemokines are small, with a molecular mass of between 8 and 10 kDa. They are approximately 20-50% identical to each other; that is, they share gene sequence and amino acid sequence homology. They all also possess conserved amino acids that are important for creating their 3-dimensional or tertiary structure, such as (in most cases) four cysteines that interact with each other in pairs to create a Greek key shape that is a characteristic of chemokines. Intramolecular disulphide bonds typically join the first to third, and the second to fourth cysteine residues, numbered as they appear in the protein sequence of the chemokine. Typical chemokine proteins are produced as pro-peptides, beginning with a signal peptide of approximately 20 amino acids that gets cleaved from the active (mature) portion of the molecule during the process of its secretion from the cell. The first two cysteines, in a chemokine, are situated close together near the N-terminal end of the mature protein, with the third cysteine residing in the centre of the molecule and the fourth close to the C-terminal end. A loop of approximately ten amino acids follows the first two cysteines and is known as the N-loop. This is followed by a single-turn helix, called a 310-helix, three β-strands and a C-terminal α-helix. These helices and strands are connected by turns called 30s, 40s and 50s loops; the third and fourth cysteines are located in the 30s and 50s loops.[1]
# Types
Members of the chemokine family are categorized into four groups depending on the spacing of their first two cysteine residues.
## CC chemokines
The CC chemokines (or β-chemokines) have two adjacent cysteines near their amino terminus. There have been at least 27 distinct members of this subgroup reported for mammals, called CC chemokine ligands (CCL)-1 to -28; CCL10 is the same as CCL9. Chemokines of this subfamily usually contain four cysteines (C4-CC chemokines), but a small number of CC chemokines possess six cysteines (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23 and CCL28.[2] CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells. An example of a CC chemokine is monocyte chemoattractant protein-1 (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissue macrophages.
CC chemokines induce cellular migration by binding to and activating CC chemokine receptors, ten of which have been discovered to date and called CCR1-10. These receptors are expressed on the surface of different cell types allowing their specific attraction by the chemokines. A CC chemokine that attracts lymphocytes is CCL28, which is chemoattractant to T cells and B cells that express the chemokine receptor CCR10. This chemokine can also attract eosinophils that express CCR3. CCL5 (or RANTES) attracts cells such as T cells, eosinophils and basophils that express the receptor CCR5.
## CXC chemokines
The two N-terminal cysteines of CXC chemokines (or α-chemokines) are separated by one amino acid, represented in this name with an "X". There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with a specific amino acid sequence (or motif) of Glutamic acid-Leucine-Arginine (or ELR for short) immediately before the first cysteine of the CXC motif (ELR-positive), and those without an ELR motif (ELR-negative). ELR-positive CXC chemokines specifically induce the migration of neutrophils, and interact with chemokine receptors CXCR1 and CXCR2. An example of an ELR-positive CXC chemokine is interleukin-8 (IL-8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors, of which seven have been discovered to date, designated CXCR1-7.
## C chemokines
The third group of chemokines is known as the C chemokines (or γ chemokines), and is unlike all other chemokines in that it has only two cysteines; one N-terminal cysteine and one cysteine downstream. Two chemokines have been described for this subgroup and are called XCL1 (lymphotactin-α) and XCL2 (lymphotactin-β). These chemokines attract T cell precursors to the thymus.
## CX3C chemokines
A fourth group has also been discovered and members have three amino acids between the two cysteines and is termed CX3C chemokine (or δ-chemokines). The only CX3C chemokine discovered to date is called fractalkine (or CX3CL1). It is both secreted and tethered to the surface of the cell that expresses it, thereby serving as both a chemoattractant and as an adhesion molecule.
# Receptors
## Structure and Features
Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains that are found on the surface of leukocytes. Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on the type of chemokine they bind; CXCR that bind CXC chemokines, CCR that bind CC chemokines, CX3CR1 that binds the sole CX3C chemokine (CX3CL1), and XCR1 that binds the two XC chemokines (XCL1 and XCL2). They share many structural features; they are similar in size (with about 350 amino acids), have a short, acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has a conserved cysteine residue that allow formation of a disulphide bridge between these loops. G proteins are coupled to the C-terminal end of the chemokine receptor to allow intracellular signaling after receptor activation, while the N-terminal domain of the chemokine receptor determines ligand binding specificity.[3]
## Signal Transduction
Chemokine receptors associate with G-proteins to transmit cell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of an enzyme known as phospholipase C (PLC). PLC cleaves a molecule called Phosphatidylinositol (4,5)-bisphosphate (PIP2) into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor.[4]
# Infection control
The discovery that the β chemokines RANTES, MIP (Macrophage Inflammatory Proteins) 1α and 1β (now known as CCL5, CCL3 and CCL4 respectively) suppress HIV-1 provided the initial connection and indicated that these molecules might control infection as part of immune responses in vivo.[5] The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in HIV infection, as well as with an uninfected status in subjects at risk for infection suggests a positive role for these molecules in controlling the natural course of HIV infection.[6]
# External links
- IUPHAR GPCR Database - Chemokine Receptors
- List of chemokines and their receptors at nlm.nih.gov
- The cytokine family database - Chemokines at kumamoto-u.ac.jp
- The correct chemokine nomenclature at rndsystems.com | https://www.wikidoc.org/index.php/Chemokine | |
f5c7c9592b24a2ee9febc9151d616e36c4a75f68 | wikidoc | Chemostat | Chemostat
A chemostat (from Chemical environment is static) is a device used in microbiology for growing and harvesting microbes. It consists of two primary parts: a nutrient reservoir and a growth chamber. The most important feature of a chemostat is that all fermentation parameters; growth chamber volume, dissolved oxygen, nutrient concentrations, pH, cell density, etc, remain constant throughout the experiment.
Some sources of concern are:
- Foaming results in overflow with the volume of liquid not exactly constant
- Some very fragile cells are ruptured when caught between the magnetic stirring bar and the glass of the vessel. Suspending the stirring bar usually corrects this fault.
- Changing pumping rate by turning the pump on and off over short time periods may not work because cells respond to sudden changes by altering their rates. Very short intervals of on/off are alright.
- Bacteria travel upstream quite easily. They will reach the reservoir of sterile medium quickly unless the liquid path is interrupted by an air break in which the medium falls in drops through air.
The chemostat is typically used to gather steady state data about an organism in order to generate a mathematical model relating to its metabolic processes.
Chemostats are frequently used in the industrial manufacture of ethanol. In this case, several chemostats are used in series, each maintained at decreasing sugar concentrations. | Chemostat
A chemostat (from Chemical environment is static) is a device used in microbiology for growing and harvesting microbes. It consists of two primary parts: a nutrient reservoir and a growth chamber. The most important feature of a chemostat is that all fermentation parameters; growth chamber volume, dissolved oxygen, nutrient concentrations, pH, cell density, etc, remain constant throughout the experiment.
Some sources of concern are:
- Foaming results in overflow with the volume of liquid not exactly constant
- Some very fragile cells are ruptured when caught between the magnetic stirring bar and the glass of the vessel. Suspending the stirring bar usually corrects this fault.
- Changing pumping rate by turning the pump on and off over short time periods may not work because cells respond to sudden changes by altering their rates. Very short intervals of on/off are alright.
- Bacteria travel upstream quite easily. They will reach the reservoir of sterile medium quickly unless the liquid path is interrupted by an air break in which the medium falls in drops through air.
The chemostat is typically used to gather steady state data about an organism in order to generate a mathematical model relating to its metabolic processes.
Chemostats are frequently used in the industrial manufacture of ethanol. In this case, several chemostats are used in series, each maintained at decreasing sugar concentrations. | https://www.wikidoc.org/index.php/Chemostat | |
3665605a853666d865d35d6968fd672a8d1a7bf2 | wikidoc | Chenodiol | Chenodiol
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# Overview
Chenodiol is a bile acid that is FDA approved for the treatment of radiolucent gallstones. Common adverse reactions include Diarrhea, Increased liver aminotransferase level, abnormal lipid profile.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Chenodiol is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. The likelihood of successful dissolution is far greater if the stones are floatable or small. For patients with nonfloatable stones, dissolution is less likely and added weight should be given to the risk that more emergent surgery might result form a delay due to unsuccessful treatment. Safety of use beyond 24 months is not established. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.
### Dosage
- The recommended dose range for Chenodiol is 13 to 16 mg/kg/day in two divided doses, morning and night, starting with 250 mg b.i.d. the first two weeks and increasing by 250 mg/day each week thereafter until the recommended or maximum tolerated dose is reached. If diarrhea occurs during dosage buildup or later in treatment, it usually can be controlled by temporary dosage adjustment until symptoms abate, after which the previous dosage usually is tolerated. Dosage less than 10 mg/kg usually is ineffective and may be associated with increased risk of cholecystectomy, so is not recommended.
- The optimal frequency of monitoring liver function tests is not known. It is suggested that serum aminotransferase levels should be monitored monthly for the first three months and every three months thereafter during Chenodiol administration. Under NCGS guidelines, if a minor, usually transient elevations (1 ½ to3 three times the upper limit of normal) persisted longer than three to six months. Chenodiol was discontinued and resumed only after the aminotransferase level returned to normal; however, allowing the elevations to persist over such an interval is not know to be safe. Elevations over three times the upper limit of normal require immediate discontinuation of Chenodiol and usually reoccur on challenge.
- Serum cholesterol should be monitored at six months intervals. It may be advisable to discontinue Chenodiol if cholesterol rises above the acceptable age-adjusted limit for given patient.
- Oral cholecystograms or ultrasonograms are recommend at six to nine month intervals to monitor response. Complete dissolutions should be confirmed by a repeat test after one to three months continued Chenodiol administration. Most patients who eventually achieve complete dissolution will show partial (or complete) dissolution at the first on-treatment test. If partial dissolution is not seen by nine to 12 months, the likelihood of success of treating loner is greatly reduced; Chenodiol should be discontinued if there is no response by 18 months. Safety of use beyond 24 months is not established.
- Stone recurrence can be expected within five years in 50% of cases. After confirmed dissolution, treatment generally should be stopped. Serial cholecystograms or ultrasonograms are recommended to monitor for recurrence, keeping in mind that radiolucency and gallbladder function should be established before starting another course of Chenodiol. A prophylactic doses is not established; reduced doses cannot be recommended; stones have recurred on 500 mg/day. Low cholesterol or carbohydrate diets, and dietary bran, have been reported to reduce biliary cholesterol; maintenance of reduced weight is recommended to forestall stone recurrence.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Chenodiol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Chenodiol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Chenodiol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Chenodiol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Chenodiol in pediatric patients.
# Contraindications
- Chenodiol is contraindicated in the presence of know hepatocyte dysfunction or bile ductal abnormalities such as intrahepatic cholestasis, primary biliary cirrhosis or sclerosing cholangitits; a gallbladder confirmed as nonvisualizing after two consecutive single doses of dye; radiopaque stones; or gallstone complications or compelling reasons for gallbladder surgery including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary gastrointestinal fistula.
- Chenodiol may cause fetal harm when administered to a pregnant woman. Serious hepatic, renal and adrenal lesions occurred in fetuses of female Rhesus monkeys given 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose, MRHD) from day 21 to day 45 of pregnancy. Hepatic lesions also occurred in neonatal baboons whose mothers had received 18 to 38 mg/kg ( 1 to 2 times the MRHD), all during pregnancy. Fetal malformations were not observed. Neither fetal liver damage nor fetal abnormalities occurred in reproduction studies in rats and hamsters. No human data are available at this time. Chenodiol is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
# Warnings
- Safe use of chenodiol depends upon selection of patients without pre-existing liver disease and upon faithful monitoring of serum aminotransferase levels to detect drug-induced liver toxicity. Aminotransferase elevations over three times the upper limit of normal have required discontinuation of chenodiol in 2% to 3% of patients. Although clinical and biopsy studies have not shown fulminant lesions, the possibility remains that an occasional patient may develop serious hepatic disease. Three patients with biochemical and histologic pictures of chronic active hepatitis while on chenodiol, 375 mg/day or 750 mg/day, have been reported. The biochemical abnormalities returned spontaneously to normal in two of the patients within 13 and 17 months; and after 17 months’ treatment with prednisone in the third. Follow-up biopsies were not done; and the causal relationship of the drug could not be determined. Another biopsied patient was terminated from therapy because of elevated aminotransferase levels and a liver biopsy was interpreted as showing active drug hepatitis.
- One patient with sclerosing cholangitis, biliary cirrhosis and history of jaundice died during chenodiol treatment for hepatic duct stones. Before treatment, serum aminotransferase and alkaline phosphate levels were over twice the upper limit of normal; within one month they rose to over 10 time normal. Chenodiol was discontinued at seven weeks, when the patient was hospitalized with advanced hepatic failure and E. coli peritonitis; death ensued at the eight week. A contribution of chenodiol to the fatal outcome could not be ruled out.
- Epidemiologic studies suggest that bile acids might contribute to human colon cancer, but direct evidence is lacking. Bile acids, including chenodiol and lithocholic acid, have no carcinogenic potential in animal models, but have been shown to increase the number of tumors when administered with certain know carcinogens. The possibility that chenodiol therapy might contribute to colon cancer in otherwise susceptible individuals cannot be ruled out.
# Adverse Reactions
## Clinical Trials Experience
- Dose-related serum aminotransferase (mainly SGPT) elevations, usually not accompanied by rises in alkaline phosphatase or bilirubin, occurred in 30% or more of patients treated with the recommended dose of Chenodiol. In most cases, these elevations were minor (1 ½ to 3 times the upper limit of laboratory normal) and transient, returning to within the normal range within six months despite continued administration of the drug. In 2% to 3% of patients, SGPT levels rose to over three times the upper limit of laboratory normal, recurred on rechallenge with the drug, and required discontinuation of chenodiol treatment. Enzyme levels have returned to normal following withdrawal of chenodiol.
- Morphologic studies of liver biopsies taken before and after 9 and 24 months of treatment with chenodiol have shown that 63% of the patients prior to chenodiol treatment had evidence of intrahepatic cholestasis. Almost all pretreatment patients had electron microscopic abnormalities. By the ninth month of treatment, reexamination of two-thirds of the patients showed an 89% incidence of the signs of intrahepatic cholestasis. Two of 89 patients at the ninth month had lithocholate-like lesions in the canalicular membrane, although there were not clinical enzyme abnormalities in the face of continued treatment and no change in Type 2 light microscopic parameters.
- Increased Cholecystectomy Rate: NCGS patients with a history of biliary pain prior to treatment had higher cholecystectomy rates during the study if assigned to low dosage chenodiol (375 mg/day) than if assigned to either placebo or high dosage chenodiol (750 mg/day). The association with low dosage chenodiol though not clearly a causal one, suggests that patients unable to take higher doses of chenodiol may be at greater risk of cholecystectomy.
- Dose-related diarrhea has been encountered in 30% to 40% of chenodiol-treated patients and may occur at any time during treatment, but is most commonly encountered when treatment is initiated. Usually, the diarrhea is mild, translucent, well-tolerated and does not interfere with therapy. Dose reduction has been required in 10% to 15% of patients, and in a controlled trial about half of these required a permanent reduction in dose. Anti-diarrhea agents have proven useful in some patients.
- Discontinuation of chenodiol because of failure to control diarrhea is to be expected in approximately 3% of patients treated. Steady epigastric pain with nausea typical of lithiasis (biliary colic) usually is easily distinguishable from the crampy abdominal pain of drug-induced diarrhea.
- Other less frequent, gastrointestinal side effects reported include urgency, cramps, heartburn, constipation, nausea, and vomiting, anorexic, epigastric distress, dyspepsia, flatulence and nonspecific abdominal pain.
- Serum total cholesterol and low-density lipoprotein (LDL) cholesterol may rise 10% or more during administration of chenodiol: no change has been seen in the high-density lipoprotein (HDL) fraction; small decreases in serum triglyceride levels for females have been reported.
- Decreases in white cell count, never below 3000, have been noted in a few patients treated with chenodiol; the drug was continued in all patients without incident.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Chenodiol in the drug label.
# Drug Interactions
- Bile acid sequestering agents, such as cholestyramine and colestipol, may interfere with the action of Chenodiol by reducing its absorption. Aluminum-based antacids have been shown to absorb bile acids in vitro and may be expected to interfere with Chenodiol in the same manner as the sequestering agents. Estrogen, oral contraceptive and collaborate (and perhaps other lipid-lowering drugs) increase biliary cholesterol secretion, and the incidence of cholesterol gallstones hence may counteract the effectiveness of Chenodiol.
- Due to its hepatotoxicity, chenodiol can affect the pharmacodynamics of coumarin and its derivatives, causing unexpected prolongation of the prothrombin time and hemorrahages. Patients on concommitant therapy with chenodiol and coumarin or its derivatives should be monitored carefully. If prolongation of prothrombin time is observed, the coumarin dosage should be readjusted to give a prothrombin time 1½ to 2 times normal. If necessary chenodiol should be discontinued.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Chenodiol may cause fetal harm when administered to a pregnant woman. Serious hepatic, renal and adrenal lesions occurred in fetuses of female Rhesus monkeys given 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose, MRHD) from day 21 to day 45 of pregnancy. Hepatic lesions also occurred in neonatal baboons whose mothers had received 18 to 38 mg/kg ( 1 to 2 times the MRHD), all during pregnancy. Fetal malformations were not observed. Neither fetal liver damage nor fetal abnormalities occurred in reproduction studies in rats and hamsters. No human data are available at this time. Chenodiol is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chenodiol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Chenodiol during labor and delivery.
### Nursing Mothers
- It is not known whether chenodiol is excreted in human mild. Because many drugs are excreted in human milk, caution should be exercised when chenodiol is administered to a nursing mother.
### Pediatric Use
- The safety and effectiveness of chenodiol in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Chenodiol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Chenodiol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Chenodiol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Chenodiol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Chenodiol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Chenodiol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Chenodiol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Safe use of chenodiol depends upon selection of patients without pre-existing liver disease and upon faithful monitoring of serum aminotransferase levels to detect drug-induced liver toxicity.
- Patients should be counseled on the importance of periodic visits for liver function tests and oral cholecystograms (or ultrasonograms) for monitoring stone dissolution
# IV Compatibility
There is limited information regarding IV Compatibility of Chenodiol in the drug label.
# Overdosage
- Accidental or intentional overdoses of chenodiol have not been reported. One patient tolerated 4 gm/day (58 mg/kg/day) for six months without incident.
# Pharmacology
## Mechanism of Action
- At therapeutic doses, chenodiol suppresses hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid in an expanded bile acid pool. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones in the presence of a gall-bladder visualized by oral cholecystography. Chenodiol has no effect on radiopaque (calcified) gallstones or on radiolucent bile pigment stones.
## Structure
- Chenodiol is the non-proprietary name for chenodeoxycholic acid, a naturally occurring human bile acid. It is a bitter-tasting white powder consisting of crystalline and amorphous particles freely soluble in methanol, acetone and acetic acid and practically insoluble in water. Its chemical name is 3α, 7α-dihydroxy-5β-cholan-24-oic acid (C24H40O4), it has a molecular weight of 392.58, and its structure is shown below;
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Chenodiol in the drug label.
## Pharmacokinetics
- Chenodiol is well absorbed from the small intestine and taken up by the liver where it is converted to its taurine and glycine conjugates and secreted in bile. Owing to 60 % to 80% first-pass hepatic clearance, the body pool of chenodiol resides mainly in the enterohepatic circulation; serum and urinary bile acid levels are not significantly affected during chenodiol therapy.
- At steady-state, an amount of chenodiol near the daily dose escapes to the colon and is converted by bacterial action to lithocholic acid. About 80% of the lithocholate is excreted in the feces; the remainder is absorbed and converted in the liver to its poorly absorbed sulfolithocholyl conjugates. During chenodiol therapy there is only a minor increase in biliary lithocholate, while fecal bile acids are increased three- to fourfold.
- Chenodiol is unequivocally hepatotoxic in many animal species, including sub-human primates at doses close to the human dose. Although the theoretical cause is the metabolite, lithocholic acid, an established hepatotoxin, and man has an efficient mechanism for sulfating and eliminating this substance, there is some evidence that the demonstrated hepatotoxicity is partly due to chenodiol per se. The hepatotoxicity of lithocholic acid is characterized biochemically and morphologically as cholestatic.
- Man has the capacity to form sulfate conjugates of lithocholic acid. Variation in this capacity among individuals has not been well established and a recent published report suggests that patients who develop chenodiol-induced serum aminotransferase elevations are poor sulfators of lithocholic acid.
- General Clinical Results: Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In the National Cooperative Gallstone Study (NCGS) involving 305 patients in each treatment group, placebo and chenodiol dosages of 375 mg and 750 mg per day were associated with complete stone dissolution in 0.8%, 5.2% and 13.5%, respectively, of enrolled subjects over 24 months of treatment. Uncontrolled clinical trials using higher doses than those used in the NCGS have shown complete dissolution rates of 28 to 38% of enrolled patients receiving body weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than six months (n = 86) achieved complete confirmed dissolutions.
- Observed stone dissolution rates achieved with chenodiol treatment are higher in subgroups having certain pretreatment characteristics. In the NCGS, patients with small {less than 15 mm in diameter} radiolucent stones, the observed rate of complete dissolution was approximately 20% on 750 mg/day. In the uncontrolled trails using 13 to 16 mg/kg/day doses of chenodiol, the rates of complete dissolution for small radiolucent stones ranged from 42% to 60%. Even higher dissolution rates have been observed in patients with small floatable stones. (See Floatable versus Nonfloatable Stones, below). Some obese patients and occasional normal weight patients fail to achieve bile desaturation even with doses of chenodiol up to 19 mg/kg/day for unknown reasons. Although dissolution is generally higher with increased dosage of chenodiol, doses that are too low are associated with increased cholecystectomy rates.
- Stones have recurred within five years in about 50% of patients following complete confirmed dissolutions. Although retreatment with chenodiol has proven successful in dissolving some newly formed stones, the indications for and safety of retreatment are not well defined. Serum aminotransferase elevations and diarrhea have been notable in all clinical trials and are dose-related .
- Floatable versus Nonfloatable Stones; A major finding in clinical trials was a difference between floatable and nonfloatable stones, with respect to both natural history and response to chenodiol. Over the two-year course of the National Cooperative Gallstone Study (NCGS), placebo – treated patients with floatable stones (n = 47) had significantly higher rates of biliary pain and cholecystectomy than patients with nonfloatable stones (n = 258) (47% versus 27% and 19%versus 4%, respectively). Chenodiol treatment (750 mg/day) compared to placebo was associated with a significant reduction in both biliary pain and the cholecystectomy rates in the group with floatable stones (27% versus 47% and 1.5% versus 19%, respectively). In an uncontrolled clinical trial using 15 mg/kg/day, 70% of the patients with small (less than 15 mm) floatable stones (n = 10) had complete confirmed dissolution.
- In the NCGS in patients with nonfloatable stones, chenodiol produced no reduction in biliary pain and showed a tendency to increase the cholecystectomy rate (8% versus 4%). This finding was more pronounced with doses of chenodiol below 10 mg/kg. The subgroup of patients with nonfloatable stones and a history of biliary pain had the highest rates of cholecystectomy and aminotransferase elevations during chenodiol treatment. Except for the NCGS subgroup with pretreatment biliary pain, dose-related aminotransferase elevations and diarrhea have occurred with equal frequency in patients with floatable or nonfloatable stones. In the uncontrolled clinical trial mentioned above, 27% of the patients with nonfloatable stones (n = 59) had complete confirmed dissolutions, including 35% with small (less than 15 mm)(n= 40) and only 11% with large, nonfloatable stones (n= 19).
- Of 916 patients enrolled NCGS, 17.6% had stones seen in upright form (horizontal X-ray beam) to float in the dye-laden bile during oral cholecystography using iopanoic acid. Other investigators report similar findings. Floatable stones are not detected by ultrasonography in the absence for dye. Chemical analysis has shown floatable stones to be essentially pure cholesterol).
- Other Radiographic and Laboratory Features: Radiolucent stones may have rims or centers of opacity representing calcification. Pigment stones and partially calcified radiolucent stones do not respond to chenodiol. Subtle calcification can sometimes be detected in flat film X-rays, if not obvious in the oral cholecystogram. Among nonfloatable stones, cholesterol stones are more apt than pigment stones to be smooth surfaced, less than 0.5 cm in diameter, and to occur in numbers less than 10. As stone size number and volume increase, the probability of dissolution within 24 months decreases. Hemolytic disorders, chronic alcoholism, biliary cirrhosis and bacterial invasion of the biliary system predispose to pigment gallstone formation. Pigment stones of primary biliary cirrhosis should be suspected in patients with elevated alkaline phosphates, especially if positive anti-mitochondrial antibodies are present. The presence of microscopic cholesterol crystals in aspirated gallbladder bile, and demonstration of cholesterol super saturation by bile lipid analysis increase the likelihood that the stones are cholesterol stones.
- Evaluation of Surgical Risk; Surgery offers the advantage of immediate and permanent stone removal, but carries a fairly high risk. In some patients. About 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum to surgical risk varies as a function of age and the presence of disease other than cholelithiasis. Selected tabulation of results from the National Halothane Study (JAMA, 1968, 197:775-778) is shown below: the study included 27,600 cholecystectomies.
- Women in good health, or having only moderate systemic disease, under 49 years of age have the lowest rate (0.054%); men in all categories have a surgical mortality rate twice that of women; common duct exploration quadruples the rates in all categories; the rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.
- Relatively young patients requiring treatment might be better treated by surgery than with Chenodiol, because treatment with chenodiol, even if successful, is associated with a high rate of recurrence, The long-term consequences of repeated courses of chenodiol in terms of liver toxicity, neoplasia and elevated cholesterol levels are not know.
- Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of moderate to severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7% and 27%in five years. Presumably the rate is higher for patients already having symptoms.
## Nonclinical Toxicology
- A two-year oral study of chenodiol in rats failed to show a carcinogenic potential at the tested levels of 15 to 60 mg/kg/day (1 to 4 times the maximum recommended human dose, MRHD). It has been reported that chenodiol given in long-term studies at oral doses up to 600 mg/kg/day (40 times the MRHD) to rats and 1000 mg/kg/day (65 times the MRHD) to mice induced benign and malignant liver cell tumors in female rats and cholangiomata in female rats and male mice. Two-year studies of lithocholic acid ( a major metabolite of chenodiol) in mice (125 to 250 mg/kg/day) and rats (250 and 500 mg/kg/day) found it not to be carcinogenic. The dietary administration of Lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.
# Clinical Studies
There is limited information regarding Clinical Studies of Chenodiol in the drug label.
# How Supplied
- Chenodiol is available as white film-coated 250 mg tablets imprinted “MP” on one side and "250" on the other in bottles of 100, NDC 0722-7121-01.
## Storage
- Store at 20oC to 25oC (68oF to 77oF)
# Images
## Drug Images
## Package and Label Display Panel
### CARTON LABEL
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be counseled on the importance of periodic visits for liver function tests and oral cholecystograms (or ultrasonograms) for monitoring stone dissolution; they should be made aware of the symptoms of gallstone complications and be warned to report immediately such symptoms to the physician. Patients should be instructed on ways to facilitate faithful compliance with the dosage regimen throughout the usual long term of therapy, and on temporary doses reduction if episodes of diarrhea occur.
# Precautions with Alcohol
- Alcohol-Chenodiol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Chenodal®
# Look-Alike Drug Names
There is limited information regarding Chenodiol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Chenodiol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Overview
Chenodiol is a bile acid that is FDA approved for the treatment of radiolucent gallstones. Common adverse reactions include Diarrhea, Increased liver aminotransferase level, abnormal lipid profile.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Chenodiol is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. The likelihood of successful dissolution is far greater if the stones are floatable or small. For patients with nonfloatable stones, dissolution is less likely and added weight should be given to the risk that more emergent surgery might result form a delay due to unsuccessful treatment. Safety of use beyond 24 months is not established. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.
### Dosage
- The recommended dose range for Chenodiol is 13 to 16 mg/kg/day in two divided doses, morning and night, starting with 250 mg b.i.d. the first two weeks and increasing by 250 mg/day each week thereafter until the recommended or maximum tolerated dose is reached. If diarrhea occurs during dosage buildup or later in treatment, it usually can be controlled by temporary dosage adjustment until symptoms abate, after which the previous dosage usually is tolerated. Dosage less than 10 mg/kg usually is ineffective and may be associated with increased risk of cholecystectomy, so is not recommended.
- The optimal frequency of monitoring liver function tests is not known. It is suggested that serum aminotransferase levels should be monitored monthly for the first three months and every three months thereafter during Chenodiol administration. Under NCGS guidelines, if a minor, usually transient elevations (1 ½ to3 three times the upper limit of normal) persisted longer than three to six months. Chenodiol was discontinued and resumed only after the aminotransferase level returned to normal; however, allowing the elevations to persist over such an interval is not know to be safe. Elevations over three times the upper limit of normal require immediate discontinuation of Chenodiol and usually reoccur on challenge.
- Serum cholesterol should be monitored at six months intervals. It may be advisable to discontinue Chenodiol if cholesterol rises above the acceptable age-adjusted limit for given patient.
- Oral cholecystograms or ultrasonograms are recommend at six to nine month intervals to monitor response. Complete dissolutions should be confirmed by a repeat test after one to three months continued Chenodiol administration. Most patients who eventually achieve complete dissolution will show partial (or complete) dissolution at the first on-treatment test. If partial dissolution is not seen by nine to 12 months, the likelihood of success of treating loner is greatly reduced; Chenodiol should be discontinued if there is no response by 18 months. Safety of use beyond 24 months is not established.
- Stone recurrence can be expected within five years in 50% of cases. After confirmed dissolution, treatment generally should be stopped. Serial cholecystograms or ultrasonograms are recommended to monitor for recurrence, keeping in mind that radiolucency and gallbladder function should be established before starting another course of Chenodiol. A prophylactic doses is not established; reduced doses cannot be recommended; stones have recurred on 500 mg/day. Low cholesterol or carbohydrate diets, and dietary bran, have been reported to reduce biliary cholesterol; maintenance of reduced weight is recommended to forestall stone recurrence.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Chenodiol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Chenodiol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Chenodiol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Chenodiol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Chenodiol in pediatric patients.
# Contraindications
- Chenodiol is contraindicated in the presence of know hepatocyte dysfunction or bile ductal abnormalities such as intrahepatic cholestasis, primary biliary cirrhosis or sclerosing cholangitits; a gallbladder confirmed as nonvisualizing after two consecutive single doses of dye; radiopaque stones; or gallstone complications or compelling reasons for gallbladder surgery including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary gastrointestinal fistula.
- Chenodiol may cause fetal harm when administered to a pregnant woman. Serious hepatic, renal and adrenal lesions occurred in fetuses of female Rhesus monkeys given 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose, MRHD) from day 21 to day 45 of pregnancy. Hepatic lesions also occurred in neonatal baboons whose mothers had received 18 to 38 mg/kg ( 1 to 2 times the MRHD), all during pregnancy. Fetal malformations were not observed. Neither fetal liver damage nor fetal abnormalities occurred in reproduction studies in rats and hamsters. No human data are available at this time. Chenodiol is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
# Warnings
- Safe use of chenodiol depends upon selection of patients without pre-existing liver disease and upon faithful monitoring of serum aminotransferase levels to detect drug-induced liver toxicity. Aminotransferase elevations over three times the upper limit of normal have required discontinuation of chenodiol in 2% to 3% of patients. Although clinical and biopsy studies have not shown fulminant lesions, the possibility remains that an occasional patient may develop serious hepatic disease. Three patients with biochemical and histologic pictures of chronic active hepatitis while on chenodiol, 375 mg/day or 750 mg/day, have been reported. The biochemical abnormalities returned spontaneously to normal in two of the patients within 13 and 17 months; and after 17 months’ treatment with prednisone in the third. Follow-up biopsies were not done; and the causal relationship of the drug could not be determined. Another biopsied patient was terminated from therapy because of elevated aminotransferase levels and a liver biopsy was interpreted as showing active drug hepatitis.
- One patient with sclerosing cholangitis, biliary cirrhosis and history of jaundice died during chenodiol treatment for hepatic duct stones. Before treatment, serum aminotransferase and alkaline phosphate levels were over twice the upper limit of normal; within one month they rose to over 10 time normal. Chenodiol was discontinued at seven weeks, when the patient was hospitalized with advanced hepatic failure and E. coli peritonitis; death ensued at the eight week. A contribution of chenodiol to the fatal outcome could not be ruled out.
- Epidemiologic studies suggest that bile acids might contribute to human colon cancer, but direct evidence is lacking. Bile acids, including chenodiol and lithocholic acid, have no carcinogenic potential in animal models, but have been shown to increase the number of tumors when administered with certain know carcinogens. The possibility that chenodiol therapy might contribute to colon cancer in otherwise susceptible individuals cannot be ruled out.
# Adverse Reactions
## Clinical Trials Experience
- Dose-related serum aminotransferase (mainly SGPT) elevations, usually not accompanied by rises in alkaline phosphatase or bilirubin, occurred in 30% or more of patients treated with the recommended dose of Chenodiol. In most cases, these elevations were minor (1 ½ to 3 times the upper limit of laboratory normal) and transient, returning to within the normal range within six months despite continued administration of the drug. In 2% to 3% of patients, SGPT levels rose to over three times the upper limit of laboratory normal, recurred on rechallenge with the drug, and required discontinuation of chenodiol treatment. Enzyme levels have returned to normal following withdrawal of chenodiol.
- Morphologic studies of liver biopsies taken before and after 9 and 24 months of treatment with chenodiol have shown that 63% of the patients prior to chenodiol treatment had evidence of intrahepatic cholestasis. Almost all pretreatment patients had electron microscopic abnormalities. By the ninth month of treatment, reexamination of two-thirds of the patients showed an 89% incidence of the signs of intrahepatic cholestasis. Two of 89 patients at the ninth month had lithocholate-like lesions in the canalicular membrane, although there were not clinical enzyme abnormalities in the face of continued treatment and no change in Type 2 light microscopic parameters.
- Increased Cholecystectomy Rate: NCGS patients with a history of biliary pain prior to treatment had higher cholecystectomy rates during the study if assigned to low dosage chenodiol (375 mg/day) than if assigned to either placebo or high dosage chenodiol (750 mg/day). The association with low dosage chenodiol though not clearly a causal one, suggests that patients unable to take higher doses of chenodiol may be at greater risk of cholecystectomy.
- Dose-related diarrhea has been encountered in 30% to 40% of chenodiol-treated patients and may occur at any time during treatment, but is most commonly encountered when treatment is initiated. Usually, the diarrhea is mild, translucent, well-tolerated and does not interfere with therapy. Dose reduction has been required in 10% to 15% of patients, and in a controlled trial about half of these required a permanent reduction in dose. Anti-diarrhea agents have proven useful in some patients.
- Discontinuation of chenodiol because of failure to control diarrhea is to be expected in approximately 3% of patients treated. Steady epigastric pain with nausea typical of lithiasis (biliary colic) usually is easily distinguishable from the crampy abdominal pain of drug-induced diarrhea.
- Other less frequent, gastrointestinal side effects reported include urgency, cramps, heartburn, constipation, nausea, and vomiting, anorexic, epigastric distress, dyspepsia, flatulence and nonspecific abdominal pain.
- Serum total cholesterol and low-density lipoprotein (LDL) cholesterol may rise 10% or more during administration of chenodiol: no change has been seen in the high-density lipoprotein (HDL) fraction; small decreases in serum triglyceride levels for females have been reported.
- Decreases in white cell count, never below 3000, have been noted in a few patients treated with chenodiol; the drug was continued in all patients without incident.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Chenodiol in the drug label.
# Drug Interactions
- Bile acid sequestering agents, such as cholestyramine and colestipol, may interfere with the action of Chenodiol by reducing its absorption. Aluminum-based antacids have been shown to absorb bile acids in vitro and may be expected to interfere with Chenodiol in the same manner as the sequestering agents. Estrogen, oral contraceptive and collaborate (and perhaps other lipid-lowering drugs) increase biliary cholesterol secretion, and the incidence of cholesterol gallstones hence may counteract the effectiveness of Chenodiol.
- Due to its hepatotoxicity, chenodiol can affect the pharmacodynamics of coumarin and its derivatives, causing unexpected prolongation of the prothrombin time and hemorrahages. Patients on concommitant therapy with chenodiol and coumarin or its derivatives should be monitored carefully. If prolongation of prothrombin time is observed, the coumarin dosage should be readjusted to give a prothrombin time 1½ to 2 times normal. If necessary chenodiol should be discontinued.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Chenodiol may cause fetal harm when administered to a pregnant woman. Serious hepatic, renal and adrenal lesions occurred in fetuses of female Rhesus monkeys given 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose, MRHD) from day 21 to day 45 of pregnancy. Hepatic lesions also occurred in neonatal baboons whose mothers had received 18 to 38 mg/kg ( 1 to 2 times the MRHD), all during pregnancy. Fetal malformations were not observed. Neither fetal liver damage nor fetal abnormalities occurred in reproduction studies in rats and hamsters. No human data are available at this time. Chenodiol is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chenodiol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Chenodiol during labor and delivery.
### Nursing Mothers
- It is not known whether chenodiol is excreted in human mild. Because many drugs are excreted in human milk, caution should be exercised when chenodiol is administered to a nursing mother.
### Pediatric Use
- The safety and effectiveness of chenodiol in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Chenodiol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Chenodiol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Chenodiol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Chenodiol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Chenodiol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Chenodiol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Chenodiol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Safe use of chenodiol depends upon selection of patients without pre-existing liver disease and upon faithful monitoring of serum aminotransferase levels to detect drug-induced liver toxicity.
- Patients should be counseled on the importance of periodic visits for liver function tests and oral cholecystograms (or ultrasonograms) for monitoring stone dissolution
# IV Compatibility
There is limited information regarding IV Compatibility of Chenodiol in the drug label.
# Overdosage
- Accidental or intentional overdoses of chenodiol have not been reported. One patient tolerated 4 gm/day (58 mg/kg/day) for six months without incident.
# Pharmacology
## Mechanism of Action
- At therapeutic doses, chenodiol suppresses hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid in an expanded bile acid pool. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones in the presence of a gall-bladder visualized by oral cholecystography. Chenodiol has no effect on radiopaque (calcified) gallstones or on radiolucent bile pigment stones.
## Structure
- Chenodiol is the non-proprietary name for chenodeoxycholic acid, a naturally occurring human bile acid. It is a bitter-tasting white powder consisting of crystalline and amorphous particles freely soluble in methanol, acetone and acetic acid and practically insoluble in water. Its chemical name is 3α, 7α-dihydroxy-5β-cholan-24-oic acid (C24H40O4), it has a molecular weight of 392.58, and its structure is shown below;
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Chenodiol in the drug label.
## Pharmacokinetics
- Chenodiol is well absorbed from the small intestine and taken up by the liver where it is converted to its taurine and glycine conjugates and secreted in bile. Owing to 60 % to 80% first-pass hepatic clearance, the body pool of chenodiol resides mainly in the enterohepatic circulation; serum and urinary bile acid levels are not significantly affected during chenodiol therapy.
- At steady-state, an amount of chenodiol near the daily dose escapes to the colon and is converted by bacterial action to lithocholic acid. About 80% of the lithocholate is excreted in the feces; the remainder is absorbed and converted in the liver to its poorly absorbed sulfolithocholyl conjugates. During chenodiol therapy there is only a minor increase in biliary lithocholate, while fecal bile acids are increased three- to fourfold.
- Chenodiol is unequivocally hepatotoxic in many animal species, including sub-human primates at doses close to the human dose. Although the theoretical cause is the metabolite, lithocholic acid, an established hepatotoxin, and man has an efficient mechanism for sulfating and eliminating this substance, there is some evidence that the demonstrated hepatotoxicity is partly due to chenodiol per se. The hepatotoxicity of lithocholic acid is characterized biochemically and morphologically as cholestatic.
- Man has the capacity to form sulfate conjugates of lithocholic acid. Variation in this capacity among individuals has not been well established and a recent published report suggests that patients who develop chenodiol-induced serum aminotransferase elevations are poor sulfators of lithocholic acid.
- General Clinical Results: Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In the National Cooperative Gallstone Study (NCGS) involving 305 patients in each treatment group, placebo and chenodiol dosages of 375 mg and 750 mg per day were associated with complete stone dissolution in 0.8%, 5.2% and 13.5%, respectively, of enrolled subjects over 24 months of treatment. Uncontrolled clinical trials using higher doses than those used in the NCGS have shown complete dissolution rates of 28 to 38% of enrolled patients receiving body weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than six months (n = 86) achieved complete confirmed dissolutions.
- Observed stone dissolution rates achieved with chenodiol treatment are higher in subgroups having certain pretreatment characteristics. In the NCGS, patients with small {less than 15 mm in diameter} radiolucent stones, the observed rate of complete dissolution was approximately 20% on 750 mg/day. In the uncontrolled trails using 13 to 16 mg/kg/day doses of chenodiol, the rates of complete dissolution for small radiolucent stones ranged from 42% to 60%. Even higher dissolution rates have been observed in patients with small floatable stones. (See Floatable versus Nonfloatable Stones, below). Some obese patients and occasional normal weight patients fail to achieve bile desaturation even with doses of chenodiol up to 19 mg/kg/day for unknown reasons. Although dissolution is generally higher with increased dosage of chenodiol, doses that are too low are associated with increased cholecystectomy rates.
- Stones have recurred within five years in about 50% of patients following complete confirmed dissolutions. Although retreatment with chenodiol has proven successful in dissolving some newly formed stones, the indications for and safety of retreatment are not well defined. Serum aminotransferase elevations and diarrhea have been notable in all clinical trials and are dose-related .
- Floatable versus Nonfloatable Stones; A major finding in clinical trials was a difference between floatable and nonfloatable stones, with respect to both natural history and response to chenodiol. Over the two-year course of the National Cooperative Gallstone Study (NCGS), placebo – treated patients with floatable stones (n = 47) had significantly higher rates of biliary pain and cholecystectomy than patients with nonfloatable stones (n = 258) (47% versus 27% and 19%versus 4%, respectively). Chenodiol treatment (750 mg/day) compared to placebo was associated with a significant reduction in both biliary pain and the cholecystectomy rates in the group with floatable stones (27% versus 47% and 1.5% versus 19%, respectively). In an uncontrolled clinical trial using 15 mg/kg/day, 70% of the patients with small (less than 15 mm) floatable stones (n = 10) had complete confirmed dissolution.
- In the NCGS in patients with nonfloatable stones, chenodiol produced no reduction in biliary pain and showed a tendency to increase the cholecystectomy rate (8% versus 4%). This finding was more pronounced with doses of chenodiol below 10 mg/kg. The subgroup of patients with nonfloatable stones and a history of biliary pain had the highest rates of cholecystectomy and aminotransferase elevations during chenodiol treatment. Except for the NCGS subgroup with pretreatment biliary pain, dose-related aminotransferase elevations and diarrhea have occurred with equal frequency in patients with floatable or nonfloatable stones. In the uncontrolled clinical trial mentioned above, 27% of the patients with nonfloatable stones (n = 59) had complete confirmed dissolutions, including 35% with small (less than 15 mm)(n= 40) and only 11% with large, nonfloatable stones (n= 19).
- Of 916 patients enrolled NCGS, 17.6% had stones seen in upright form (horizontal X-ray beam) to float in the dye-laden bile during oral cholecystography using iopanoic acid. Other investigators report similar findings. Floatable stones are not detected by ultrasonography in the absence for dye. Chemical analysis has shown floatable stones to be essentially pure cholesterol).
- Other Radiographic and Laboratory Features: Radiolucent stones may have rims or centers of opacity representing calcification. Pigment stones and partially calcified radiolucent stones do not respond to chenodiol. Subtle calcification can sometimes be detected in flat film X-rays, if not obvious in the oral cholecystogram. Among nonfloatable stones, cholesterol stones are more apt than pigment stones to be smooth surfaced, less than 0.5 cm in diameter, and to occur in numbers less than 10. As stone size number and volume increase, the probability of dissolution within 24 months decreases. Hemolytic disorders, chronic alcoholism, biliary cirrhosis and bacterial invasion of the biliary system predispose to pigment gallstone formation. Pigment stones of primary biliary cirrhosis should be suspected in patients with elevated alkaline phosphates, especially if positive anti-mitochondrial antibodies are present. The presence of microscopic cholesterol crystals in aspirated gallbladder bile, and demonstration of cholesterol super saturation by bile lipid analysis increase the likelihood that the stones are cholesterol stones.
- Evaluation of Surgical Risk; Surgery offers the advantage of immediate and permanent stone removal, but carries a fairly high risk. In some patients. About 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum to surgical risk varies as a function of age and the presence of disease other than cholelithiasis. Selected tabulation of results from the National Halothane Study (JAMA, 1968, 197:775-778) is shown below: the study included 27,600 cholecystectomies.
- Women in good health, or having only moderate systemic disease, under 49 years of age have the lowest rate (0.054%); men in all categories have a surgical mortality rate twice that of women; common duct exploration quadruples the rates in all categories; the rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.
- Relatively young patients requiring treatment might be better treated by surgery than with Chenodiol, because treatment with chenodiol, even if successful, is associated with a high rate of recurrence, The long-term consequences of repeated courses of chenodiol in terms of liver toxicity, neoplasia and elevated cholesterol levels are not know.
- Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of moderate to severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7% and 27%in five years. Presumably the rate is higher for patients already having symptoms.
## Nonclinical Toxicology
- A two-year oral study of chenodiol in rats failed to show a carcinogenic potential at the tested levels of 15 to 60 mg/kg/day (1 to 4 times the maximum recommended human dose, MRHD). It has been reported that chenodiol given in long-term studies at oral doses up to 600 mg/kg/day (40 times the MRHD) to rats and 1000 mg/kg/day (65 times the MRHD) to mice induced benign and malignant liver cell tumors in female rats and cholangiomata in female rats and male mice. Two-year studies of lithocholic acid ( a major metabolite of chenodiol) in mice (125 to 250 mg/kg/day) and rats (250 and 500 mg/kg/day) found it not to be carcinogenic. The dietary administration of Lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.
# Clinical Studies
There is limited information regarding Clinical Studies of Chenodiol in the drug label.
# How Supplied
- Chenodiol is available as white film-coated 250 mg tablets imprinted “MP” on one side and "250" on the other in bottles of 100, NDC 0722-7121-01.
## Storage
- Store at 20oC to 25oC (68oF to 77oF)
# Images
## Drug Images
## Package and Label Display Panel
### CARTON LABEL
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be counseled on the importance of periodic visits for liver function tests and oral cholecystograms (or ultrasonograms) for monitoring stone dissolution; they should be made aware of the symptoms of gallstone complications and be warned to report immediately such symptoms to the physician. Patients should be instructed on ways to facilitate faithful compliance with the dosage regimen throughout the usual long term of therapy, and on temporary doses reduction if episodes of diarrhea occur.
# Precautions with Alcohol
- Alcohol-Chenodiol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Chenodal®[1]
# Look-Alike Drug Names
There is limited information regarding Chenodiol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Chenodiol | |
a17526f9a5af55529a2e77d927b2c59192bcabab | wikidoc | Cherubism | Cherubism
Cherubism is a rare genetic disorder that causes prominence in the lower portion in the face. The name is derived from the temporary chubby-cheeked resemblance to putti, often confused with cherubs, in Renaissance paintings.
# Presentation
The appearance of people with the disorder is caused by a loss of bone in the mandible which the body replaces with excessive amounts of tissue. In most cases, the condition fades as the child grows, but in a few even rarer cases the condition continues to deform the afflicted person's face. Also causes premature loss of the primary teeth and uneruption of the permanent teeth.
# Genetics
Mutations in the SH3BP2 gene have been identified in about 80 percent of people with cherubism. In most of the remaining cases, the genetic cause of the condition is unknown. The SH3BP2 gene provides instructions for making a protein whose exact function is unclear. The protein plays a role in transmitting chemical signals within cells, particularly cells involved in the replacement of old bone tissue with new bone (bone remodeling) and certain immune system cells.
Mutations in the SH3BP2 gene lead to the production of an overly active version of this protein. The effects of SH3BP2 mutations are still under study, but researchers believe that the abnormal protein disrupts critical signaling pathways in cells associated with the maintenance of bone tissue and in some immune system cells. The overactive protein likely causes inflammation in the jaw bones and triggers the production of osteoclasts, which are cells that break down bone tissue during bone remodeling. An excess of these bone-eating cells contributes to the destruction of bone in the upper and lower jaws. A combination of bone loss and inflammation likely underlies the cyst-like growths characteristic of cherubism.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. | Cherubism
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cherubism is a rare genetic disorder that causes prominence in the lower portion in the face. The name is derived from the temporary chubby-cheeked resemblance to putti, often confused with cherubs, in Renaissance paintings.
# Presentation
The appearance of people with the disorder is caused by a loss of bone in the mandible which the body replaces with excessive amounts of tissue. In most cases, the condition fades as the child grows, but in a few even rarer cases the condition continues to deform the afflicted person's face. Also causes premature loss of the primary teeth and uneruption of the permanent teeth.
# Genetics
Mutations in the SH3BP2 gene have been identified in about 80 percent of people with cherubism. In most of the remaining cases, the genetic cause of the condition is unknown. The SH3BP2 gene provides instructions for making a protein whose exact function is unclear. The protein plays a role in transmitting chemical signals within cells, particularly cells involved in the replacement of old bone tissue with new bone (bone remodeling) and certain immune system cells.
Mutations in the SH3BP2 gene lead to the production of an overly active version of this protein. The effects of SH3BP2 mutations are still under study, but researchers believe that the abnormal protein disrupts critical signaling pathways in cells associated with the maintenance of bone tissue and in some immune system cells. The overactive protein likely causes inflammation in the jaw bones and triggers the production of osteoclasts, which are cells that break down bone tissue during bone remodeling. An excess of these bone-eating cells contributes to the destruction of bone in the upper and lower jaws. A combination of bone loss and inflammation likely underlies the cyst-like growths characteristic of cherubism.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. | https://www.wikidoc.org/index.php/Cherubism | |
676e6c5d15a806c85576505eacbcf08200fd1db9 | wikidoc | Chitinase | Chitinase
Chitinases (chitodextrinase, 1,4-beta-poly-N-acetylglucosaminidase, poly-beta-glucosaminidase, beta-1,4-poly-N-acetyl glucosamidinase, poly glycanohydrolase, (1->4)-2-acetamido-2-deoxy-beta-D-glucan glycanohydrolase) are hydrolytic enzymes that break down glycosidic bonds in chitin.
As chitin is a component of the cell walls of fungi and exoskeletal elements of some animals (including worms and arthropods), chitinases are generally found in organisms that either need to reshape their own chitin or dissolve and digest the chitin of fungi or animals.
# Species distribution
Chitinivorous organisms include many bacteria (Aeromonads, Bacillus, Vibrio, among others), which may be pathogenic or detritivorous. They attack living arthropods, zooplankton or fungi or they may degrade the remains of these organisms.
Fungi, such as Coccidioides immitis, also possess degradative chitinases related to their role as detritivores and also to their potential as arthropod pathogens.
Chitinases are also present in plants (barley seed chitinase: PDB: 1CNS, EC 3.2.1.14); some of these are pathogenesis related (PR) proteins that are induced as part of systemic acquired resistance. Expression is mediated by the NPR1 gene and the salicylic acid pathway, both involved in resistance to fungal and insect attack. Other plant chitinases may be required for creating fungal symbioses.
Although mammals do not produce chitin, they have two functional chitinases, Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase), as well as chitinase-like proteins (such as YKL-40) that have high sequence similarity but lack chitinase activity.
# Classification
- Endochitinases (EC 3.2.1.14) randomly split chitin at internal sites of the chitin microfibril, forming soluble, low molecular mass multimer products. The multimer products includes di-acetylchitobiose, chitotriose, and chitotetraose, with the dimer being the predominant product.File:Endochitinase.pngEndochitinase breaking down chitin into multimer products.
- Exochitinases have also been divided into two sub categories:
Chitobiosidases (EC 3.2.1.29) act on the non-reducing end of the chitin microfibril, releasing the dimer, di-acetylchitobiose, one by one from the chitin chain. Therefore, there is no release of monosaccharides or oligosaccharides in this reaction.
β-1,4- N-acetylglucosaminidases (EC 3.2.1.30) split the multimer products, such as di-acetylchitobiose, chitotriose, and chitotetraose, into monomers of N-acetylglucoseamine (GlcNAc).
- Chitobiosidases (EC 3.2.1.29) act on the non-reducing end of the chitin microfibril, releasing the dimer, di-acetylchitobiose, one by one from the chitin chain. Therefore, there is no release of monosaccharides or oligosaccharides in this reaction.
- β-1,4- N-acetylglucosaminidases (EC 3.2.1.30) split the multimer products, such as di-acetylchitobiose, chitotriose, and chitotetraose, into monomers of N-acetylglucoseamine (GlcNAc).
Chitinases were also classified based on the amino acid sequences, as that would be more helpful in understanding the evolutionary relationships of these enzymes to each other. Therefore, the chitinases were grouped into three families: 18, 19, and 20. Both families 18 and 19 consists of endochitinases from a variety of different organisms, including viruses, bacteria, fungi, insect, and plants. However, family 19 mainly comprises plant chitinases. Family 20 includes N-acetylglucosaminidase and a similar enzyme, N-acetylhexosaminidase.
And as the gene sequences of the chitinases were known, they were further classified into six classes based on their sequences. Characteristics that determined the classes of chitinases were the N-terminal sequence, localization of the enzyme, isoelectric pH, signal peptide, and inducers.
Class I chitinases had a cysteine-rich N-terminal, leucine- or valine-rich signal peptide, and vacuolar localization. And then, Class I chitinases were further subdivided based on their acidic or basic nature into Class Ia and Class Ib, respectively. Class 1 chitinases were found to comprise only plant chitinases and mostly endochitinases.
Class II chitinases did not have the cysteine-rich N-terminal but had a similar sequence to Class I chitinases. Class II chitinases were found in plants, fungi, and bacteria and mostly consisted of exochitinases.
Class III chitinases did not have similar sequences to chitinases in Class I or Class II.
Class IV chitinases had similar characteristics, including the immunological properties, as Class I chitinases. However, Class IV chitinases were significantly smaller in size compared to Class I chitinases.
Class V and Class VI chitinases are not well characterized. However, one example of a Class V chitinase showed two chitin binding domains in tandem, and based on the gene sequence, the cysteine-rich N-terminal seemed to have been lost during evolution, probably due to less selection pressure that caused the catalytic domain to lose its function.
# Function
Like cellulose, chitin is an abundant biopolymer that is relatively resistant to degradation. It is typically not digested by animals, though certain fish are able to digest chitin. It is currently assumed that chitin digestion by animals requires bacterial symbionts and lengthy fermentations, similar to cellulase digestion by ruminants. Nevertheless, chitinases have been isolated from the stomachs of certain mammals, including humans.
Chitinase activity can also be detected in human blood and possibly cartilage. As in plant chitinases this may be related to pathogen resistance.
# Clinical significance
Chitinases produced in the human body (known as "human chitinases") may be related in response to allergies, and asthma has been linked to enhanced chitinase expression levels.
Human chitinases may explain the link between some of the most common allergies (dust mites, mold spores—both of which contain chitin) and worm (helminth) infections, as part of one version of the hygiene hypothesis (worms have chitinous mouthparts to hold the intestinal wall). Finally, the link between chitinases and salicylic acid in plants is well established—but there is a hypothetical link between salicylic acid and allergies in humans.
# Regulation in fungi
Regulation varies from species to species, and within an organism, chitinases with different physiological functions would be under different regulation mechanisms. For example, chitinases that are involved in maintenance, such as remodeling the cell wall, are constitutively expressed. However, chitinases that are involved in maintenance, such as remodeling the cell wall, are constitutively expressed. However, chitinases that have specialized functions, such as degrading exogenous chitin or participating in cell division, need spatio-temporal regulation of the chitinase activity.
The regulation of an endochitinase in Trichoderma atroviride is dependent on a N-acetylglucosaminidase, and the data indicates a feedback-loop where the break down of chitin produces N-acetylglucosamine, which would be possibly taken up and triggers up-regulation of the chitinbiosidases.
In Saccharomyces cerevisiae and the regulation of ScCts1p (S. cerevisiae chitinase 1), one of the chitinases involved in cell separation after cytokinesis by degrading the chitin of the primary septum. As these types of chitinases are important in cell division, there must be tight regulation and activation. Specifically, Cts1 expression has to be activated in daughter cells during late mitosis and the protein has to localize at the daughter site of the septum. And to do this, there must be coordination with other networks controlling the different phases of the cell, such as Cdc14 Early Anaphase Release (FEAR), mitotic exit network (MEN), and regulation of Ace2p (transcription factor) and cellular morphogenesis (RAM) signalling networks. Overall, the integration of the different regulatory networks allows for the cell wall degrading chitinase to function dependent on the cell's stage in the cell cycle and at specific locations among the daughter cells.
# Presence in food
Chitinases occur naturally in many common foods. Bananas, chestnuts, kiwis, avocados, papaya, and tomatoes, for example, all contain significant levels of chitinase, as defense against fungal and invertebrate attack. Stress, or environmental signals like ethylene gas, may stimulate increased production of chitinase.
Some parts of chitinase molecules, almost identical in structure to hevein or other proteins in rubber latex due to their similar function in plant defense, may trigger an allergic cross-reaction known as latex-fruit syndrome.
# Applications
Chitinases have a wealth of applications, some of which have already been realized by industry. This includes bio-conversion of chitin to useful products such as fertilizer, the production of non-allergenic, non-toxic, biocompatible, and biodegradable materials (contact lenses, artificial skin and sutures with these qualities are already being produced) and enhancement of insecticides and fungicides.
Possible future applications of chitinases are as food additives to increase shelf life, therapeutic agent for asthma and chronic rhinosinusitis, as an anti-fungal remedy, an anti-tumor drug and as a general ingredient to be used in protein engineering. | Chitinase
Chitinases (chitodextrinase, 1,4-beta-poly-N-acetylglucosaminidase, poly-beta-glucosaminidase, beta-1,4-poly-N-acetyl glucosamidinase, poly[1,4-(N-acetyl-beta-D-glucosaminide)] glycanohydrolase, (1->4)-2-acetamido-2-deoxy-beta-D-glucan glycanohydrolase) are hydrolytic enzymes that break down glycosidic bonds in chitin.[1]
As chitin is a component of the cell walls of fungi and exoskeletal elements of some animals (including worms and arthropods), chitinases are generally found in organisms that either need to reshape their own chitin[2] or dissolve and digest the chitin of fungi or animals.
# Species distribution
Chitinivorous organisms include many bacteria[3] (Aeromonads, Bacillus, Vibrio,[4] among others), which may be pathogenic or detritivorous. They attack living arthropods, zooplankton or fungi or they may degrade the remains of these organisms.
Fungi, such as Coccidioides immitis, also possess degradative chitinases related to their role as detritivores and also to their potential as arthropod pathogens.
Chitinases are also present in plants (barley seed chitinase: PDB: 1CNS, EC 3.2.1.14); some of these are pathogenesis related (PR) proteins that are induced as part of systemic acquired resistance. Expression is mediated by the NPR1 gene and the salicylic acid pathway, both involved in resistance to fungal and insect attack. Other plant chitinases may be required for creating fungal symbioses.[5]
Although mammals do not produce chitin, they have two functional chitinases, Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase), as well as chitinase-like proteins (such as YKL-40) that have high sequence similarity but lack chitinase activity.[6]
# Classification
- Endochitinases (EC 3.2.1.14) randomly split chitin at internal sites of the chitin microfibril, forming soluble, low molecular mass multimer products. The multimer products includes di-acetylchitobiose, chitotriose, and chitotetraose, with the dimer being the predominant product.[7]File:Endochitinase.pngEndochitinase breaking down chitin into multimer products.
- Exochitinases have also been divided into two sub categories:
Chitobiosidases (EC 3.2.1.29) act on the non-reducing end of the chitin microfibril, releasing the dimer, di-acetylchitobiose, one by one from the chitin chain. Therefore, there is no release of monosaccharides or oligosaccharides in this reaction.[8]
β-1,4- N-acetylglucosaminidases (EC 3.2.1.30) split the multimer products, such as di-acetylchitobiose, chitotriose, and chitotetraose, into monomers of N-acetylglucoseamine (GlcNAc).[7]
- Chitobiosidases (EC 3.2.1.29) act on the non-reducing end of the chitin microfibril, releasing the dimer, di-acetylchitobiose, one by one from the chitin chain. Therefore, there is no release of monosaccharides or oligosaccharides in this reaction.[8]
- β-1,4- N-acetylglucosaminidases (EC 3.2.1.30) split the multimer products, such as di-acetylchitobiose, chitotriose, and chitotetraose, into monomers of N-acetylglucoseamine (GlcNAc).[7]
Chitinases were also classified based on the amino acid sequences, as that would be more helpful in understanding the evolutionary relationships of these enzymes to each other.[9] Therefore, the chitinases were grouped into three families: 18, 19, and 20.[10] Both families 18 and 19 consists of endochitinases from a variety of different organisms, including viruses, bacteria, fungi, insect, and plants. However, family 19 mainly comprises plant chitinases. Family 20 includes N-acetylglucosaminidase and a similar enzyme, N-acetylhexosaminidase.[9]
And as the gene sequences of the chitinases were known, they were further classified into six classes based on their sequences. Characteristics that determined the classes of chitinases were the N-terminal sequence, localization of the enzyme, isoelectric pH, signal peptide, and inducers.[9]
Class I chitinases had a cysteine-rich N-terminal, leucine- or valine-rich signal peptide, and vacuolar localization. And then, Class I chitinases were further subdivided based on their acidic or basic nature into Class Ia and Class Ib, respectively.[11] Class 1 chitinases were found to comprise only plant chitinases and mostly endochitinases.
Class II chitinases did not have the cysteine-rich N-terminal but had a similar sequence to Class I chitinases. Class II chitinases were found in plants, fungi, and bacteria and mostly consisted of exochitinases.[9]
Class III chitinases did not have similar sequences to chitinases in Class I or Class II.[9]
Class IV chitinases had similar characteristics, including the immunological properties, as Class I chitinases.[9] However, Class IV chitinases were significantly smaller in size compared to Class I chitinases.[12]
Class V and Class VI chitinases are not well characterized. However, one example of a Class V chitinase showed two chitin binding domains in tandem, and based on the gene sequence, the cysteine-rich N-terminal seemed to have been lost during evolution, probably due to less selection pressure that caused the catalytic domain to lose its function.[9]
# Function
Like cellulose, chitin is an abundant biopolymer that is relatively resistant to degradation.[13] It is typically not digested by animals, though certain fish are able to digest chitin.[14] It is currently assumed that chitin digestion by animals requires bacterial symbionts and lengthy fermentations, similar to cellulase digestion by ruminants. Nevertheless, chitinases have been isolated from the stomachs of certain mammals, including humans.[15]
Chitinase activity can also be detected in human blood[16][17][17] and possibly cartilage.[18] As in plant chitinases this may be related to pathogen resistance.[19][20]
# Clinical significance
Chitinases produced in the human body (known as "human chitinases") may be related in response to allergies, and asthma has been linked to enhanced chitinase expression levels.[21][22][23][24][25]
Human chitinases may explain the link between some of the most common allergies (dust mites, mold spores—both of which contain chitin) and worm (helminth) infections, as part of one version of the hygiene hypothesis[26][27][28] (worms have chitinous mouthparts to hold the intestinal wall). Finally, the link between chitinases and salicylic acid in plants is well established[further explanation needed]—but there is a hypothetical link between salicylic acid and allergies in humans.[29]
# Regulation in fungi
Regulation varies from species to species, and within an organism, chitinases with different physiological functions would be under different regulation mechanisms. For example, chitinases that are involved in maintenance, such as remodeling the cell wall, are constitutively expressed. However, chitinases that are involved in maintenance, such as remodeling the cell wall, are constitutively expressed. However, chitinases that have specialized functions, such as degrading exogenous chitin or participating in cell division, need spatio-temporal regulation of the chitinase activity.[30]
The regulation of an endochitinase in Trichoderma atroviride is dependent on a N-acetylglucosaminidase, and the data indicates a feedback-loop where the break down of chitin produces N-acetylglucosamine, which would be possibly taken up and triggers up-regulation of the chitinbiosidases.[31]
In Saccharomyces cerevisiae and the regulation of ScCts1p (S. cerevisiae chitinase 1), one of the chitinases involved in cell separation after cytokinesis by degrading the chitin of the primary septum.[32] As these types of chitinases are important in cell division, there must be tight regulation and activation. Specifically, Cts1 expression has to be activated in daughter cells during late mitosis and the protein has to localize at the daughter site of the septum.[33] And to do this, there must be coordination with other networks controlling the different phases of the cell, such as Cdc14 Early Anaphase Release (FEAR), mitotic exit network (MEN), and regulation of Ace2p (transcription factor) and cellular morphogenesis (RAM)[34] signalling networks. Overall, the integration of the different regulatory networks allows for the cell wall degrading chitinase to function dependent on the cell's stage in the cell cycle and at specific locations among the daughter cells.[30]
# Presence in food
Chitinases occur naturally in many common foods. Bananas, chestnuts, kiwis, avocados, papaya, and tomatoes, for example, all contain significant levels of chitinase, as defense against fungal and invertebrate attack. Stress, or environmental signals like ethylene gas, may stimulate increased production of chitinase.
Some parts of chitinase molecules, almost identical in structure to hevein or other proteins in rubber latex due to their similar function in plant defense, may trigger an allergic cross-reaction known as latex-fruit syndrome.[35]
# Applications
Chitinases have a wealth of applications, some of which have already been realized by industry. This includes bio-conversion of chitin to useful products such as fertilizer, the production of non-allergenic, non-toxic, biocompatible, and biodegradable materials (contact lenses, artificial skin and sutures with these qualities are already being produced) and enhancement of insecticides and fungicides.[36]
Possible future applications of chitinases are as food additives to increase shelf life, therapeutic agent for asthma and chronic rhinosinusitis, as an anti-fungal remedy, an anti-tumor drug and as a general ingredient to be used in protein engineering.[36] | https://www.wikidoc.org/index.php/Chitinase | |
4b77e247e2dc08fec68da3227247907ea9e1e010 | wikidoc | Cordotomy | Cordotomy
Cordotomy (or chordotomy) is a surgical procedure that disables selected pain-conducting tracts in the spinal cord, in order to achieve loss of pain and temperature perception. This procedure is commonly performed on patients experiencing severe pain due to cancer or other diseases for which there are currently no cure. Anterolateral cordotomy is effective for relieving unilateral, somatic pain while bilateral cordotomies may be required for visceral or bilateral pain.
Cordotomy is usually done percutaneously with fluoroscopic guidance while the patient is under local anesthesia. Open cordotomy, which requires a laminectomy, is often risky for patients with poor medical conditions, but may be required if percutaneous cordotomy is not feasible or an attempt has failed.
Cordotomy is now used exclusively for pain due to cancer where treatment to level 3 of the World Health Organisation analgesic ladder has proved ineffective. Cordotomy is especially indicated for pain due to mesothelioma (asbestos-related lung cancer).
A number of alternative surgical procedures have evolved in the 20th century; these include:
"Commissural myelotomy", with limited rostro-caudal range; it produces bilateral analgesia (Armour 1927; Hitchcock 1970; 74).
"Limited midline myelotomy" for the treatment of pelvic visceral cancer pain (Gildenberg and Hirshberg, 1984).
Recently, Dr. Elie D. Al-Chaer and his colleagues discovered a new pathway in the spinal cord relatively specific for visceral pain - the pain that originates from visceral organs such as the colon, the bladder and the pancreas. The new pathway is located in the posterior columns, traditionally believed to mediate light touch and kinesthesia. This discovery led to a paradigm shift in our understanding of pain pathways and in the approach to treat intractable visceral pain. As a result, "punctate midline myelotomy" was introduced around the world as a new surgical procedure for the treatment of visceral pain residual to cancer and refractory to conventional treatment. | Cordotomy
Template:Interventions infobox
Cordotomy (or chordotomy) is a surgical procedure that disables selected pain-conducting tracts in the spinal cord, in order to achieve loss of pain and temperature perception. This procedure is commonly performed on patients experiencing severe pain due to cancer or other diseases for which there are currently no cure. Anterolateral cordotomy is effective for relieving unilateral, somatic pain while bilateral cordotomies may be required for visceral or bilateral pain.
Cordotomy is usually done percutaneously with fluoroscopic guidance while the patient is under local anesthesia. Open cordotomy, which requires a laminectomy, is often risky for patients with poor medical conditions, but may be required if percutaneous cordotomy is not feasible or an attempt has failed.
Cordotomy is now used exclusively for pain due to cancer where treatment to level 3 of the World Health Organisation analgesic ladder has proved ineffective. Cordotomy is especially indicated for pain due to mesothelioma (asbestos-related lung cancer).
A number of alternative surgical procedures have evolved in the 20th century; these include:
"Commissural myelotomy", with limited rostro-caudal range; it produces bilateral analgesia (Armour 1927; Hitchcock 1970; 74).
"Limited midline myelotomy" for the treatment of pelvic visceral cancer pain (Gildenberg and Hirshberg, 1984).
Recently, Dr. Elie D. Al-Chaer and his colleagues discovered a new pathway in the spinal cord relatively specific for visceral pain - the pain that originates from visceral organs such as the colon, the bladder and the pancreas. The new pathway is located in the posterior columns, traditionally believed to mediate light touch and kinesthesia. This discovery led to a paradigm shift in our understanding of pain pathways and in the approach to treat intractable visceral pain. As a result, "punctate midline myelotomy" was introduced around the world as a new surgical procedure for the treatment of visceral pain residual to cancer and refractory to conventional treatment.
# External links
• Al-Chaer ED et al. A role for the dorsal column in nociceptive visceral input into the thalamus of primates. J Neurophysiol. 1998 Jun;79(6):3143-50
• Laboratory of Elie D. Al-Chaer for the Study of Pain
• Science News Online (2/13/99): Pain, Pain, Go Away
Template:Neurosurgical procedures
Template:Surgery-stub | https://www.wikidoc.org/index.php/Chordotomy | |
2edc9c3d95d95503178209e2e122b865c387903a | wikidoc | Factor IX | Factor IX
Factor IX (or Christmas factor) (EC 3.4.21.22) is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to haemophilia.
Factor IX complex is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.
# Physiology
Factor IX is produced as a zymogen, an inactive precursor. It is processed to remove the signal peptide, glycosylated and then cleaved by factor XIa (of the contact pathway) or factor VIIa (of the tissue factor pathway) to produce a two-chain form where the chains are linked by a disulfide bridge. When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine-isoleucine bond in factor X to form factor Xa.
Factor IX is inhibited by antithrombin.
Factor IX expression increases with age in humans and mice. In mouse models mutations within the promoter region of factor IX have an age-dependent phenotype.
# Domain architecture
Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture. The factor IX protein is composed of four protein domains: the Gla domain, two tandem copies of the EGF domain and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.
The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor. Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex.
The structures of all four domains have been solved. A structure of the two EGF domains and the trypsin-like domain was determined for the pig protein. The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.
Several structures of 'super active' mutants have been solved, which reveal the nature of factor IX activation by other proteins in the clotting cascade.
# Genetics
The gene for factor IX is located on the X chromosome (Xq27.1-q27.2) and is therefore X-linked recessive: mutations in this gene affect males much more frequently than females. It was first cloned in 1982 by Kotoku Kurachi and Earl Davie.
Polly, a transgenic cloned Poll Dorset sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut at the Roslin Institute in 1997.
# Role in disease
Deficiency of factor IX causes Christmas disease (hemophilia B). Over 100 mutations of factor IX have been described; some cause no symptoms, but many lead to a significant bleeding disorder. The original Christmas disease mutation was identified by sequencing of Christmas' DNA, revealing a mutation which changed a cysteine to a serine.
Recombinant factor IX is used to treat Christmas disease. Formulations include:
- nonacog alfa (trade name BeneFix)
- albutrepenonacog alfa (trade name Idelvion)
- eftrenonacog alfa (trade name Alprolix)
Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis.
Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. Tranexamic acid may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.
A list of all the mutations in Factor IX is compiled and maintained at the Factor IX mutation database maintained at the University College London. | Factor IX
Factor IX (or Christmas factor) (EC 3.4.21.22) is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to haemophilia.[1]
Factor IX complex is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[2]
# Physiology
Factor IX is produced as a zymogen, an inactive precursor. It is processed to remove the signal peptide, glycosylated and then cleaved by factor XIa (of the contact pathway) or factor VIIa (of the tissue factor pathway) to produce a two-chain form where the chains are linked by a disulfide bridge.[3][4] When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine-isoleucine bond in factor X to form factor Xa.
Factor IX is inhibited by antithrombin.[3]
Factor IX expression increases with age in humans and mice. In mouse models mutations within the promoter region of factor IX have an age-dependent phenotype.[5]
# Domain architecture
Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture.[6] The factor IX protein is composed of four protein domains: the Gla domain, two tandem copies of the EGF domain and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.
The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor.[6] Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex.[7]
The structures of all four domains have been solved. A structure of the two EGF domains and the trypsin-like domain was determined for the pig protein.[8] The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR.[9]
Several structures of 'super active' mutants have been solved,[10] which reveal the nature of factor IX activation by other proteins in the clotting cascade.
# Genetics
The gene for factor IX is located on the X chromosome (Xq27.1-q27.2) and is therefore X-linked recessive: mutations in this gene affect males much more frequently than females. It was first cloned in 1982 by Kotoku Kurachi and Earl Davie.[11]
Polly, a transgenic cloned Poll Dorset sheep carrying the gene for factor IX, was produced by Dr Ian Wilmut at the Roslin Institute in 1997.[12]
# Role in disease
Deficiency of factor IX causes Christmas disease (hemophilia B).[1] Over 100 mutations of factor IX have been described; some cause no symptoms, but many lead to a significant bleeding disorder. The original Christmas disease mutation was identified by sequencing of Christmas' DNA, revealing a mutation which changed a cysteine to a serine.[13]
Recombinant factor IX is used to treat Christmas disease. Formulations include:
- nonacog alfa (trade name BeneFix)[14]
- albutrepenonacog alfa (trade name Idelvion)[15]
- eftrenonacog alfa (trade name Alprolix)[16]
Some rare mutations of factor IX result in elevated clotting activity, and can result in clotting diseases, such as deep vein thrombosis.[17]
Factor IX deficiency is treated by injection of purified factor IX produced through cloning in various animal or animal cell vectors. Tranexamic acid may be of value in patients undergoing surgery who have inherited factor IX deficiency in order to reduce the perioperative risk of bleeding.[18]
A list of all the mutations in Factor IX is compiled and maintained at the Factor IX mutation database[19] maintained at the University College London. | https://www.wikidoc.org/index.php/Christmas_factor | |
a8fdf313b5a48d6f6e17009a871612d3f73647cc | wikidoc | Chromatid | Chromatid
A chromatid is one of two identical copies of DNA making up a chromosome that are joined at their centromeres, for the process of nuclear division (mitosis or meiosis). The term is used so long as the centromeres remain in contact. When they separate (during anaphase of mitosis and anaphase 2 of meiosis), the strands are called daughter-chromosomes. The tips of the chromatid are called telomeres. They are there to prevent the ends of the chromosome from attaching to other chromosomes. It has been said that after repeated cell replication, the telomeres get shorter resulting in cell death. This means that the way telomeres work could determine the lifespan of a cell. However this has not been proven.
In other words, a chromatid is "one-half of a replicated chromosome". It should not be confused with the ploidy of an organism, which is the number of homologous versions of a chromosome.
# Quantity
In humans, for example, there are normally 23 pairs of chromosomes in each cell. N=23. However, the quantity of chromatids is various 46. It can be either 4N, 2N or 1N. The latter is only seen in haploid gametes, with only one of each homologous chromosome pair. Such are created in gametogenesis.
## 4N
In a cell with 4N chromatids, there are 23 chromosome pairs (46 chromosomes), and each chromosome has 2 chromatids. Thus, there are 92 chromatids in each cell (4xN) which occurs during anaphase 2 of meiosis.
## 2N
Immediately after a mitosis, where a cell has divided in two, but not yet duplicated its DNA, there are still 23 chromosome pairs (46 chromosomes). However, each chromosome only has one chromatid. Thus there are 46 chromatids (2xN)
Alternatively, a haploid cell with two chromatids per chromosome also has 46 chromatids. However, this doesn't occur naturally in humans.
## 1N
Immediately after meiosis, each cell, called a gamete, only has half the amount of chromosomes (23 chromosomes). Furthermore, each chromosome only has one chromatid. Thus, there are 23 chromatids (1xN)
# Etymology
The term chromatid was proposed by McClung (1900) for each of the four threads making up a chromosome-pair during meiosis. It was later used also for mitosis.
The term derives from the Greek chroma (colour); for the derivation of -id, see diploid. | Chromatid
A chromatid is one of two identical copies of DNA making up a chromosome that are joined at their centromeres, for the process of nuclear division (mitosis or meiosis). The term is used so long as the centromeres remain in contact. When they separate (during anaphase of mitosis and anaphase 2 of meiosis), the strands are called daughter-chromosomes. The tips of the chromatid are called telomeres. They are there to prevent the ends of the chromosome from attaching to other chromosomes. It has been said that after repeated cell replication, the telomeres get shorter resulting in cell death. This means that the way telomeres work could determine the lifespan of a cell. However this has not been proven.[1]
In other words, a chromatid is "one-half of a replicated chromosome".[2] It should not be confused with the ploidy of an organism, which is the number of homologous versions of a chromosome.
# Quantity
In humans, for example, there are normally 23 pairs of chromosomes in each cell. N=23. However, the quantity of chromatids is various 46. It can be either 4N, 2N or 1N. The latter is only seen in haploid gametes, with only one of each homologous chromosome pair. Such are created in gametogenesis.
## 4N
In a cell with 4N chromatids, there are 23 chromosome pairs (46 chromosomes), and each chromosome has 2 chromatids. Thus, there are 92 chromatids in each cell (4xN) which occurs during anaphase 2 of meiosis.
## 2N
Immediately after a mitosis, where a cell has divided in two, but not yet duplicated its DNA, there are still 23 chromosome pairs (46 chromosomes). However, each chromosome only has one chromatid. Thus there are 46 chromatids (2xN)
Alternatively, a haploid cell with two chromatids per chromosome also has 46 chromatids. However, this doesn't occur naturally in humans.
## 1N
Immediately after meiosis, each cell, called a gamete, only has half the amount of chromosomes (23 chromosomes). Furthermore, each chromosome only has one chromatid. Thus, there are 23 chromatids (1xN)
# Etymology
The term chromatid was proposed by McClung (1900) for each of the four threads making up a chromosome-pair during meiosis. It was later used also for mitosis.
The term derives from the Greek chroma (colour); for the derivation of -id, see diploid. | https://www.wikidoc.org/index.php/Chromatid | |
5504bd495672cacebe59b3f07719cad6213f9ccb | wikidoc | Chromatin | Chromatin
Chromatin is the complex combination of DNA, RNA, and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells, and within the nucleoid in prokaryotic cells. It is divided between heterochromatin (condensed) and euchromatin (extended) forms.
The major components of chromatin are DNA and histone proteins, although many other chromosomal proteins have prominent roles too. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. Chromatin contains genetic material-instructions to direct cell functions. Changes in chromatin structure are affected by chemical modifications of histone proteins such as methylation (DNA and proteins) and acetylation (proteins), and by non-histone, DNA-binding proteins.
Chromatin is easily visualised by staining, hence its name, which literally means coloured,lightend material.
# Basic Structure
Simplistically, there are seven levels of chromatin organization (Fig. 1):
- DNA wrapping around nucleosomes - The "beads on a string" structure.
- A 30 nm condensed chromatin fiber consisting of nucleosome arrays in their most compact form.
- Higher level DNA packaging into the metaphase chromosome....
These structures do not occur in all reem prokaryotic cells. Examples of cells with more extreme packaging are spermatozoa and avian red blood cells.
During spermiogenesis, the spermatid's chromatin is remodelled into a more spaced packaged, widened, almost crystal-like structure. This process is associated with the cessation of transcription and involves nuclear protein exchange. The histones are mostly displaced, and replaced by protamines (small, arginine-rich proteins). To put it simply, chromotins are the building blocks of proteins.
It should also be noted that during mitosis, while most of the chromatin is tightly compacted, there are small regions that are not as tightly compacted. These regions often correspond to promoter regions of genes that were active in that cell type prior to entry into cromitosis. The lack of compaction of these regiongs is called bookmarking, which is an epigenetic mechanism believed to be important for transmitting to daughter cells the "memory" of which genes were active prior to entry into mitosis. This bookmarking mechanism is needed to help transmit this memory because transcription ceases during mitosis.
It is found in a plant cell.
# Levels of organization
# During interphase
The structure of chromatin during interphase is optimised to allow easy access of transcription and DNA repair factors to the DNA while compacting the DNA into the nucleus. The structure varies depending on the access required to the DNA. Genes that require regular access by RNA polymerase require the looser structure provided by euchromatin.
# Change in structure
Chromatin undergoes various forms of change in its structure. Histone proteins, the foundation blocks of chromatin, are modified by various post-translational modification to alter DNA packing. Acetylation results in the loosening of chromatin and lends itself to replication and transcription. When methylated they hold DNA together strongly and restrict access to various enzymes. A recent study showed that there is a bivalent structure present in the chromatin: methylated lysine residues at location 4 and 27 on histone 3. It is thought that this may be involved in development; there is more methylation of lysine 27 in embryonic cells than in differentiated cells, whereas lysine 4 methylation positively regulates transcription by recruiting nucleosome remodeling enzymes and histone acetylases.
Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure.
For additional information see Histone modifications in chromatin regulation and RNA polymerase control by chromatin structure
### DNA structure
The vast majority of DNA within the cell is the normal DNA structure. However in nature DNA can form three structures, A-, B- and Z-DNA. A and B chromosomes are very similar, forming right-handed helices, while Z-DNA is a more unusual left-handed helix with a zig-zag phosphate backbone. Z-DNA is thought to play a specific role in chromatin structure and transcription because of the properties of the junction between B- and Z-DNA.
At the junction of B- and Z-DNA one pair of bases is flipped out from normal bonding. These play a dual role of a site of recognition by many proteins and as a sink for torsional stress from RNA polymerase or nucleosome binding.
## The nucleosome and "beads-on-a-string"
The basic repeat element of chromatin is the nucleosome, interconnected by sections of linker DNA, a far shorter arrangement than pure DNA in solution.
In addition to the core histones there is the linker histone, H1, which contacts the exit/entry of the DNA strand on the nucleosome. The nucleosome, together with histone H1, is known as a chromatosome. Chromatosomes, connected by about 20 to 60 base pairs of linker DNA, form an approximately 10 nm "beads-on-a-string" fibre. (Fig. 1-2).
The nucleosomes bind DNA non-specifically, as required by their function in general DNA packaging. There is, however, some preference in the sequences the nucleosomes will bind. This is largely through the properties of DNA; adenosine and thymine are more favorably compressed into the inner minor grooves. This means nucleosomes bind preferentially at one position every 10 base pairs - where the DNA is rotated to maximise the number of A and T bases which will lie in the inner minor groove. (See mechanical properties of DNA.)
## 30 nm chromatin fibre
The "beads-on-a-string" structure in turn coils into a 30 nm diameter helical structure known as the 30nm fibre or filament. The precise structure of the chromatin fibre in the cell is not known in detail, and there is still some debate over this.
This level of chromatin structure is thought to be the form of euchromatin, which contains actively transcribed genes. EM studies have demonstrated that the 30 nm fibre is highly dynamic such that it unfolds into a 10 nm fiber ("beads-on-a-string") structure when transversed by an RNA polymerase engaged in transcription.
The existing models commonly accept that the nucleosomes lie perpendicular to the axis of the fibre, with linker histones arranged internally.
A stable 30 nm fibre relies on the regular positioning of nucleosomes along DNA. Linker DNA is relatively resistant to bending and rotation. This makes the length of linker DNA critical to the stability of the fibre, requiring nucleosomes to be separated by lengths that permit rotation and folding into the required orientation without excessive stress to the DNA.
In this view, different length of the linker DNA should produce different folding topologies of the chromatin fiber. Recent theoretical work, based on electron-microscopy images
-f reconstituted fibers support this view.
## Spatial organization of chromatin in the cell nucleus
Hypothetical Model of the Territorial Organization of Chromatin in the Cell Nucleus. The diagram (Fig. 4) represents a model of a cell (gray oval) with a nucleus (dark gray oval). Two chromosomes are shown as chromatin fibers (yellow and red lines). Proteins are represented as small ovals. Note the association of the chromatin components with the nuclear membrane. Chromosomes are territorially interlinked by chromatin protein complexes (scaffold proteins see above).]]" --->
The layout of the genome within the nucleus is not random - specific regions of the genome are always found in certain areas. Specific regions of the chromatin are thought to be bound to the nuclear membrane, while other regions are bound together by protein complexes. The layout of this is not, however, well characterised apart from the compaction of one of the two X chromosomes in mammalian females into the Barr body. This serves the role of permanently deactivating these genes, which prevents females getting a 'double dose' of relative to males.
# Metaphase chromatin
The metaphase structure of chromatin differs vastly to that of interphase. It is optimised for physical strength and manageability, forming the classic chromosome structure seen in karyotypes. The structure of the condensed chromosome is thought to be loops of 30nm fibre to a central scaffold of proteins. It is, however, not well characterised.
The physical strength of chromatin is vital for this stage of division to prevent shear damage to the DNA as the daughter chromosomes are separated. To maximise strength the composition of the chromatin changes as it approaches the centromere, primarily through alternative histone H1 anologues.
# Non-histone chromosomal proteins
The proteins that are found associated with isolated chromatin fall into several functional categories:
- chromatin-bound enzymes
- high mobility group (HMG) proteins
- transcription factors
- scaffold proteins
- transition proteins (testis specific proteins)
- protamines (present in mature sperm)
Enzymes associated with chromatin are those involved in DNA transcription, replication and repair, and in post-translational modification of histones. They include various types of nucleases and proteases. Scaffold proteins encompass chromatin proteins such as insulators, domain boundary factors and cellular memory modules (CMMs).
# Chromatin: alternative definitions
- Simple and concise definition: Chromatin is DNA plus the proteins (and RNA) that package DNA within the cell nucleus.
- A biochemists’ operational definition: Chromatin is the DNA/protein/RNA complex extracted from eukaryotic lysed interphase nuclei. Just which of the multitudinous substances present in a nucleus will constitute a part of the extracted material will depend in part on the technique each researcher uses. Furthermore, the composition and properties of chromatin vary from one cell type to the another, during development of a specific cell type, and at different stages in the cell cycle.
- The DNA – plus – histone – equals – chromatin definition: The DNA double helix in the cell nucleus is packaged by special proteins termed histones. The formed protein/DNA complex is called chromatin. The structural entity of chromatin is the nucleosome.
# Nobel Prizes
The following scientists were recognized for their contributions to chromatin research with Nobel Prizes: | Chromatin
Chromatin is the complex combination of DNA, RNA, and protein that makes up chromosomes. It is found inside the nuclei of eukaryotic cells, and within the nucleoid in prokaryotic cells. It is divided between heterochromatin (condensed) and euchromatin (extended) forms.[1]
[2]
The major components of chromatin are DNA and histone proteins, although many other chromosomal proteins have prominent roles too. The functions of chromatin are to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. Chromatin contains genetic material-instructions to direct cell functions. Changes in chromatin structure are affected by chemical modifications of histone proteins such as methylation (DNA and proteins) and acetylation (proteins), and by non-histone, DNA-binding proteins.
Chromatin is easily visualised by staining, hence its name, which literally means coloured,lightend material.
# Basic Structure
Simplistically, there are seven levels of chromatin organization (Fig. 1):
- DNA wrapping around nucleosomes - The "beads on a string" structure.
- A 30 nm condensed chromatin fiber consisting of nucleosome arrays in their most compact form.
- Higher level DNA packaging into the metaphase chromosome....
These structures do not occur in all reem prokaryotic cells. Examples of cells with more extreme packaging are spermatozoa and avian red blood cells.
During spermiogenesis, the spermatid's chromatin is remodelled into a more spaced packaged, widened, almost crystal-like structure. This process is associated with the cessation of transcription and involves nuclear protein exchange. The histones are mostly displaced, and replaced by protamines (small, arginine-rich proteins). To put it simply, chromotins are the building blocks of proteins.
It should also be noted that during mitosis, while most of the chromatin is tightly compacted, there are small regions that are not as tightly compacted. These regions often correspond to promoter regions of genes that were active in that cell type prior to entry into cromitosis. The lack of compaction of these regiongs is called bookmarking, which is an epigenetic mechanism believed to be important for transmitting to daughter cells the "memory" of which genes were active prior to entry into mitosis. This bookmarking mechanism is needed to help transmit this memory because transcription ceases during mitosis.
It is found in a plant cell.
# Levels of organization
# During interphase
The structure of chromatin during interphase is optimised to allow easy access of transcription and DNA repair factors to the DNA while compacting the DNA into the nucleus. The structure varies depending on the access required to the DNA. Genes that require regular access by RNA polymerase require the looser structure provided by euchromatin.
# Change in structure
Chromatin undergoes various forms of change in its structure. Histone proteins, the foundation blocks of chromatin, are modified by various post-translational modification to alter DNA packing. Acetylation results in the loosening of chromatin and lends itself to replication and transcription. When methylated they hold DNA together strongly and restrict access to various enzymes. A recent study showed that there is a bivalent structure present in the chromatin: methylated lysine residues at location 4 and 27 on histone 3. It is thought that this may be involved in development; there is more methylation of lysine 27 in embryonic cells than in differentiated cells, whereas lysine 4 methylation positively regulates transcription by recruiting nucleosome remodeling enzymes and histone acetylases.[3]
Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure.[4]
For additional information see Histone modifications in chromatin regulation and RNA polymerase control by chromatin structure
### DNA structure
The vast majority of DNA within the cell is the normal DNA structure. However in nature DNA can form three structures, A-, B- and Z-DNA. A and B chromosomes are very similar, forming right-handed helices, while Z-DNA is a more unusual left-handed helix with a zig-zag phosphate backbone. Z-DNA is thought to play a specific role in chromatin structure and transcription because of the properties of the junction between B- and Z-DNA.
At the junction of B- and Z-DNA one pair of bases is flipped out from normal bonding. These play a dual role of a site of recognition by many proteins and as a sink for torsional stress from RNA polymerase or nucleosome binding.
## The nucleosome and "beads-on-a-string"
The basic repeat element of chromatin is the nucleosome, interconnected by sections of linker DNA, a far shorter arrangement than pure DNA in solution.
In addition to the core histones there is the linker histone, H1, which contacts the exit/entry of the DNA strand on the nucleosome. The nucleosome, together with histone H1, is known as a chromatosome. Chromatosomes, connected by about 20 to 60 base pairs of linker DNA, form an approximately 10 nm "beads-on-a-string" fibre. (Fig. 1-2).
The nucleosomes bind DNA non-specifically, as required by their function in general DNA packaging. There is, however, some preference in the sequences the nucleosomes will bind. This is largely through the properties of DNA; adenosine and thymine are more favorably compressed into the inner minor grooves. This means nucleosomes bind preferentially at one position every 10 base pairs - where the DNA is rotated to maximise the number of A and T bases which will lie in the inner minor groove. (See mechanical properties of DNA.)
## 30 nm chromatin fibre
The "beads-on-a-string" structure in turn coils into a 30 nm diameter helical structure known as the 30nm fibre or filament. The precise structure of the chromatin fibre in the cell is not known in detail, and there is still some debate over this.
This level of chromatin structure is thought to be the form of euchromatin, which contains actively transcribed genes. EM studies have demonstrated that the 30 nm fibre is highly dynamic such that it unfolds into a 10 nm fiber ("beads-on-a-string") structure when transversed by an RNA polymerase engaged in transcription.
The existing models commonly accept that the nucleosomes lie perpendicular to the axis of the fibre, with linker histones arranged internally.
A stable 30 nm fibre relies on the regular positioning of nucleosomes along DNA. Linker DNA is relatively resistant to bending and rotation. This makes the length of linker DNA critical to the stability of the fibre, requiring nucleosomes to be separated by lengths that permit rotation and folding into the required orientation without excessive stress to the DNA.
In this view, different length of the linker DNA should produce different folding topologies of the chromatin fiber. Recent theoretical work, based on electron-microscopy images[5]
of reconstituted fibers support this view.[6]
## Spatial organization of chromatin in the cell nucleus
Hypothetical Model of the Territorial Organization of Chromatin in the Cell Nucleus. The diagram (Fig. 4) represents a model of a cell (gray oval) with a nucleus (dark gray oval). Two chromosomes are shown as chromatin fibers (yellow and red lines). Proteins are represented as small ovals. Note the association of the chromatin components with the nuclear membrane. Chromosomes are territorially interlinked by chromatin protein complexes (scaffold proteins see above).]]" --->
The layout of the genome within the nucleus is not random - specific regions of the genome are always found in certain areas. Specific regions of the chromatin are thought to be bound to the nuclear membrane, while other regions are bound together by protein complexes. The layout of this is not, however, well characterised apart from the compaction of one of the two X chromosomes in mammalian females into the Barr body. This serves the role of permanently deactivating these genes, which prevents females getting a 'double dose' of relative to males.
# Metaphase chromatin
The metaphase structure of chromatin differs vastly to that of interphase. It is optimised for physical strength and manageability, forming the classic chromosome structure seen in karyotypes. The structure of the condensed chromosome is thought to be loops of 30nm fibre to a central scaffold of proteins. It is, however, not well characterised.
The physical strength of chromatin is vital for this stage of division to prevent shear damage to the DNA as the daughter chromosomes are separated. To maximise strength the composition of the chromatin changes as it approaches the centromere, primarily through alternative histone H1 anologues.
# Non-histone chromosomal proteins
The proteins that are found associated with isolated chromatin fall into several functional categories:
- chromatin-bound enzymes
- high mobility group (HMG) proteins
- transcription factors
- scaffold proteins
- transition proteins (testis specific proteins)
- protamines (present in mature sperm)
Enzymes associated with chromatin are those involved in DNA transcription, replication and repair, and in post-translational modification of histones. They include various types of nucleases and proteases. Scaffold proteins encompass chromatin proteins such as insulators, domain boundary factors and cellular memory modules (CMMs).
# Chromatin: alternative definitions
- Simple and concise definition: Chromatin is DNA plus the proteins (and RNA) that package DNA within the cell nucleus.
- A biochemists’ operational definition: Chromatin is the DNA/protein/RNA complex extracted from eukaryotic lysed interphase nuclei. Just which of the multitudinous substances present in a nucleus will constitute a part of the extracted material will depend in part on the technique each researcher uses. Furthermore, the composition and properties of chromatin vary from one cell type to the another, during development of a specific cell type, and at different stages in the cell cycle.
- The DNA – plus – histone – equals – chromatin definition: The DNA double helix in the cell nucleus is packaged by special proteins termed histones. The formed protein/DNA complex is called chromatin. The structural entity of chromatin is the nucleosome.
# Nobel Prizes
The following scientists were recognized for their contributions to chromatin research with Nobel Prizes: | https://www.wikidoc.org/index.php/Chromatin | |
50238465fce1f3372e75263f87e3fafa4063431b | wikidoc | Trisomy 9 | Trisomy 9
Synonyms and keywords:
# Overview
Trisomy 9 is a chromosomal disorder caused by having three copies (trisomy) of chromosome number 9. It can appear with or without mosaicism.
# Symptoms
Symptoms vary, but usually result in dysmorphisms in the skull, nervous system, and mental retardation. Dysmorphisms in the heart, kidneys, and musculoskeletal system may also occur.
# Diagnosis
## Laboratory Findings
Trisomy 9 can be detected prenatally with chorionic villus sampling and cordocentesis, and can be suggested by obstetric ultrasonography.
Because trisomy 9 may appear with mosaicism, it is suggested that doctors take samples from multiple tissues when karyotyping for diagnosis. | Trisomy 9
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords:
# Overview
Trisomy 9 is a chromosomal disorder caused by having three copies (trisomy) of chromosome number 9. It can appear with or without mosaicism.
# Symptoms
Symptoms vary, but usually result in dysmorphisms in the skull, nervous system, and mental retardation. Dysmorphisms in the heart, kidneys, and musculoskeletal system may also occur.
# Diagnosis
## Laboratory Findings
Trisomy 9 can be detected prenatally with chorionic villus sampling and cordocentesis, and can be suggested by obstetric ultrasonography.
Because trisomy 9 may appear with mosaicism, it is suggested that doctors take samples from multiple tissues when karyotyping for diagnosis.[1] | https://www.wikidoc.org/index.php/Chromosome_9_trisomy_syndrome | |
8817280645f5d0c98df1c06f9fd4e236d7eb07c6 | wikidoc | Tadalafil | Tadalafil
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Tadalafil is a phosphodiesterase 5 inhibitor that is FDA approved for the treatment of erectile dysfunction, benign prostatic hyperplasia. Common adverse reactions include flushing, indigestion, nausea, backache, myalgia, headache, nasopharyngitis, respiratory tract infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Erectile dysfunction
- Dosing information
- Initial dosage: 10 mg taken prior to anticipated sexual activity.
- Dosage range: 20 mg -- 5 mg, based on individual efficacy and tolerability.
- The maximum recommended dosing frequency is once per day in most patients.
- Tadalafil for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of Tadalafil , this should be taken into consideration.
- Dosing information for once daily use
- Recommended initial dosage: 2.5 mg PO qd, taken at approximately the same time every day, without regard to timing of sexual activity.
- The Tadalafil dose for once daily use may be increased to ‘’‘5 mg’‘’, based on individual efficacy and tolerability.
### Benign Prostatic Hyperplasia
- Dosing information
- Recommended dosage:‘’‘5 mg PO qd‘’‘, taken at approximately the same time every day.
- When therapy for BPH is initiated with Tadalafil and finasteride
- Recommended dosage: ’‘’5 mg PO qd‘’‘, taken at approximately the same time every day for up to 26 weeks.
- Use with Food
- Tadalafil may be taken without regard to food.
### Use in Specific Populations
- Renal Impairment
- Tadalafil for Use as Needed
- Creatinine clearance 30 to 50 mL/min:
- Start dosage: 5 mg not more than once per day is recommended
- Maximum dose: 10 mg not more than once in every 48 hours.
- Creatinine clearance less than 30 mL/min or on hemodialysis
- Maximum dosage: 5 mg not more than once in every 72 hours .
- Tadalafil for Once Daily Use
- erectile dysfunction
- Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil for once daily use is not recommended .
- Benign Prostatic Hyperplasia and erectile dysfunction/Benign Prostatic Hyperplasia
- Creatinine clearance 30 to 50 mL/min
- Starting dosage: 2.5 mg . An increase to 5 mg may be considered based on individual response.
- Creatinine clearance less than 30 mL/min or on hemodialysis
- Tadalafil for once daily use is not recommended .
- Hepatic Impairment
- Tadalafil for Use as Needed
- Mild or moderate (Child Pugh Class A or B)
- Dosage should not exceed 10 mg PO qd. The use of Tadalafil once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised.
Severe (Child Pugh Class C): The use of Tadalafil is not recommended .
- Tadalafil for Once Daily Use
- Mild or moderate (Child Pugh Class A or B)
- Tadalafil for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if Tadalafil for once daily use is prescribed to these patients.
- Sever (Child Pugh Class C)
- The use of Tadalafil is not recommended .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tadalafil in adult patients.
### Non–Guideline-Supported Use
### Secondary Raynaud's phenomenon
- Dosing information
- 20 mg qd or qod
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tadalafil FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tadalafil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tadalafil in pediatric patients.
# Contraindications
Felodipine extended-release tablets are contraindicated in patients who are hypersensitive to this product.
# Warnings
Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.
Before prescribing Tadalafil , it is important to note the following:
## Cardiovascular
Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including Tadalafil , should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention.
Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of Tadalafil . In such a patient, who has taken Tadalafil , where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of Tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking Tadalafil should seek immediate medical attention.
Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic sub aortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors.
The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for Tadalafil , and therefore until further information is available, Tadalafil is not recommended for the following groups of patients:
myocardial infarction within the last 90 days
unstable angina or angina occurring during sexual intercourse
New York Heart Association Class 2 or greater heart failure in the last 6 months
uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension
stroke within the last 6 months.
As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects . While this effect should not be of consequence in most patients, prior to prescribing Tadalafil , physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.
## Potential for Drug Interactions When Taking Tadalafil for Once Daily Use
Physicians should be aware that Tadalafil for once daily use provides continuous plasma tadalafil levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and potent inhibitors of CYP3A4) and with substantial consumption of alcohol .
## Prolonged Erection
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.
Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease).
## Effects on the Eye
Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including Tadalafil , and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAIONis 2.5-11.8 cases per 100,000 in males aged ≥50. An observational study evaluated whether recent use ofPDE5 inhibitors, as a class, was associated with acute onset ofNAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitors use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors.
Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use ofPDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including Tadalafil , should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population; however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Tadalafil , for this uncommon condition.
Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.
## Sudden Hearing Loss
Physicians should advise patients to stop takingPDE5 inhibitors, including Tadalafil , and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Tadalafil . It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors .
## alpha-blockers and Antihypertensives
Physicians should discuss with patients the potential for Tadalafil to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications.
Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including Tadalafil , and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly , which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:
ED
Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitors. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended dose.
In those patients already taking an optimized dose of PDE5 inhibitors, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitors.
Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other antihypertensive drugs.
BPH
The efficacy of the coadministration of an alpha-blocker and Tadalafil for the treatment of BPH has not been adequately studied, and due to the potential vasodilatory effects of combined use resulting in blood pressure lowering, the combination of Tadalafil and alpha-blockers is not recommended for the treatment of BPH.
Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting Tadalafil for once daily use for the treatment of BPH.
## Renal Impairment
Tadalafil for Use as Needed
Tadalafil should be limited to 5 mg not more than once in every 72 hours in patients with creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis. The starting dose of Tadalafil in patients with creatinine clearance 30 – 50 mL/min should be 5 mg not more than once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours.
Tadalafil for Once Daily Use
ED
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, Tadalafil for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min .
BPH and ED/BPH
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, Tadalafil for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 – 50 mL/min, start dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response .
## Hepatic Impairment
Tadalafil for Use as Needed
In patients with mild or moderate hepatic impairment, the dose of Tadalafil should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of Tadalafil in this group is not recommended .
Tadalafil for Once Daily Use
Tadalafil for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if Tadalafil for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of Tadalafil in this group is not recommended .
## Alcohol
Patients should be made aware that both alcohol and Tadalafil , a PDE5 inhibitors, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache .
## Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4)
Tadalafil is metabolized predominantly by CYP3A4 in the liver. The dose of Tadalafil for use as needed should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole . In patients taking potent inhibitors of CYP3A4 and Tadalafil for once daily use, the maximum recommended dose is 2.5 mg .
## Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies
The safety and efficacy of combinations of Tadalafil and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take Tadalafil with other PDE5 inhibitors, including ADCIRCA.
## Effects on Bleeding
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. Tadalafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although Tadalafil has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution.
## Counseling Patients About Sexually Transmitted Diseases
The use of Tadalafil offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
## Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH
Prior to initiating treatment with Tadalafil for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Tadalafil was administered to over 9000 men during clinical trials worldwide. In trials of Tadalafil for once daily use, a total of 1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For Tadalafil for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively.
Tadalafil for Use as Needed for ED
In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared to 1.4% in placebo treated patients.
When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1) for Tadalafil for use as needed:
Tadalafil for Once Daily Use for ED
In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the discontinuation rate due to adverse events in patients treated with tadalafil was 4.1%, compared to 2.8% in placebo-treated patients.
The following adverse reactions were reported (see Table 2) in clinical trials of 12 weeks duration:
The following adverse reactions were reported (see Table 3) over 24 weeks treatment duration in one placebo-controlled clinical study:
Tadalafil for Once Daily Use for BPH and for ED and BPH
In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with tadalafil was 3.6% compared to 1.6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients treated with tadalafil included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported (see Table 4).
Additional, less frequent adverse reactions (<1%) reported in the controlled clinical trials of Tadalafil for BPH or ED and BPH included: gastroesophageal reflux disease, upper abdominal pain, nausea, vomiting, arthralgia, and muscle spasm.
Back pain or myalgia was reported at incidence rates described in Tables 1 through 4. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia associated with tadalafil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity and resolved without medical treatment, but severe back pain was reported with a low frequency (<5% of all reports). When medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; however, in a small percentage of subjects who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all subjects treated with Tadalafil for on demand use discontinued treatment as a consequence of back pain/myalgia. In the 1-year open label extension study, back pain and myalgia were reported in 5.5% and 1.3% of patients, respectively. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no evidence of medically significant underlying pathology. Incidence rates for Tadalafil for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of Tadalafil for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of <1% across all indications.
Across all studies with any Tadalafil dose, reports of changes in color vision were rare (<0.1% of patients).
The following section identifies additional, less frequent events (<2%) reported in controlled clinical trials of Tadalafil for once daily use or use as needed. A causal relationship of these events to Tadalafil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful:
Body as a Whole — asthenia, face edema, fatigue, pain
Cardiovascular — angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension, palpitations, syncope, tachycardia
Digestive — abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease, hemorrhoidal hemorrhage, rectal hemorrhage
Musculoskeletal — arthralgia, neck pain
Nervous — dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo
Renal and Urinary — renal impairment
Respiratory — dyspnea, epistaxis, pharyngitis
Skin and Appendages — pruritus, rash, sweating
Ophthalmologic — blurred vision, changes in color vision, conjunctivitis (including conjunctival hyperemia), eye pain, lacrimation increase, swelling of eyelids
Otologic — sudden decrease or loss of hearing, tinnitus
Urogenital — erection increased, spontaneous penile erection
## Postmarketing Experience
The following adverse reactions have been identified during post approval use of Tadalafil . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.
Cardiovascular and Cerebrovascular — Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of Tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of Tadalafil and sexual activity. It is not possible to determine whether these events are related directly to Tadalafil , to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors .
Body as a Whole — hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis
Nervous — migraine, seizure and seizure recurrence, transient global amnesia
Ophthalmologic — visual field defect, retinal vein occlusion, retinal artery occlusion
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including Tadalafil . Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors .
Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including Tadalafil . In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of Tadalafil , to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors .
Urogenital — priapism .
# Drug Interactions
## Potential for Pharmacodynamic Interactions with ADCIRCA
## Nitrates
Do not use ADCIRCA in patients who are using any form of organic nitrate . In clinical pharmacology studies ADCIRCA potentiated the hypotensive effect of nitrates . In a patient who has taken ADCIRCA, where nitrate administration is deemed medically necessary in a life–threatening situation, at least 48 hours should elapse after the last dose of ADCIRCA before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.
## Alpha-Blockers
PDE5 inhibitors, including ADCIRCA, and alpha–adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, alfuzosin or tamsulosin .
## Antihypertensives
PDE5 inhibitors, including ADCIRCA, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood–pressure–lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo .
## Alcohol
Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure–lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with ADCIRCA can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
## Potential for Other Drugs to Affect ADCIRCA
## Ritonavir
Ritonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady state of ritonavir (about 1 week), the exposure to tadalafil is similar as in the absence of ritonavir
## Other Potent Inhibitors of CYP3A
Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole, and itraconazole, avoid use of ADCIRCA
## Potent Inducers of CYP3A
For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of ADCIRCA .
## Potential for ADCIRCA to Affect Other Drugs
Cytochrome P450 Substrates
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms (e.g., theophylline, warfarin, midazolam,lovastatin, bosentan) .
## Aspirin
Tadalafil (10 mg and 20 mg once daily) does not potentiate the increase in bleeding time caused by aspirin.
## P-glycoprotein (e.g., digoxin]
Coadministration of tadalafil (40 mg once daily) for 10 days did not significantly alter digoxin pharmacokinetics in healthy subjects
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Pregnancy Category B — Tadalafil (tadalafil) is not indicated for use in women. There are no adequate and well controlled studies of Tadalafil use in pregnant women.
Risk Summary — Based on animal data, Tadalafil is not predicted to increase the risk of adverse developmental abnormalities in humans.
Animal Data — Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis. In one of two perinatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance.
In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg.
Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tadalafil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tadalafil during labor and delivery.
### Nursing Mothers
Tadalafil is not indicated for use in women.
Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma.
### Pediatric Use
Tadalafil is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.
### Geriatic Use
Of the total number of subjects in ED clinical studies of tadalafil, approximately 25 percent were 65 and over, while approximately 3 percent were 75 and over. Of the total number of subjects in BPH clinical studies of tadalafil (including the ED/BPH study), approximately 40 percent were over 65, while approximately 10 percent were 75 and over. In these clinical trials, no overall differences in efficacy or safety were observed between older (>65 and ≥75 years of age) and younger subjects (≤65 years of age). Therefore no dose adjustment is warranted based on age alone. However, a greater sensitivity to medications in some older individuals should be considered. .
### Gender
There is no FDA guidance on the use of Tadalafil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tadalafil with respect to specific racial populations.
### Renal Impairment
In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with creatinine clearance 30 to 80 mL/min. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.8-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination. In a clinical pharmacology study (N=28) at a dose of 10 mg, back pain was reported as a limiting adverse event in male patients with creatinine clearance 30 to 50 mL/min. At a dose of 5 mg, the incidence and severity of back pain was not significantly different than in the general population. In patients on hemodialysis taking 10- or 20-mg tadalafil, there were no reported cases of back pain.
### Hepatic Impairment
In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tadalafil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tadalafil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Tadalafil contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis contributes negligibly to tadalafil elimination.
# Pharmacology
## Mechanism of Action
Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.
In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000–fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000–fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700–fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14–fold more potent for PDE5 than for PDE11A1 and 40–fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.
## Structure
Tadalafil (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is:
The chemical designation is pyrazinopyridoindole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.
Tadalafil is available as almond-shaped tablets for oral administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
## Pharmacodynamics
Effects on Blood Pressure
Tadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate.
Effects on Blood Pressure When Administered with Nitrates
In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of Tadalafil in patients taking any form of nitrates is contraindicated .
A study was conducted to assess the degree of interaction between nitroglycerin and tadalafil, should nitroglycerin be required in an emergency situation after tadalafil was taken. This was a double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) and receiving daily doses of tadalafil 20 mg or matching placebo for 7 days. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints, following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). The objective of the study was to determine when, after tadalafil dosing, no apparent blood pressure interaction was observed. In this study, a significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the interaction was not detectable (see Figure 1).
Therefore, Tadalafil administration with nitrates is contraindicated. In a patient who has taken Tadalafil , where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of Tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring .
Effect on Blood Pressure When Administered With Alpha-Blockers
Six randomized, double-blinded, crossover clinical pharmacology studies were conducted to investigate the potential interaction of tadalafil with alpha-blocker agents in healthy male subjects . In four studies, a single oral dose of tadalafil was administered to healthy male subjects taking daily (at least 7 days duration) an oral alpha-blocker. In two studies, a daily oral alpha-blocker (at least 7 days duration) was administered to healthy male subjects taking repeated daily doses of tadalafil.
Doxazosin— Three clinical pharmacology studies were conducted with tadalafil and doxazosin, an alpha-adrenergic blocker.
In the first doxazosin study, a single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking oral doxazosin 8 mg daily (N=18 subjects). Doxazosin was administered at the same time as tadalafil or placebo after a minimum of seven days of doxazosin dosing (see Table 5 and Figure 2).
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo administration. Outliers were defined as subjects with a standing systolic blood pressure of 30 mm Hg at one or more time points. There were nine and three outliers following administration of tadalafil 20 mg and placebo, respectively. Five and two subjects were outliers due to a decrease from baseline in standing systolic BP of >30 mm Hg, while five and one subject were outliers due to standing systolic BP <85 mm Hg following tadalafil and placebo, respectively. Severe adverse events potentially related to blood-pressure effects were assessed. No such events were reported following placebo. Two such events were reported following administration of tadalafil. Vertigo was reported in one subject that began 7 hours after dosing and lasted about 5 days. This subject previously experienced a mild episode of vertigo on doxazosin and placebo. Dizziness was reported in another subject that began 25 minutes after dosing and lasted 1 day. No syncope was reported.
In the second doxazosin study, a single oral dose of tadalafil 20 mg was administered to healthy subjects taking oral doxazosin, either 4 or 8 mg daily. The study (N=72 subjects) was conducted in three parts, each a 3-period crossover.
In part A (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 a.m. Tadalafil was administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.
In part B (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 p.m. Tadalafil was administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.
In part C (N=24), subjects were titrated to doxazosin 8 mg administered daily at 8 a.m. In this part, tadalafil or placebo were administered at either 8 a.m. or 8 p.m.
The placebo-subtracted mean maximal decreases in systolic blood pressure over a 12-hour period after dosing in the placebo-controlled portion of the study (part C) are shown in Table 6 and Figure 3.
Blood pressure was measured by ABPM every 15 to 30 minutes for up to 36 hours after tadalafil or placebo. Subjects were categorized as outliers if one or more systolic blood pressure readings of 30 mm Hg from a time-matched baseline occurred during the analysis interval.
Of the 24 subjects in part C, 16 subjects were categorized as outliers following administration of tadalafil and 6 subjects were categorized as outliers following placebo during the 24-hour period after 8 a.m. dosing of tadalafil or placebo. Of these, 5 and 2 were outliers due to systolic BP 30 mm Hg following tadalafil and placebo, respectively.
During the 24-hour period after 8 p.m. dosing, 17 subjects were categorized as outliers following administration of tadalafil and 7 subjects following placebo. Of these, 10 and 2 subjects were outliers due to systolic BP 30 mm Hg, following tadalafil and placebo, respectively.
Some additional subjects in both the tadalafil and placebo groups were categorized as outliers in the period beyond 24 hours.
Severe adverse events potentially related to blood-pressure effects were assessed. In the study (N=72 subjects), 2 such events were reported following administration of tadalafil (symptomatic hypotension in one subject that began 10 hours after dosing and lasted approximately 1 hour, and dizziness in another subject that began 11 hours after dosing and lasted 2 minutes). No such events were reported following placebo. In the period prior to tadalafil dosing, one severe event (dizziness) was reported in a subject during the doxazosin run-in phase.
In the third doxazosin study, healthy subjects (N=45 treated; 37 completed) received 28 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. After 7 days, doxazosin was initiated at 1 mg and titrated up to 4 mg daily over the last 21 days of each period (7 days on 1 mg; 7 days of 2 mg; 7 days of 4 mg doxazosin). The results are shown in Table 7.
Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours post dose on the first day of each doxazosin dose, (1 mg, 2 mg, 4 mg), as well as on the seventh day of 4 mg doxazosin administration.
Following the first dose of doxazosin 1 mg, there were no outliers on tadalafil 5 mg and one outlier on placebo due to a decrease from baseline in standing systolic BP of >30 mm Hg.
There were 2 outliers on tadalafil 5 mg and none on placebo following the first dose of doxazosin 2 mg due to a decrease from baseline in standing systolic BP of >30 mm Hg.
There were no outliers on tadalafil 5 mg and two on placebo following the first dose of doxazosin 4 mg due to a decrease from baseline in standing systolic BP of >30 mm Hg. There was one outlier on tadalafil 5 mg and three on placebo following the first dose of doxazosin 4 mg due to standing systolic BP 30 mm Hg in standing systolic blood pressure, and one subject on placebo had standing systolic blood pressure <85 mm Hg. All adverse events potentially related to blood pressure effects were rated as mild or moderate. There were two episodes of syncope in this study, one subject following a dose of tadalafil 5 mg alone, and another subject following coadministration of tadalafil 5 mg and doxazosin 4 mg.
Tamsulosin— In the first tamsulosin study, a single oral dose of tadalafil 10, 20 mg, or placebo was administered in a 3 period, crossover design to healthy subjects taking 0.4 mg once per day tamsulosin, a selective alpha-adrenergic blocker (N=18 subjects). Tadalafil or placebo was administered 2 hours after tamsulosin following a minimum of seven days of tamsulosin dosing.
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo dosing. There were 2, 2, and 1 outliers (subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points) following administration of tadalafil 10 mg, 20 mg, and placebo, respectively. There were no subjects with a standing systolic blood pressure <85 mm Hg. No severe adverse events potentially related to blood-pressure effects were reported. No syncope was reported.
In the second tamsulosin study, healthy subjects (N=39 treated; and 35 completed) received 14 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. Daily dosing of tamsulosin 0.4 mg was added for the last seven days of each period.
Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours post dose on the first, sixth and seventh days of tamsulosin administration. There were no outliers (subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points). One subject on placebo plus tamsulosin (Day 7) and one subject on tadalafil plus tamsulosin (Day 6) had standing systolic blood pressure <85 mm Hg. No severe adverse events potentially related to blood pressure were reported. No syncope was reported.
Alfuzosin — A single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking once-daily alfuzosin HCl 10 mg extended-release tablets, an alpha-adrenergic blocker (N=17 completed subjects). Tadalafil or placebo was administered 4 hours after alfuzosin following a minimum of seven days of alfuzosin dosing.
Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20, and 24 hours after tadalafil or placebo dosing. There was 1 outlier (subject with a standing systolic blood pressure 30 mm Hg at one or more time points. No severe adverse events potentially related to blood pressure effects were reported. No syncope was reported.
Effects on Blood Pressure When Administered with Antihypertensives
Amlodipine — A study was conducted to assess the interaction of amlodipine (5 mg daily) and tadalafil 10 mg. There was no effect of tadalafil on amlodipine blood levels and no effect of amlodipine on tadalafil blood levels. The mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking amlodipine was 3/2 mm Hg, compared to placebo. In a similar study using tadalafil 20 mg, there were no clinically significant differences between tadalafil and placebo in subjects taking amlodipine.
Angiotensin II receptor blockers (with and without other antihypertensives) — A study was conducted to assess the interaction of angiotensin II receptor blockers and tadalafil 20 mg. Subjects in the study were taking any marketed angiotensin II receptor blocker, either alone, as a component of a combination product, or as part of a multiple antihypertensive regimen. Following dosing, ambulatory measurements of blood pressure revealed differences between tadalafil and placebo of 8/4 mm Hg in systolic/diastolic blood pressure.
Bendrofluazide — A study was conducted to assess the interaction of bendrofluazide (2.5 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking bendrofluazide was 6/4 mm Hg, compared to placebo.
Enalapril — A study was conducted to assess the interaction of enalapril (10 to 20 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking enalapril was 4/1 mm Hg, compared to placebo.
Metoprolol — A study was conducted to assess the interaction of sustained-release metoprolol (25 to 200 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking metoprolol was 5/3 mm Hg, compared to placebo.
Effects on Blood Pressure When Administered with Alcohol
Alcohol and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. The interaction of tadalafil with alcohol was evaluated in 3 clinical pharmacology studies. In 2 of these, alcohol was administered at a dose of 0.7 g/kg, which is equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male, and tadalafil was administered at a dose of 10 mg in one study and 20 mg in another. In both these studies, all patients imbibed the entire alcohol dose within 10 minutes of starting. In one of these two studies, blood alcohol levels of 0.08% were confirmed. In these two studies, more patients had clinically significant decreases in blood pressure on the combination of tadalafil and alcohol as compared to alcohol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects. When tadalafil 20 mg was administered with a lower dose of alcohol (0.6 g/kg, which is equivalent to approximately 4 ounces of 80-proof vodka, administered in less than 10 minutes), orthostatic hypotension was not observed, dizziness occurred with similar frequency to alcohol alone, and the hypotensive effects of alcohol were not potentiated.
Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
Effects on Exercise Stress Testing
The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates.
Effects on Vision
Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupilometry. Across all clinical studies with Tadalafil , reports of changes in color vision were rare (<0.1% of patients).
Effects on Sperm Characteristics
Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6 month study) and 20 mg (one 6 month and one 9 month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.
Effects on Cardiac Electrophysiology
The effect of a single 100-mg dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide) -controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.
## Pharmacokinetics
Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once per day dosing and exposure is approximately 1.6-fold greater than after a single dose. Mean tadalafil concentrations measured after the administration of a single oral dose of 20 mg and single and once daily multiple doses of 5 mg, from a separate study, (see Figure 4) to healthy male subjects are depicted in Figure 4.
Absorption — After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food; thus Tadalafil may be taken with or without food.
Distribution — The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Metabolism — Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Excretion — The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Geriatric — Healthy male elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax relative to that observed in healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered .
Pediatric — Tadalafil has not been evaluated in individuals less than 18 years old .
Patients with Diabetes Mellitus — In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.
Patients with BPH — In patients with BPH following single and multiple-doses of 20 mg tadalafil, no statistically significant differences in exposure (AUC and Cmax) were observed between elderly (70 to 85 years) and younger (≤60 years of age) subjects. No dose adjustment is warranted.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis — Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 10-fold for mice, and 14- and 26-fold for male and female rats, respectively, the exposures in human males given Maximum Recommended Human Dose (MRHD) of 20 mg.
Mutagenesis — Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays.
Impairment of Fertility — There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 14-fold for males or 26-fold for females the exposures observed in human males given the MRHD of 20 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment-related non-reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20-100% of the dogs that resulted in a decrease in spermatogenesis in 40-75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no-observed-adverse-effect-level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 20 mg.
There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.
## Animal Toxicology and/or Pharmacology
Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 2- to 33-fold above the human exposure (AUCs) at the MRHD of 20 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound tadalafil exposure of 1- to 54-fold above the human exposure (AUC) at the MRHD of 20 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 14- to 18-fold the human exposure at the MRHD of 20 mg. The abnormal blood-cell findings were reversible within 2 weeks after stopping treatment.
# Clinical Studies
## Tadalafil for Use as Needed for ED
The efficacy and safety of tadalafil in the treatment of erectile dysfunction has been evaluated in 22 clinical trials of up to 24-weeks duration, involving over 4000 patients. Tadalafil , when taken as needed up to once per day, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).
Tadalafil was studied in the general ED population in 7 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12-weeks duration. Two of these studies were conducted in the United States and 5 were conducted in centers outside the US. Additional efficacy and safety studies were performed in ED patients with diabetes mellitus and in patients who developed ED status post bilateral nerve-sparing radical prostatectomy.
In these 7 trials, Tadalafil was taken as needed, at doses ranging from 2.5 to 20 mg, up to once per day. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted.
Several assessment tools were used to evaluate the effect of Tadalafil on erectile function. The 3 primary outcome measures were the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at the end of a treatment-free baseline period and subsequently at follow-up visits after randomization. The IIEF EF domain has a 30-point total score, where higher scores reflect better erectile function. SEP is a diary in which patients recorded each sexual attempt made throughout the study. SEP Question 2 asks, “Were you able to insert your penis into the partner's vagina?” SEP Question 3 asks, “Did your erection last long enough for you to have successful intercourse?” The overall percentage of successful attempts to insert the penis into the vagina (SEP2) and to maintain the erection for successful intercourse (SEP3) is derived for each patient.
Results in ED Population in US Trials — The 2 primary US efficacy and safety trials included a total of 402 men with erectile dysfunction, with a mean age of 59 years (range 27 to 87 years). The population was 78% White, 14% Black, 7% Hispanic, and 1% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (>90%) patients reported ED of at least 1-year duration. Study A was conducted primarily in academic centers. Study B was conducted primarily in community-based urology practices. In each of these 2 trials, Tadalafil 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables . The treatment effect of Tadalafil did not diminish over time.
Results in General ED Population in Trials Outside the US — The 5 primary efficacy and safety studies conducted in the general ED population outside the US included 1112 patients, with a mean age of 59 years (range 21 to 82 years). The population was 76% White, 1% Black, 3% Hispanic, and 20% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (90%) patients reported ED of at least 1-year duration. In these 5 trials, Tadalafil 5, 10, and 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Tables 12, 13 and 14). The treatment effect of Tadalafil did not diminish over time.
In addition, there were improvements in EF domain scores, success rates based upon SEP Questions 2 and 3, and patient-reported improvement in erections across patients with ED of all degrees of disease severity while taking Tadalafil , compared to patients on placebo.
Therefore, in all 7 primary efficacy and safety studies, Tadalafil showed statistically significant improvement in patients' ability to achieve an erection sufficient for vaginal penetration and to maintain the erection long enough for successful intercourse, as measured by the IIEF questionnaire and by SEP diaries.
Efficacy Results in ED Patients with Diabetes Mellitus — Tadalafil was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in all 7 primary efficacy studies in the general ED population (N=235) and in one study that specifically assessed Tadalafil in ED patients with type 1 or type 2 diabetes (N=216). In this randomized, placebo-controlled, double-blinded, parallel-arm design prospective trial, Tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 15).
Efficacy Results in ED Patients following Radical Prostatectomy — Tadalafil was shown to be effective in treating patients who developed ED following bilateral nerve-sparing radical prostatectomy. In 1 randomized, placebo-controlled, double-blinded, parallel-arm design prospective trial in this population (N=303), Tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 16).
Results in Studies to Determine the Optimal Use of Tadalafil — Several studies were conducted with the objective of determining the optimal use of Tadalafil in the treatment of ED. In one of these studies, the percentage of patients reporting successful erections within 30 minutes of dosing was determined. In this randomized, placebo-controlled, double-blinded trial, 223 patients were randomized to placebo, Tadalafil 10, or 20 mg. Using a stopwatch, patients recorded the time following dosing at which a successful erection was obtained. A successful erection was defined as at least 1 erection in 4 attempts that led to successful intercourse. At or prior to 30 minutes, 35% (26/74), 38% (28/74), and 52% (39/75) of patients in the placebo, 10-, and 20-mg groups, respectively, reported successful erections as defined above.
Two studies were conducted to assess the efficacy of Tadalafil at a given timepoint after dosing, specifically at 24 hours and at 36 hours after dosing.
In the first of these studies, 348 patients with ED were randomized to placebo or Tadalafil 20 mg. Patients were encouraged to make 4 total attempts at intercourse; 2 attempts were to occur at 24 hours after dosing and 2 completely separate attempts were to occur at 36 hours after dosing. The results demonstrated a difference between the placebo group and the Tadalafil group at each of the pre-specified timepoints. At the 24-hour timepoint, (more specifically, 22 to 26 hours), 53/144 (37%) patients reported at least 1 successful intercourse in the placebo group versus 84/138 (61%) in the Tadalafil 20-mg group. At the 36-hour timepoint (more specifically, 33 to 39 hours), 49/133 (37%) of patients reported at least 1 successful intercourse in the placebo group versus 88/137 (64%) in the Tadalafil 20-mg group.
In the second of these studies, a total of 483 patients were evenly randomized to 1 of 6 groups: 3 different dosing groups (placebo, Tadalafil 10, or 20 mg) that were instructed to attempt intercourse at 2 different times (24 and 36 hours post-dosing). Patients were encouraged to make 4 separate attempts at their assigned dose and assigned timepoint. In this study, the results demonstrated a statistically significant difference between the placebo group and the Tadalafil groups at each of the pre-specified timepoints. At the 24-hour timepoint, the mean, per patient percentage of attempts resulting in successful intercourse were 42, 56, and 67% for the placebo, Tadalafil 10-, and 20-mg groups, respectively. At the 36-hour timepoint, the mean, per-patient percentage of attempts resulting in successful intercourse were 33, 56, and 62% for placebo, Tadalafil 10-, and 20-mg groups, respectively.
## Tadalafil for Once Daily Use for ED
The efficacy and safety of Tadalafil for once daily use in the treatment of erectile dysfunction has been evaluated in 2 clinical trials of 12-weeks duration and 1 clinical trial of 24-weeks duration, involving a total of 853 patients. Tadalafil , when taken once daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).
Tadalafil was studied in the general ED population in 2 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12- and 24-weeks duration, respectively. One of these studies was conducted in the United States and one was conducted in centers outside the US. An additional efficacy and safety study was performed in ED patients with diabetes mellitus. Tadalafil was taken once daily at doses ranging from 2.5 to 10 mg. Food and alcohol intake were not restricted. Timing of sexual activity was not restricted relative to when patients took Tadalafil .
Results in General ED Population — The primary US efficacy and safety trial included a total of 287 patients, with a mean age of 59 years (range 25 to 82 years). The population was 86% White, 6% Black, 6% Hispanic, and 2% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (>96%) patients reported ED of at least 1-year duration.
The primary efficacy and safety study conducted outside the US included 268 patients, with a mean age of 56 years (range 21 to 78 years). The population was 86% White, 3% Black, 0.4% Hispanic, and 10% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Ninety-three percent of patients reported ED of at least 1-year duration.
In each of these trials, conducted without regard to the timing of dose and sexual intercourse, Tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 17). When taken as directed, Tadalafil was effective at improving erectile function.
In the 6 month double-blind study, the treatment effect of Tadalafil did not diminish over time.
Efficacy Results in ED Patients with Diabetes Mellitus — Tadalafil for once daily use was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in both studies in the general ED population (N=79). A third randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design trial included only ED patients with type 1 or type 2 diabetes (N=298). In this third trial, Tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 18).
## Tadalafil 5 mg for Once Daily Use for Benign Prostatic Hyperplasia (BPH)
The efficacy and safety of Tadalafil for once daily use for the treatment of the signs and symptoms of BPH was evaluated in 3 randomized, multinational, double-blinded, placebo-controlled, parallel-design, efficacy and safety studies of 12 weeks duration. Two of these studies were in men with BPH and one study was specific to men with both ED and BPH . The first study (Study J) randomized 1058 patients to receive either Tadalafil 2.5 mg, 5 mg, 10 mg or 20 mg for once daily use or placebo. The second study (Study K) randomized 325 patients to receive either Tadalafil 5 mg for once daily use or placebo. The full study population was 87% White, 2% Black, 11% other races; 15% was of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.
The primary efficacy endpoint in the two studies that evaluated the effect of Tadalafil for the signs and symptoms of BPH was the International Prostate Symptom Score (IPSS), a four week recall questionnaire that was administered at the beginning and end of a placebo run-in period and subsequently at follow-up visits after randomization. The IPSS assesses the severity of irritative (frequency, urgency, nocturia) and obstructive symptoms (incomplete emptying, stopping and starting, weak stream, and pushing or straining), with scores ranging from 0 to 35; higher numeric scores representing greater severity. Maximum urinary flow rate (Qmax), an objective measure of urine flow, was assessed as a secondary efficacy endpoint in Study J and as a safety endpoint in Study K.
The results for BPH patients with moderate to severe symptoms and a mean age of 63.2 years (range 44 to 87) who received either Tadalafil 5 mg for once daily use or placebo (N=748) in Studies J and K are shown in Table 19 and Figures 5 and 6, respectively.
In each of these 2 trials, Tadalafil 5 mg for once daily use resulted in statistically significant improvement in the total IPSS compared to placebo. Mean total IPSS showed a decrease starting at the first scheduled observation (4 weeks) in Study K and remained decreased through 12 weeks.
In Study J, the effect of Tadalafil 5 mg once daily on maximum urinary flow rate (Qmax) was evaluated as a secondary efficacy endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (Tadalafil 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.
In Study K, the effect of Tadalafil 5 mg once daily on Qmax was evaluated as a safety endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (Tadalafil 5 mg: 1.6 mL/sec, placebo: 1.1 mL/sec); however, these changes were not significantly different between groups.
Efficacy Results in Patients with BPH initiating Tadalafil and Finasteride – Tadalafil for once daily use initiated together with finasteride was shown to be effective in treating the signs and symptoms of BPH in men with an enlarged prostate (>30 cc) for up to 26 weeks. This additional double-blinded, parallel-design study of 26 weeks duration randomized 696 men to initiate either Tadalafil 5 mg with finasteride 5 mg or placebo with finasteride 5 mg. The study population had a mean age of 64 years (range 46-86). Patients with multiple co-morbid conditions such as erectile dysfunction, diabetes mellitus, hypertension, and other cardiovascular disease were included.
Tadalafil with finasteride demonstrated statistically significant improvement in the signs and symptoms of BPH compared to placebo with finasteride, as measured by the total IPSS at 12 weeks, the primary study endpoint (see Table 20). Key secondary endpoints demonstrated improvement in total IPSS starting at the first scheduled observation at week 4 (Tadalafil -4.0, placebo -2.3: p<.001) and the score remained decreased through 26 weeks (Tadalafil -5.5, placebo -4.5; p=.022). However, the magnitude of the treatment difference between placebo/finasteride and Tadalafil /finasteride decreased from 1.7 points at Week 4 to 1.0 point at Week 26, as shown in Table 20 and in Figure 7. The incremental benefit of Tadalafil beyond 26 weeks is unknown.
In the 404 patients who had both ED and BPH at baseline, changes in erectile function were assessed as key secondary endpoints using the EF domain of the IIEF questionnaire. Tadalafil with finasteride (N=203) was compared to placebo with finasteride (N=201). A statistically significant improvement from baseline (Tadalafil /finasteride 13.7, placebo/finasteride 15.1) was observed at week 4 (Tadalafil /finasteride 3.7, placebo/finasteride -1.1; p<.001), week 12 (Tadalafil /finasteride 4.7, placebo/finasteride 0.6; p<.001), and week 26 (Tadalafil /finasteride 4.7, placebo/finasteride 0.0; p<.001).
## Tadalafil 5 mg for Once Daily Use for ED and BPH
The efficacy and safety of Tadalafil for once daily use for the treatment of ED, and the signs and symptoms of BPH, in patients with both conditions was evaluated in one placebo-controlled, multinational, double-blind, parallel-arm study which randomized 606 patients to receive either Tadalafil 2.5 mg, 5 mg, for once daily use or placebo. ED severity ranged from mild to severe and BPH severity ranged from moderate to severe. The full study population had a mean age of 63 years (range 45 to 83) and was 93% White, 4% Black, 3% other races; 16% were of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.
In this study, the co-primary endpoints were total IPSS and the Erectile Function (EF) domain score of the International Index of Erectile Function (IIEF). One of the key secondary endpoints in this study was Question 3 of the Sexual Encounter Profile diary (SEP3). Timing of sexual activity was not restricted relative to when patients took Tadalafil .
The efficacy results for patients with both ED and BPH, who received either Tadalafil 5 mg for once daily use or placebo (N=408) are shown in Tables 21 and 22 and Figure 8.
Tadalafil 5 mg for once daily use resulted in statistically significant improvements in the total IPSS and in the EF domain of the IIEF questionnaire. Tadalafil 5 mg for once daily use also resulted in statistically significant improvement in SEP3. Tadalafil 2.5 mg did not result in statistically significant improvement in the total IPSS.
In this study, the effect of Tadalafil 5 mg once daily on Qmax was evaluated as a safety endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (Tadalafil 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.
# How Supplied
Tadalafil (tadalafil) is supplied as follows:
Four strengths of almond-shaped tablets are available in different sizes and different shades of yellow, and supplied in the following package sizes:
## Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) .
Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
## Nitrates
Physicians should discuss with patients the contraindication of Tadalafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of Tadalafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of Tadalafil . In such a patient, who has taken Tadalafil , where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of Tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking Tadalafil should seek immediate medical attention
## Cardiovascular Considerations
Physicians should consider the potential cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Physicians should advise patients who experience symptoms upon initiation of sexual activity to refrain from further sexual activity and seek immediate medical attention .
## Concomitant Use with Drugs Which Lower Blood Pressure
Physicians should discuss with patients the potential for Tadalafil to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications
## Potential for Drug Interactions When Taking Tadalafil for Once Daily Use
Physicians should discuss with patients the clinical implications of continuous exposure to tadalafil when prescribing Tadalafil for once daily use, especially the potential for interactions with medications (e.g., nitrates, alpha-blockers, antihypertensives and potent inhibitors of cytochrome P450 3A4) and with substantial consumption of alcohol.
## Priapism
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Physicians should advise patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention.
## Sudden Loss of Vision
Physicians should advise patients to stop use of all PDE5 inhibitors, including Tadalafil , and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including possible permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Tadalafil , for this uncommon condition .
## Sudden Hearing Loss
Physicians should advise patients to stop taking PDE5 inhibitors, including Tadalafil , and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Tadalafil . It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors .
## Alcohol
Patients should be made aware that both alcohol and Tadalafil , a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache .
## Sexually Transmitted Disease
The use of Tadalafil offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
## Recommended Administration
Physicians should instruct patients on the appropriate administration of Tadalafil to allow optimal use.
For Tadalafil for use as needed in men with ED, patients should be instructed to take one tablet at least 30 minutes before anticipated sexual activity. In most patients, the ability to have sexual intercourse is improved for up to 36 hours.
For Tadalafil for once daily use in men with ED or ED/BPH, patients should be instructed to take one tablet at approximately the same time every day without regard for the timing of sexual activity. Tadalafil is effective at improving erectile function over the course of therapy.
For Tadalafil for once daily use in men with BPH, patients should be instructed to take one tablet at approximately the same time every day.
# Precautions with Alcohol
Alcohol-Tadalafil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cialis
- Adcirca
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price | Tadalafil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2];Aparna Vuppala, M.B.B.S. [3]
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# Overview
Tadalafil is a phosphodiesterase 5 inhibitor that is FDA approved for the treatment of erectile dysfunction, benign prostatic hyperplasia. Common adverse reactions include flushing, indigestion, nausea, backache, myalgia, headache, nasopharyngitis, respiratory tract infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Erectile dysfunction
- Dosing information
- Initial dosage: 10 mg taken prior to anticipated sexual activity.
- Dosage range: 20 mg -- 5 mg, based on individual efficacy and tolerability.
- The maximum recommended dosing frequency is once per day in most patients.
- Tadalafil for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of Tadalafil , this should be taken into consideration.
- Dosing information for once daily use
- Recommended initial dosage: 2.5 mg PO qd, taken at approximately the same time every day, without regard to timing of sexual activity.
- The Tadalafil dose for once daily use may be increased to ‘’‘5 mg’‘’, based on individual efficacy and tolerability.
### Benign Prostatic Hyperplasia
- Dosing information
- Recommended dosage:‘’‘5 mg PO qd‘’‘, taken at approximately the same time every day.
- When therapy for BPH is initiated with Tadalafil and finasteride
- Recommended dosage: ’‘’5 mg PO qd‘’‘, taken at approximately the same time every day for up to 26 weeks.
- Use with Food
- Tadalafil may be taken without regard to food.
### Use in Specific Populations
- Renal Impairment
- Tadalafil for Use as Needed
- Creatinine clearance 30 to 50 mL/min:
- Start dosage: 5 mg not more than once per day is recommended
- Maximum dose: 10 mg not more than once in every 48 hours.
- Creatinine clearance less than 30 mL/min or on hemodialysis
- Maximum dosage: 5 mg not more than once in every 72 hours .
- Tadalafil for Once Daily Use
- erectile dysfunction
- Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil for once daily use is not recommended .
- Benign Prostatic Hyperplasia and erectile dysfunction/Benign Prostatic Hyperplasia
- Creatinine clearance 30 to 50 mL/min
- Starting dosage: 2.5 mg . An increase to 5 mg may be considered based on individual response.
- Creatinine clearance less than 30 mL/min or on hemodialysis
- Tadalafil for once daily use is not recommended .
- Hepatic Impairment
- Tadalafil for Use as Needed
- Mild or moderate (Child Pugh Class A or B)
- Dosage should not exceed 10 mg PO qd. The use of Tadalafil once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised.
Severe (Child Pugh Class C): The use of Tadalafil is not recommended .
- Tadalafil for Once Daily Use
- Mild or moderate (Child Pugh Class A or B)
- Tadalafil for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if Tadalafil for once daily use is prescribed to these patients.
- Sever (Child Pugh Class C)
- The use of Tadalafil is not recommended .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tadalafil in adult patients.
### Non–Guideline-Supported Use
### Secondary Raynaud's phenomenon
- Dosing information
- 20 mg qd or qod [1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tadalafil FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tadalafil in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tadalafil in pediatric patients.
# Contraindications
Felodipine extended-release tablets are contraindicated in patients who are hypersensitive to this product.
# Warnings
Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.
Before prescribing Tadalafil , it is important to note the following:
## Cardiovascular
Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including Tadalafil , should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention.
Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of Tadalafil . In such a patient, who has taken Tadalafil , where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of Tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking Tadalafil should seek immediate medical attention.
Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic sub aortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors.
The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for Tadalafil , and therefore until further information is available, Tadalafil is not recommended for the following groups of patients:
myocardial infarction within the last 90 days
unstable angina or angina occurring during sexual intercourse
New York Heart Association Class 2 or greater heart failure in the last 6 months
uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension
stroke within the last 6 months.
As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects . While this effect should not be of consequence in most patients, prior to prescribing Tadalafil , physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.
## Potential for Drug Interactions When Taking Tadalafil for Once Daily Use
Physicians should be aware that Tadalafil for once daily use provides continuous plasma tadalafil levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and potent inhibitors of CYP3A4) and with substantial consumption of alcohol .
## Prolonged Erection
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.
Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease).
## Effects on the Eye
Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including Tadalafil , and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. Based on published literature, the annual incidence of NAIONis 2.5-11.8 cases per 100,000 in males aged ≥50. An observational study evaluated whether recent use ofPDE5 inhibitors, as a class, was associated with acute onset ofNAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitors use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or other factors.
Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use ofPDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including Tadalafil , should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with "crowded" optic disc are also considered at greater risk for NAION compared to the general population; however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Tadalafil , for this uncommon condition.
Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.
## Sudden Hearing Loss
Physicians should advise patients to stop takingPDE5 inhibitors, including Tadalafil , and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Tadalafil . It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors .
## alpha-blockers and Antihypertensives
Physicians should discuss with patients the potential for Tadalafil to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications.
Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including Tadalafil , and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly , which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:
ED
Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitors. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended dose.
In those patients already taking an optimized dose of PDE5 inhibitors, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitors.
Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other antihypertensive drugs.
BPH
The efficacy of the coadministration of an alpha-blocker and Tadalafil for the treatment of BPH has not been adequately studied, and due to the potential vasodilatory effects of combined use resulting in blood pressure lowering, the combination of Tadalafil and alpha-blockers is not recommended for the treatment of BPH.
Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting Tadalafil for once daily use for the treatment of BPH.
## Renal Impairment
Tadalafil for Use as Needed
Tadalafil should be limited to 5 mg not more than once in every 72 hours in patients with creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis. The starting dose of Tadalafil in patients with creatinine clearance 30 – 50 mL/min should be 5 mg not more than once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours.
Tadalafil for Once Daily Use
ED
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, Tadalafil for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min .
BPH and ED/BPH
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, Tadalafil for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 – 50 mL/min, start dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response .
## Hepatic Impairment
Tadalafil for Use as Needed
In patients with mild or moderate hepatic impairment, the dose of Tadalafil should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of Tadalafil in this group is not recommended .
Tadalafil for Once Daily Use
Tadalafil for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if Tadalafil for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of Tadalafil in this group is not recommended .
## Alcohol
Patients should be made aware that both alcohol and Tadalafil , a PDE5 inhibitors, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache .
## Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4)
Tadalafil is metabolized predominantly by CYP3A4 in the liver. The dose of Tadalafil for use as needed should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole . In patients taking potent inhibitors of CYP3A4 and Tadalafil for once daily use, the maximum recommended dose is 2.5 mg .
## Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies
The safety and efficacy of combinations of Tadalafil and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take Tadalafil with other PDE5 inhibitors, including ADCIRCA.
## Effects on Bleeding
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. Tadalafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although Tadalafil has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution.
## Counseling Patients About Sexually Transmitted Diseases
The use of Tadalafil offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
## Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH
Prior to initiating treatment with Tadalafil for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Tadalafil was administered to over 9000 men during clinical trials worldwide. In trials of Tadalafil for once daily use, a total of 1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For Tadalafil for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively.
Tadalafil for Use as Needed for ED
In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared to 1.4% in placebo treated patients.
When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1) for Tadalafil for use as needed:
Tadalafil for Once Daily Use for ED
In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the discontinuation rate due to adverse events in patients treated with tadalafil was 4.1%, compared to 2.8% in placebo-treated patients.
The following adverse reactions were reported (see Table 2) in clinical trials of 12 weeks duration:
The following adverse reactions were reported (see Table 3) over 24 weeks treatment duration in one placebo-controlled clinical study:
Tadalafil for Once Daily Use for BPH and for ED and BPH
In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with tadalafil was 3.6% compared to 1.6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients treated with tadalafil included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported (see Table 4).
Additional, less frequent adverse reactions (<1%) reported in the controlled clinical trials of Tadalafil for BPH or ED and BPH included: gastroesophageal reflux disease, upper abdominal pain, nausea, vomiting, arthralgia, and muscle spasm.
Back pain or myalgia was reported at incidence rates described in Tables 1 through 4. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia associated with tadalafil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity and resolved without medical treatment, but severe back pain was reported with a low frequency (<5% of all reports). When medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; however, in a small percentage of subjects who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all subjects treated with Tadalafil for on demand use discontinued treatment as a consequence of back pain/myalgia. In the 1-year open label extension study, back pain and myalgia were reported in 5.5% and 1.3% of patients, respectively. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no evidence of medically significant underlying pathology. Incidence rates for Tadalafil for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of Tadalafil for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of <1% across all indications.
Across all studies with any Tadalafil dose, reports of changes in color vision were rare (<0.1% of patients).
The following section identifies additional, less frequent events (<2%) reported in controlled clinical trials of Tadalafil for once daily use or use as needed. A causal relationship of these events to Tadalafil is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful:
Body as a Whole — asthenia, face edema, fatigue, pain
Cardiovascular — angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension, palpitations, syncope, tachycardia
Digestive — abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease, hemorrhoidal hemorrhage, rectal hemorrhage
Musculoskeletal — arthralgia, neck pain
Nervous — dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo
Renal and Urinary — renal impairment
Respiratory — dyspnea, epistaxis, pharyngitis
Skin and Appendages — pruritus, rash, sweating
Ophthalmologic — blurred vision, changes in color vision, conjunctivitis (including conjunctival hyperemia), eye pain, lacrimation increase, swelling of eyelids
Otologic — sudden decrease or loss of hearing, tinnitus
Urogenital — erection increased, spontaneous penile erection
## Postmarketing Experience
The following adverse reactions have been identified during post approval use of Tadalafil . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.
Cardiovascular and Cerebrovascular — Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of tadalafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of Tadalafil without sexual activity. Others were reported to have occurred hours to days after the use of Tadalafil and sexual activity. It is not possible to determine whether these events are related directly to Tadalafil , to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors .
Body as a Whole — hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis
Nervous — migraine, seizure and seizure recurrence, transient global amnesia
Ophthalmologic — visual field defect, retinal vein occlusion, retinal artery occlusion
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including Tadalafil . Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors .
Otologic — Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including Tadalafil . In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of Tadalafil , to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors .
Urogenital — priapism .
# Drug Interactions
## Potential for Pharmacodynamic Interactions with ADCIRCA
## Nitrates
Do not use ADCIRCA in patients who are using any form of organic nitrate . In clinical pharmacology studies ADCIRCA potentiated the hypotensive effect of nitrates . In a patient who has taken ADCIRCA, where nitrate administration is deemed medically necessary in a life–threatening situation, at least 48 hours should elapse after the last dose of ADCIRCA before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.
## Alpha-Blockers
PDE5 inhibitors, including ADCIRCA, and alpha–adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, alfuzosin or tamsulosin .
## Antihypertensives
PDE5 inhibitors, including ADCIRCA, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood–pressure–lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendroflumethiazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo .
## Alcohol
Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood pressure–lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with ADCIRCA can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil (10 mg or 20 mg) did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
## Potential for Other Drugs to Affect ADCIRCA
## Ritonavir
Ritonavir initially inhibits and later induces CYP3A, the enzyme involved in the metabolism of tadalafil. At steady state of ritonavir (about 1 week), the exposure to tadalafil is similar as in the absence of ritonavir
## Other Potent Inhibitors of CYP3A
Tadalafil is metabolized predominantly by CYP3A in the liver. In patients taking potent inhibitors of CYP3A such as ketoconazole, and itraconazole, avoid use of ADCIRCA
## Potent Inducers of CYP3A
For patients chronically taking potent inducers of CYP3A, such as rifampin, avoid use of ADCIRCA .
## Potential for ADCIRCA to Affect Other Drugs
Cytochrome P450 Substrates
Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms (e.g., theophylline, warfarin, midazolam,lovastatin, bosentan) .
## Aspirin
Tadalafil (10 mg and 20 mg once daily) does not potentiate the increase in bleeding time caused by aspirin.
## P-glycoprotein (e.g., digoxin]
Coadministration of tadalafil (40 mg once daily) for 10 days did not significantly alter digoxin pharmacokinetics in healthy subjects
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Pregnancy Category B — Tadalafil (tadalafil) is not indicated for use in women. There are no adequate and well controlled studies of Tadalafil use in pregnant women.
Risk Summary — Based on animal data, Tadalafil is not predicted to increase the risk of adverse developmental abnormalities in humans.
Animal Data — Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis. In one of two perinatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance.
In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16 and 10 fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg.
Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tadalafil in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tadalafil during labor and delivery.
### Nursing Mothers
Tadalafil is not indicated for use in women.
Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma.
### Pediatric Use
Tadalafil is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.
### Geriatic Use
Of the total number of subjects in ED clinical studies of tadalafil, approximately 25 percent were 65 and over, while approximately 3 percent were 75 and over. Of the total number of subjects in BPH clinical studies of tadalafil (including the ED/BPH study), approximately 40 percent were over 65, while approximately 10 percent were 75 and over. In these clinical trials, no overall differences in efficacy or safety were observed between older (>65 and ≥75 years of age) and younger subjects (≤65 years of age). Therefore no dose adjustment is warranted based on age alone. However, a greater sensitivity to medications in some older individuals should be considered. .
### Gender
There is no FDA guidance on the use of Tadalafil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tadalafil with respect to specific racial populations.
### Renal Impairment
In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with creatinine clearance 30 to 80 mL/min. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.8-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination. In a clinical pharmacology study (N=28) at a dose of 10 mg, back pain was reported as a limiting adverse event in male patients with creatinine clearance 30 to 50 mL/min. At a dose of 5 mg, the incidence and severity of back pain was not significantly different than in the general population. In patients on hemodialysis taking 10- or 20-mg tadalafil, there were no reported cases of back pain.
### Hepatic Impairment
In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tadalafil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tadalafil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Tadalafil contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis contributes negligibly to tadalafil elimination.
# Pharmacology
## Mechanism of Action
Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Pulmonary arterial hypertension is associated with impaired release of nitric oxide by the vascular endothelium and consequent reduction of cGMP concentrations in the pulmonary vascular smooth muscle. PDE5 is the predominant phosphodiesterase in the pulmonary vasculature. Inhibition of PDE5 by tadalafil increases the concentrations of cGMP resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.
In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000–fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is >10,000–fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700–fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14–fold more potent for PDE5 than for PDE11A1 and 40–fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.
## Structure
Tadalafil (tadalafil) is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is:
The chemical designation is pyrazino[1´,2´:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.
Tadalafil is available as almond-shaped tablets for oral administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
## Pharmacodynamics
Effects on Blood Pressure
Tadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate.
Effects on Blood Pressure When Administered with Nitrates
In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of Tadalafil in patients taking any form of nitrates is contraindicated .
A study was conducted to assess the degree of interaction between nitroglycerin and tadalafil, should nitroglycerin be required in an emergency situation after tadalafil was taken. This was a double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) and receiving daily doses of tadalafil 20 mg or matching placebo for 7 days. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints, following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). The objective of the study was to determine when, after tadalafil dosing, no apparent blood pressure interaction was observed. In this study, a significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the interaction was not detectable (see Figure 1).
Therefore, Tadalafil administration with nitrates is contraindicated. In a patient who has taken Tadalafil , where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of Tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring .
Effect on Blood Pressure When Administered With Alpha-Blockers
Six randomized, double-blinded, crossover clinical pharmacology studies were conducted to investigate the potential interaction of tadalafil with alpha-blocker agents in healthy male subjects . In four studies, a single oral dose of tadalafil was administered to healthy male subjects taking daily (at least 7 days duration) an oral alpha-blocker. In two studies, a daily oral alpha-blocker (at least 7 days duration) was administered to healthy male subjects taking repeated daily doses of tadalafil.
Doxazosin— Three clinical pharmacology studies were conducted with tadalafil and doxazosin, an alpha[1]-adrenergic blocker.
In the first doxazosin study, a single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking oral doxazosin 8 mg daily (N=18 subjects). Doxazosin was administered at the same time as tadalafil or placebo after a minimum of seven days of doxazosin dosing (see Table 5 and Figure 2).
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo administration. Outliers were defined as subjects with a standing systolic blood pressure of <85 mm Hg or a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points. There were nine and three outliers following administration of tadalafil 20 mg and placebo, respectively. Five and two subjects were outliers due to a decrease from baseline in standing systolic BP of >30 mm Hg, while five and one subject were outliers due to standing systolic BP <85 mm Hg following tadalafil and placebo, respectively. Severe adverse events potentially related to blood-pressure effects were assessed. No such events were reported following placebo. Two such events were reported following administration of tadalafil. Vertigo was reported in one subject that began 7 hours after dosing and lasted about 5 days. This subject previously experienced a mild episode of vertigo on doxazosin and placebo. Dizziness was reported in another subject that began 25 minutes after dosing and lasted 1 day. No syncope was reported.
In the second doxazosin study, a single oral dose of tadalafil 20 mg was administered to healthy subjects taking oral doxazosin, either 4 or 8 mg daily. The study (N=72 subjects) was conducted in three parts, each a 3-period crossover.
In part A (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 a.m. Tadalafil was administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.
In part B (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 p.m. Tadalafil was administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.
In part C (N=24), subjects were titrated to doxazosin 8 mg administered daily at 8 a.m. In this part, tadalafil or placebo were administered at either 8 a.m. or 8 p.m.
The placebo-subtracted mean maximal decreases in systolic blood pressure over a 12-hour period after dosing in the placebo-controlled portion of the study (part C) are shown in Table 6 and Figure 3.
Blood pressure was measured by ABPM every 15 to 30 minutes for up to 36 hours after tadalafil or placebo. Subjects were categorized as outliers if one or more systolic blood pressure readings of <85 mm Hg were recorded or one or more decreases in systolic blood pressure of >30 mm Hg from a time-matched baseline occurred during the analysis interval.
Of the 24 subjects in part C, 16 subjects were categorized as outliers following administration of tadalafil and 6 subjects were categorized as outliers following placebo during the 24-hour period after 8 a.m. dosing of tadalafil or placebo. Of these, 5 and 2 were outliers due to systolic BP <85 mm Hg, while 15 and 4 were outliers due to a decrease from baseline in systolic BP of >30 mm Hg following tadalafil and placebo, respectively.
During the 24-hour period after 8 p.m. dosing, 17 subjects were categorized as outliers following administration of tadalafil and 7 subjects following placebo. Of these, 10 and 2 subjects were outliers due to systolic BP <85 mm Hg, while 15 and 5 subjects were outliers due to a decrease from baseline in systolic BP of >30 mm Hg, following tadalafil and placebo, respectively.
Some additional subjects in both the tadalafil and placebo groups were categorized as outliers in the period beyond 24 hours.
Severe adverse events potentially related to blood-pressure effects were assessed. In the study (N=72 subjects), 2 such events were reported following administration of tadalafil (symptomatic hypotension in one subject that began 10 hours after dosing and lasted approximately 1 hour, and dizziness in another subject that began 11 hours after dosing and lasted 2 minutes). No such events were reported following placebo. In the period prior to tadalafil dosing, one severe event (dizziness) was reported in a subject during the doxazosin run-in phase.
In the third doxazosin study, healthy subjects (N=45 treated; 37 completed) received 28 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. After 7 days, doxazosin was initiated at 1 mg and titrated up to 4 mg daily over the last 21 days of each period (7 days on 1 mg; 7 days of 2 mg; 7 days of 4 mg doxazosin). The results are shown in Table 7.
Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours post dose on the first day of each doxazosin dose, (1 mg, 2 mg, 4 mg), as well as on the seventh day of 4 mg doxazosin administration.
Following the first dose of doxazosin 1 mg, there were no outliers on tadalafil 5 mg and one outlier on placebo due to a decrease from baseline in standing systolic BP of >30 mm Hg.
There were 2 outliers on tadalafil 5 mg and none on placebo following the first dose of doxazosin 2 mg due to a decrease from baseline in standing systolic BP of >30 mm Hg.
There were no outliers on tadalafil 5 mg and two on placebo following the first dose of doxazosin 4 mg due to a decrease from baseline in standing systolic BP of >30 mm Hg. There was one outlier on tadalafil 5 mg and three on placebo following the first dose of doxazosin 4 mg due to standing systolic BP <85 mm Hg. Following the seventh day of doxazosin 4 mg, there were no outliers on tadalafil 5 mg, one subject on placebo had a decrease >30 mm Hg in standing systolic blood pressure, and one subject on placebo had standing systolic blood pressure <85 mm Hg. All adverse events potentially related to blood pressure effects were rated as mild or moderate. There were two episodes of syncope in this study, one subject following a dose of tadalafil 5 mg alone, and another subject following coadministration of tadalafil 5 mg and doxazosin 4 mg.
Tamsulosin— In the first tamsulosin study, a single oral dose of tadalafil 10, 20 mg, or placebo was administered in a 3 period, crossover design to healthy subjects taking 0.4 mg once per day tamsulosin, a selective alpha[1A]-adrenergic blocker (N=18 subjects). Tadalafil or placebo was administered 2 hours after tamsulosin following a minimum of seven days of tamsulosin dosing.
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo dosing. There were 2, 2, and 1 outliers (subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points) following administration of tadalafil 10 mg, 20 mg, and placebo, respectively. There were no subjects with a standing systolic blood pressure <85 mm Hg. No severe adverse events potentially related to blood-pressure effects were reported. No syncope was reported.
In the second tamsulosin study, healthy subjects (N=39 treated; and 35 completed) received 14 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. Daily dosing of tamsulosin 0.4 mg was added for the last seven days of each period.
Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours post dose on the first, sixth and seventh days of tamsulosin administration. There were no outliers (subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points). One subject on placebo plus tamsulosin (Day 7) and one subject on tadalafil plus tamsulosin (Day 6) had standing systolic blood pressure <85 mm Hg. No severe adverse events potentially related to blood pressure were reported. No syncope was reported.
Alfuzosin — A single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking once-daily alfuzosin HCl 10 mg extended-release tablets, an alpha[1]-adrenergic blocker (N=17 completed subjects). Tadalafil or placebo was administered 4 hours after alfuzosin following a minimum of seven days of alfuzosin dosing.
Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20, and 24 hours after tadalafil or placebo dosing. There was 1 outlier (subject with a standing systolic blood pressure <85 mm Hg) following administration of tadalafil 20 mg. There were no subjects with a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points. No severe adverse events potentially related to blood pressure effects were reported. No syncope was reported.
Effects on Blood Pressure When Administered with Antihypertensives
Amlodipine — A study was conducted to assess the interaction of amlodipine (5 mg daily) and tadalafil 10 mg. There was no effect of tadalafil on amlodipine blood levels and no effect of amlodipine on tadalafil blood levels. The mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking amlodipine was 3/2 mm Hg, compared to placebo. In a similar study using tadalafil 20 mg, there were no clinically significant differences between tadalafil and placebo in subjects taking amlodipine.
Angiotensin II receptor blockers (with and without other antihypertensives) — A study was conducted to assess the interaction of angiotensin II receptor blockers and tadalafil 20 mg. Subjects in the study were taking any marketed angiotensin II receptor blocker, either alone, as a component of a combination product, or as part of a multiple antihypertensive regimen. Following dosing, ambulatory measurements of blood pressure revealed differences between tadalafil and placebo of 8/4 mm Hg in systolic/diastolic blood pressure.
Bendrofluazide — A study was conducted to assess the interaction of bendrofluazide (2.5 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking bendrofluazide was 6/4 mm Hg, compared to placebo.
Enalapril — A study was conducted to assess the interaction of enalapril (10 to 20 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking enalapril was 4/1 mm Hg, compared to placebo.
Metoprolol — A study was conducted to assess the interaction of sustained-release metoprolol (25 to 200 mg daily) and tadalafil 10 mg. Following dosing, the mean reduction in supine systolic/diastolic blood pressure due to tadalafil 10 mg in subjects taking metoprolol was 5/3 mm Hg, compared to placebo.
Effects on Blood Pressure When Administered with Alcohol
Alcohol and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. The interaction of tadalafil with alcohol was evaluated in 3 clinical pharmacology studies. In 2 of these, alcohol was administered at a dose of 0.7 g/kg, which is equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male, and tadalafil was administered at a dose of 10 mg in one study and 20 mg in another. In both these studies, all patients imbibed the entire alcohol dose within 10 minutes of starting. In one of these two studies, blood alcohol levels of 0.08% were confirmed. In these two studies, more patients had clinically significant decreases in blood pressure on the combination of tadalafil and alcohol as compared to alcohol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects. When tadalafil 20 mg was administered with a lower dose of alcohol (0.6 g/kg, which is equivalent to approximately 4 ounces of 80-proof vodka, administered in less than 10 minutes), orthostatic hypotension was not observed, dizziness occurred with similar frequency to alcohol alone, and the hypotensive effects of alcohol were not potentiated.
Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.
Effects on Exercise Stress Testing
The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates.
Effects on Vision
Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupilometry. Across all clinical studies with Tadalafil , reports of changes in color vision were rare (<0.1% of patients).
Effects on Sperm Characteristics
Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6 month study) and 20 mg (one 6 month and one 9 month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.
Effects on Cardiac Electrophysiology
The effect of a single 100-mg dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide) -controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two-sided 90% CI=1.2, 4.4). A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.
## Pharmacokinetics
Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with dose in healthy subjects. Steady-state plasma concentrations are attained within 5 days of once per day dosing and exposure is approximately 1.6-fold greater than after a single dose. Mean tadalafil concentrations measured after the administration of a single oral dose of 20 mg and single and once daily multiple doses of 5 mg, from a separate study, (see Figure 4) to healthy male subjects are depicted in Figure 4.
Absorption — After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food; thus Tadalafil may be taken with or without food.
Distribution — The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Metabolism — Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Excretion — The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Geriatric — Healthy male elderly subjects (65 years or over) had a lower oral clearance of tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax relative to that observed in healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered .
Pediatric — Tadalafil has not been evaluated in individuals less than 18 years old .
Patients with Diabetes Mellitus — In male patients with diabetes mellitus after a 10 mg tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.
Patients with BPH — In patients with BPH following single and multiple-doses of 20 mg tadalafil, no statistically significant differences in exposure (AUC and Cmax) were observed between elderly (70 to 85 years) and younger (≤60 years of age) subjects. No dose adjustment is warranted.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis — Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 10-fold for mice, and 14- and 26-fold for male and female rats, respectively, the exposures in human males given Maximum Recommended Human Dose (MRHD) of 20 mg.
Mutagenesis — Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitro chromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays.
Impairment of Fertility — There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 14-fold for males or 26-fold for females the exposures observed in human males given the MRHD of 20 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment-related non-reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20-100% of the dogs that resulted in a decrease in spermatogenesis in 40-75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no-observed-adverse-effect-level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 20 mg.
There were no treatment-related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.
## Animal Toxicology and/or Pharmacology
Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 2- to 33-fold above the human exposure (AUCs) at the MRHD of 20 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound tadalafil exposure of 1- to 54-fold above the human exposure (AUC) at the MRHD of 20 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 14- to 18-fold the human exposure at the MRHD of 20 mg. The abnormal blood-cell findings were reversible within 2 weeks after stopping treatment.
# Clinical Studies
## Tadalafil for Use as Needed for ED
The efficacy and safety of tadalafil in the treatment of erectile dysfunction has been evaluated in 22 clinical trials of up to 24-weeks duration, involving over 4000 patients. Tadalafil , when taken as needed up to once per day, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).
Tadalafil was studied in the general ED population in 7 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12-weeks duration. Two of these studies were conducted in the United States and 5 were conducted in centers outside the US. Additional efficacy and safety studies were performed in ED patients with diabetes mellitus and in patients who developed ED status post bilateral nerve-sparing radical prostatectomy.
In these 7 trials, Tadalafil was taken as needed, at doses ranging from 2.5 to 20 mg, up to once per day. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted.
Several assessment tools were used to evaluate the effect of Tadalafil on erectile function. The 3 primary outcome measures were the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4-week recall questionnaire that was administered at the end of a treatment-free baseline period and subsequently at follow-up visits after randomization. The IIEF EF domain has a 30-point total score, where higher scores reflect better erectile function. SEP is a diary in which patients recorded each sexual attempt made throughout the study. SEP Question 2 asks, “Were you able to insert your penis into the partner's vagina?” SEP Question 3 asks, “Did your erection last long enough for you to have successful intercourse?” The overall percentage of successful attempts to insert the penis into the vagina (SEP2) and to maintain the erection for successful intercourse (SEP3) is derived for each patient.
Results in ED Population in US Trials — The 2 primary US efficacy and safety trials included a total of 402 men with erectile dysfunction, with a mean age of 59 years (range 27 to 87 years). The population was 78% White, 14% Black, 7% Hispanic, and 1% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (>90%) patients reported ED of at least 1-year duration. Study A was conducted primarily in academic centers. Study B was conducted primarily in community-based urology practices. In each of these 2 trials, Tadalafil 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables . The treatment effect of Tadalafil did not diminish over time.
Results in General ED Population in Trials Outside the US — The 5 primary efficacy and safety studies conducted in the general ED population outside the US included 1112 patients, with a mean age of 59 years (range 21 to 82 years). The population was 76% White, 1% Black, 3% Hispanic, and 20% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (90%) patients reported ED of at least 1-year duration. In these 5 trials, Tadalafil 5, 10, and 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Tables 12, 13 and 14). The treatment effect of Tadalafil did not diminish over time.
In addition, there were improvements in EF domain scores, success rates based upon SEP Questions 2 and 3, and patient-reported improvement in erections across patients with ED of all degrees of disease severity while taking Tadalafil , compared to patients on placebo.
Therefore, in all 7 primary efficacy and safety studies, Tadalafil showed statistically significant improvement in patients' ability to achieve an erection sufficient for vaginal penetration and to maintain the erection long enough for successful intercourse, as measured by the IIEF questionnaire and by SEP diaries.
Efficacy Results in ED Patients with Diabetes Mellitus — Tadalafil was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in all 7 primary efficacy studies in the general ED population (N=235) and in one study that specifically assessed Tadalafil in ED patients with type 1 or type 2 diabetes (N=216). In this randomized, placebo-controlled, double-blinded, parallel-arm design prospective trial, Tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 15).
Efficacy Results in ED Patients following Radical Prostatectomy — Tadalafil was shown to be effective in treating patients who developed ED following bilateral nerve-sparing radical prostatectomy. In 1 randomized, placebo-controlled, double-blinded, parallel-arm design prospective trial in this population (N=303), Tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 16).
Results in Studies to Determine the Optimal Use of Tadalafil — Several studies were conducted with the objective of determining the optimal use of Tadalafil in the treatment of ED. In one of these studies, the percentage of patients reporting successful erections within 30 minutes of dosing was determined. In this randomized, placebo-controlled, double-blinded trial, 223 patients were randomized to placebo, Tadalafil 10, or 20 mg. Using a stopwatch, patients recorded the time following dosing at which a successful erection was obtained. A successful erection was defined as at least 1 erection in 4 attempts that led to successful intercourse. At or prior to 30 minutes, 35% (26/74), 38% (28/74), and 52% (39/75) of patients in the placebo, 10-, and 20-mg groups, respectively, reported successful erections as defined above.
Two studies were conducted to assess the efficacy of Tadalafil at a given timepoint after dosing, specifically at 24 hours and at 36 hours after dosing.
In the first of these studies, 348 patients with ED were randomized to placebo or Tadalafil 20 mg. Patients were encouraged to make 4 total attempts at intercourse; 2 attempts were to occur at 24 hours after dosing and 2 completely separate attempts were to occur at 36 hours after dosing. The results demonstrated a difference between the placebo group and the Tadalafil group at each of the pre-specified timepoints. At the 24-hour timepoint, (more specifically, 22 to 26 hours), 53/144 (37%) patients reported at least 1 successful intercourse in the placebo group versus 84/138 (61%) in the Tadalafil 20-mg group. At the 36-hour timepoint (more specifically, 33 to 39 hours), 49/133 (37%) of patients reported at least 1 successful intercourse in the placebo group versus 88/137 (64%) in the Tadalafil 20-mg group.
In the second of these studies, a total of 483 patients were evenly randomized to 1 of 6 groups: 3 different dosing groups (placebo, Tadalafil 10, or 20 mg) that were instructed to attempt intercourse at 2 different times (24 and 36 hours post-dosing). Patients were encouraged to make 4 separate attempts at their assigned dose and assigned timepoint. In this study, the results demonstrated a statistically significant difference between the placebo group and the Tadalafil groups at each of the pre-specified timepoints. At the 24-hour timepoint, the mean, per patient percentage of attempts resulting in successful intercourse were 42, 56, and 67% for the placebo, Tadalafil 10-, and 20-mg groups, respectively. At the 36-hour timepoint, the mean, per-patient percentage of attempts resulting in successful intercourse were 33, 56, and 62% for placebo, Tadalafil 10-, and 20-mg groups, respectively.
## Tadalafil for Once Daily Use for ED
The efficacy and safety of Tadalafil for once daily use in the treatment of erectile dysfunction has been evaluated in 2 clinical trials of 12-weeks duration and 1 clinical trial of 24-weeks duration, involving a total of 853 patients. Tadalafil , when taken once daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).
Tadalafil was studied in the general ED population in 2 randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design, primary efficacy and safety studies of 12- and 24-weeks duration, respectively. One of these studies was conducted in the United States and one was conducted in centers outside the US. An additional efficacy and safety study was performed in ED patients with diabetes mellitus. Tadalafil was taken once daily at doses ranging from 2.5 to 10 mg. Food and alcohol intake were not restricted. Timing of sexual activity was not restricted relative to when patients took Tadalafil .
Results in General ED Population — The primary US efficacy and safety trial included a total of 287 patients, with a mean age of 59 years (range 25 to 82 years). The population was 86% White, 6% Black, 6% Hispanic, and 2% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (>96%) patients reported ED of at least 1-year duration.
The primary efficacy and safety study conducted outside the US included 268 patients, with a mean age of 56 years (range 21 to 78 years). The population was 86% White, 3% Black, 0.4% Hispanic, and 10% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co-morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Ninety-three percent of patients reported ED of at least 1-year duration.
In each of these trials, conducted without regard to the timing of dose and sexual intercourse, Tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 17). When taken as directed, Tadalafil was effective at improving erectile function.
In the 6 month double-blind study, the treatment effect of Tadalafil did not diminish over time.
Efficacy Results in ED Patients with Diabetes Mellitus — Tadalafil for once daily use was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in both studies in the general ED population (N=79). A third randomized, multicenter, double-blinded, placebo-controlled, parallel-arm design trial included only ED patients with type 1 or type 2 diabetes (N=298). In this third trial, Tadalafil demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 18).
## Tadalafil 5 mg for Once Daily Use for Benign Prostatic Hyperplasia (BPH)
The efficacy and safety of Tadalafil for once daily use for the treatment of the signs and symptoms of BPH was evaluated in 3 randomized, multinational, double-blinded, placebo-controlled, parallel-design, efficacy and safety studies of 12 weeks duration. Two of these studies were in men with BPH and one study was specific to men with both ED and BPH . The first study (Study J) randomized 1058 patients to receive either Tadalafil 2.5 mg, 5 mg, 10 mg or 20 mg for once daily use or placebo. The second study (Study K) randomized 325 patients to receive either Tadalafil 5 mg for once daily use or placebo. The full study population was 87% White, 2% Black, 11% other races; 15% was of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.
The primary efficacy endpoint in the two studies that evaluated the effect of Tadalafil for the signs and symptoms of BPH was the International Prostate Symptom Score (IPSS), a four week recall questionnaire that was administered at the beginning and end of a placebo run-in period and subsequently at follow-up visits after randomization. The IPSS assesses the severity of irritative (frequency, urgency, nocturia) and obstructive symptoms (incomplete emptying, stopping and starting, weak stream, and pushing or straining), with scores ranging from 0 to 35; higher numeric scores representing greater severity. Maximum urinary flow rate (Qmax), an objective measure of urine flow, was assessed as a secondary efficacy endpoint in Study J and as a safety endpoint in Study K.
The results for BPH patients with moderate to severe symptoms and a mean age of 63.2 years (range 44 to 87) who received either Tadalafil 5 mg for once daily use or placebo (N=748) in Studies J and K are shown in Table 19 and Figures 5 and 6, respectively.
In each of these 2 trials, Tadalafil 5 mg for once daily use resulted in statistically significant improvement in the total IPSS compared to placebo. Mean total IPSS showed a decrease starting at the first scheduled observation (4 weeks) in Study K and remained decreased through 12 weeks.
In Study J, the effect of Tadalafil 5 mg once daily on maximum urinary flow rate (Qmax) was evaluated as a secondary efficacy endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (Tadalafil 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.
In Study K, the effect of Tadalafil 5 mg once daily on Qmax was evaluated as a safety endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (Tadalafil 5 mg: 1.6 mL/sec, placebo: 1.1 mL/sec); however, these changes were not significantly different between groups.
Efficacy Results in Patients with BPH initiating Tadalafil and Finasteride – Tadalafil for once daily use initiated together with finasteride was shown to be effective in treating the signs and symptoms of BPH in men with an enlarged prostate (>30 cc) for up to 26 weeks. This additional double-blinded, parallel-design study of 26 weeks duration randomized 696 men to initiate either Tadalafil 5 mg with finasteride 5 mg or placebo with finasteride 5 mg. The study population had a mean age of 64 years (range 46-86). Patients with multiple co-morbid conditions such as erectile dysfunction, diabetes mellitus, hypertension, and other cardiovascular disease were included.
Tadalafil with finasteride demonstrated statistically significant improvement in the signs and symptoms of BPH compared to placebo with finasteride, as measured by the total IPSS at 12 weeks, the primary study endpoint (see Table 20). Key secondary endpoints demonstrated improvement in total IPSS starting at the first scheduled observation at week 4 (Tadalafil -4.0, placebo -2.3: p<.001) and the score remained decreased through 26 weeks (Tadalafil -5.5, placebo -4.5; p=.022). However, the magnitude of the treatment difference between placebo/finasteride and Tadalafil /finasteride decreased from 1.7 points at Week 4 to 1.0 point at Week 26, as shown in Table 20 and in Figure 7. The incremental benefit of Tadalafil beyond 26 weeks is unknown.
In the 404 patients who had both ED and BPH at baseline, changes in erectile function were assessed as key secondary endpoints using the EF domain of the IIEF questionnaire. Tadalafil with finasteride (N=203) was compared to placebo with finasteride (N=201). A statistically significant improvement from baseline (Tadalafil /finasteride 13.7, placebo/finasteride 15.1) was observed at week 4 (Tadalafil /finasteride 3.7, placebo/finasteride -1.1; p<.001), week 12 (Tadalafil /finasteride 4.7, placebo/finasteride 0.6; p<.001), and week 26 (Tadalafil /finasteride 4.7, placebo/finasteride 0.0; p<.001).
## Tadalafil 5 mg for Once Daily Use for ED and BPH
The efficacy and safety of Tadalafil for once daily use for the treatment of ED, and the signs and symptoms of BPH, in patients with both conditions was evaluated in one placebo-controlled, multinational, double-blind, parallel-arm study which randomized 606 patients to receive either Tadalafil 2.5 mg, 5 mg, for once daily use or placebo. ED severity ranged from mild to severe and BPH severity ranged from moderate to severe. The full study population had a mean age of 63 years (range 45 to 83) and was 93% White, 4% Black, 3% other races; 16% were of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.
In this study, the co-primary endpoints were total IPSS and the Erectile Function (EF) domain score of the International Index of Erectile Function (IIEF). One of the key secondary endpoints in this study was Question 3 of the Sexual Encounter Profile diary (SEP3). Timing of sexual activity was not restricted relative to when patients took Tadalafil .
The efficacy results for patients with both ED and BPH, who received either Tadalafil 5 mg for once daily use or placebo (N=408) are shown in Tables 21 and 22 and Figure 8.
Tadalafil 5 mg for once daily use resulted in statistically significant improvements in the total IPSS and in the EF domain of the IIEF questionnaire. Tadalafil 5 mg for once daily use also resulted in statistically significant improvement in SEP3. Tadalafil 2.5 mg did not result in statistically significant improvement in the total IPSS.
In this study, the effect of Tadalafil 5 mg once daily on Qmax was evaluated as a safety endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (Tadalafil 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.
# How Supplied
Tadalafil (tadalafil) is supplied as follows:
Four strengths of almond-shaped tablets are available in different sizes and different shades of yellow, and supplied in the following package sizes:
## Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
## Nitrates
Physicians should discuss with patients the contraindication of Tadalafil with regular and/or intermittent use of organic nitrates. Patients should be counseled that concomitant use of Tadalafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of Tadalafil . In such a patient, who has taken Tadalafil , where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed after the last dose of Tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring. Therefore, patients who experience anginal chest pain after taking Tadalafil should seek immediate medical attention
## Cardiovascular Considerations
Physicians should consider the potential cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Physicians should advise patients who experience symptoms upon initiation of sexual activity to refrain from further sexual activity and seek immediate medical attention .
## Concomitant Use with Drugs Which Lower Blood Pressure
Physicians should discuss with patients the potential for Tadalafil to augment the blood-pressure-lowering effect of alpha-blockers and antihypertensive medications
## Potential for Drug Interactions When Taking Tadalafil for Once Daily Use
Physicians should discuss with patients the clinical implications of continuous exposure to tadalafil when prescribing Tadalafil for once daily use, especially the potential for interactions with medications (e.g., nitrates, alpha-blockers, antihypertensives and potent inhibitors of cytochrome P450 3A4) and with substantial consumption of alcohol.
## Priapism
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Physicians should advise patients who have an erection lasting greater than 4 hours, whether painful or not, to seek emergency medical attention.
## Sudden Loss of Vision
Physicians should advise patients to stop use of all PDE5 inhibitors, including Tadalafil , and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including possible permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a "crowded" optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including Tadalafil , for this uncommon condition .
## Sudden Hearing Loss
Physicians should advise patients to stop taking PDE5 inhibitors, including Tadalafil , and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Tadalafil . It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors .
## Alcohol
Patients should be made aware that both alcohol and Tadalafil , a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache .
## Sexually Transmitted Disease
The use of Tadalafil offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
## Recommended Administration
Physicians should instruct patients on the appropriate administration of Tadalafil to allow optimal use.
For Tadalafil for use as needed in men with ED, patients should be instructed to take one tablet at least 30 minutes before anticipated sexual activity. In most patients, the ability to have sexual intercourse is improved for up to 36 hours.
For Tadalafil for once daily use in men with ED or ED/BPH, patients should be instructed to take one tablet at approximately the same time every day without regard for the timing of sexual activity. Tadalafil is effective at improving erectile function over the course of therapy.
For Tadalafil for once daily use in men with BPH, patients should be instructed to take one tablet at approximately the same time every day.
# Precautions with Alcohol
Alcohol-Tadalafil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cialis
- Adcirca
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cialis | |
8fab34d74fe6851f4583848440964bc6810bc9ec | wikidoc | Cidofovir | Cidofovir
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# Black Box Warning
# Overview
Cidofovir is an antiviral, cytosine nucleoside analog that is FDA approved for the treatment of Citomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). The safety and efficacy of Cidofovir have not been established for treatment of other CMV infections (such as pneumonitis or gastroenteritis), congenital or neonatal CMV disease, or CMV disease in non-HIV-infected individuals. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, rash, oral candidiasis, anemia, neutropenia, infections, asthenia, headache, iritis, uveitis, proteinuria, elevated serum creatinine, cough, dyspnea, fever, pain and shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### CMV Retinitis
- The recommended induction dose of Cidofovir for patients with a serum creatinine of ≤ 1.5 mg/dL, a calculated creatinine clearance > 55 mL/min, and a urine protein < 100 mg/dL (equivalent to < 2+ proteinuria) is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once weekly for two consecutive weeks. Because serum creatinine in patients with advanced AIDS and CMV retinitis may not provide a complete picture of the patient's underlying renal status, it is important to utilize the Cockcroft-Gault formula to more precisely estimate creatinine clearance (CrCl). As creatinine clearance is dependent on serum creatinine and patient weight, it is necessary to calculate clearance prior to initiation of Cidofovir CrCl (mL/min) should be calculated according to the following formula:
- The recommended maintenance dose of Cidofovir is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr), administered once every 2 weeks.
- Probenecid must be administered orally with each Cidofovir dose. Two grams must be administered 3 hr prior to the Cidofovir dose and one gram administered at 2 and again at 8 hr after completion of the 1 hr Cidofovir infusion (for a total of 4 grams).
- Ingestion of food prior to each dose of probenecid may reduce drug-related nausea and vomiting. Administration of an antiemetic may reduce the potential for nausea associated with probenecid ingestion. In patients who develop allergic or hypersensitivity symptoms to probenecid, the use of an appropriate prophylactic or therapeutic antihistamine and/or acetaminophen should be considered.
- Patients must receive at least one liter of 0.9% (normal) saline solution intravenously with each infusion of Cidofovir. The saline solution should be infused over a 1–2 hr period immediately before the Cidofovir infusion. Patients who can tolerate the additional fluid load should receive a second liter. If administered, the second liter of saline should be initiated either at the start of the Cidofovir infusion or immediately afterwards, and infused over a 1 to 3 hr period.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosage: 5 mg/kg once weekly
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cidofovir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Cidofovir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cidofovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cidofovir in pediatric patients.
# Contraindications
- Initiation of therapy with Cidofovir is contraindicated in patients with a serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
- Cidofovir is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with Cidofovir.
- Cidofovir is contraindicated in patients with hypersensitivity to cidofovir.
- Cidofovir is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications.
- Direct intraocular injection of Cidofovir is contraindicated; direct injection of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.
# Warnings
- Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to Cidofovir administration. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of Cidofovir. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of Cidofovir Dose adjustment or discontinuation is required for changes in renal function (serum creatinine and/or urine protein) while on therapy. Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indicator of Cidofovir-related nephrotoxicity. Continued administration of Cidofovir may lead to additional proximal tubule cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis. Patients with these adverse events occurring concurrently and meeting a criteria of Fanconi's syndrome have been reported. Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of Cidofovir.
- Intravenous normal saline hydration and oral probenecid must accompany each Cidofovir infusion. Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs. The safety of Cidofovir has not been evaluated in patients receiving other known potentially nephrotoxic agents, such as intravenous aminoglycosides (tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents.
- Initiation of therapy with Cidofovir is contraindicated in patients with a baseline serum creatinine > 1.5 mg/dL, a creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
- Neutropenia may occur during Cidofovir therapy. Neutrophil count should be monitored while receiving Cidofovir therapy.
- Decreased intraocular pressure may occur during Cidofovir therapy, and in some instances has been associated with decreased visual acuity. Intraocular pressure should be monitored during Cidofovir therapy.
- Decreased serum bicarbonate associated with proximal tubule injury and renal wasting syndrome (including Fanconi's syndrome) have been reported in patients receiving Cidofovir. Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving Cidofovir.
# Adverse Reactions
## Clinical Trials Experience
- Renal toxicity, as manifested by ≥ 2+ proteinuria, serum creatinine elevations of ≥ 0.4 mg/dL, or decreased creatinine clearance ≤ 55 mL/min, occurred in 79 of 135 (59%) patients receiving Cidofovir at a maintenance dose of 5 mg/kg every other week. Maintenance dose reductions from 5 mg/kg to 3 mg/kg due to proteinuria or serum creatinine elevations were made in 12 of 41 (29%) patients who had not received prior therapy for CMV retinitis (Study 106) and in 19 of 74 (26%) patients who had received prior therapy for CMV retinitis (Study 107). Prior foscarnet use has been associated with an increased risk of nephrotoxicity; therefore, such patients must be monitored closely.
- In clinical trials, at the 5 mg/kg maintenance dose, a decrease in absolute neutrophil count to ≤ 500 cells/mm 3 occurred in 24% of patients. Granulocyte colony stimulating factor (GCSF) was used in 39% of patients.
- Among the subset of patients monitored for intraocular pressure changes, a ≥ 50% decrease from baseline intraocular pressure was reported in 17 of 70 (24%) patients at the 5 mg/kg maintenance dose. Severe hypotony (intraocular pressure of 0–1 mm Hg) has been reported in 3 patients. Risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus.
- Uveitis or iritis has been reported in clinical trials and during postmarketing in patients receiving Cidofovir therapy. Uveitis or iritis was reported in 15 of 135 (11%) patients receiving 5 mg/kg maintenance dosing. Treatment with topical corticosteroids with or without topical cycloplegic agents may be considered. Patients should be monitored for signs and symptoms of uveitis/iritis during Cidofovir therapy.
- A diagnosis of Fanconi's syndrome, as manifested by multiple abnormalities of proximal renal tubular function, was reported in 1% of patients. Decreases in serum bicarbonate to ≤ 16 mEq/L occurred in 16% of cidofovir-treated patients. Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving Cidofovir In clinical trials, Cidofovir was withdrawn due to adverse events in 39% of patients treated with 5 mg/kg every other week as maintenance therapy.
- The incidence of adverse reactions reported as serious in three controlled clinical studies in patients with CMV retinitis, regardless of presumed relationship to drug, is listed in Table 4.
- The most frequently reported adverse events regardless of relationship to study drugs (cidofovir or probenecid) or severity are shown in Table 5.
The following additional list of adverse events/intercurrent illnesses have been observed in clinical studies of Cidofovir and are listed below regardless of causal relationship to Cidofovir Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medicines.
- Abdominal pain
- Accidental injury
- AIDS
- Allergic reaction
- Back pain
- Catheter blocked
- Cellulitis
- Chest pain
- Chills and fever
- Cryptococcosis
- Cyst
- Death
- Face edema
- Flu-like syndrome
- Hypothermia
- Injection site reaction
- Malaise
- Mucous membrane disorder
- Neck pain
- Overdose
- Photosensitivity reaction
- Sarcoma
- Sepsis
- Cardiomyopathy
- Cardiovascular disorder
- Congestive heart failure
- Hypertension
- hypotension
- Migraine
- Pallor
- Peripheral vascular disorder
- Phlebitis
- Postural hypotension
- Shock
- Syncope
- Tachycardia
- Vascular disorder
- Edema
- Cholangitis
- Colitis
- Constipation
- Esophagitis
- Dyspepsia
- Dysphagia
- Fecal incontinence
- Flatulence
- Gastritis
- Gastrointestinal hemorrhage
- Gingivitis
- Hepatitis
- Hepatomegaly
- Hepatosplenomegaly
- Jaundice
- Abnormal liver function
- Liver damage
- Liver necrosis
- Melena
- Pancreatitis
- Proctitis
- Rectal disorder
- Stomatitis
- Aphthous stomatitis
- Tongue discoloration
- Mouth ulceration
- Tooth caries
- Adrenal cortex insufficiency
- Hypochromic anemia
- Leukocytosis
- Leukopenia
- Lymphadenopathy
- Lymphoma like reaction
- Pancytopenia
- Splenic disorder
- Splenomegaly
- Thrombocytopenia
- Thrombocytopenic purpura
- Cachexia
- Dehydration
- Edema
- Hypercalcemia
- Hyperglycemia
- Hyperkalemia
- Hyperlipemia
- Hypocalcemia
- Hypoglycemia
- Hypoglycemic reaction
- Hypokalemia
- Hypomagnesemia
- Hyponatremia
- Hypophosphatemia
- Hypoproteinemia
- Increased alkaline phosphatase
- Increased BUN
- Increased lactic dehydrogenase
- Increased SGOT/SGPT
- Peripheral edema
- Respirator alkalosis
- Thirst
- Weight loss
- Weight gain
- Arthralgia
- Arthrosis
- Bone necrosis
- Bone pain
- Joint disorder
- Leg cramps
- Myalgia
- Myasthenia
- Pathological fracture
- Abnormal dreams
- Abnormal gait
- Acute brain syndrome
- Agitation
- Amnesia
- Anxiety
- Ataxia
- Cerebrovascular disorder
- Confusion
- Convulsion
- Delirium
- Dementia
- Depression
- Dizziness
- Drug dependence
- Dry mouth
- Encephalopathy
- Facial paralysis
- Hallucinations
- Hemiplegia
- Hyperesthesia
- Hypertonia
- Hypotony
- Incoordination
- Increased libido
- Insomnia
- Myoclonus
- Nervousness
- Neuropathy
- Paresthesia
- Personality disorder
- Somnolence
- Speech disorder
- Tremor
- Twitching
- Vasodilatation
- Vertigo
- Asthma
- Bronchitis
- Epistaxis
- Hemoptysis
- Hiccups
- Hyperventilation
- Hjypoxia
- Increased sputum
- Larynx edema
- Lung disorder
- Pharyngitis
- Pneumothorax
- Rhinitis
- Sinusitis
- Acne
- Angioedema
- Dry skin
- Eczema
- Exfoliative dermatitis
- Furunculosis
- Herpes simplex
- Nail disorder
- Pruritus
- Rash
- Seborrhea
- Skin discoloration
- Skin disorder
- Skin hypertrophy
- Skin ulcer
- Sweating
- Urticaria
- Abnormal vision
- Amblyopia
- Blindness
- Cataract
- Conjunctivitis
- Corneal lesion
- Corneal opacity
- Diplopia
- Dry eyes
- Ear disorder
- Ear pain
- Eye disorder
- Eye pain
- Hyperacusis
- Iritis
- Keratitis
- Miosis
- Otitis externa
- Otitis media
- Refraction disorder
- Retinal detachment
- Retinal disorder
- Taste perversion
- Tinnitus
- Uveitis
- Visual field defect
- Hearing loss
- Decreased creatinine clearance
- Dysuria
- Glycosuria
- Hematuria
- Kidney stone
- Mastitis
- Metorrhagia
- Nocturia
- Polyuria
- Prostatic disorder
- Toxic nephrophathy
- Urethritis
- Urinary casts
- Urinary incontinence
- Urinary retention
- Urinary tract infection
## Postmarketing Experience
There is limited information regarding Cidofovir Postmarketing Experience in the drug label.
# Drug Interactions
### Zidovudine
- The pharmacokinetics of zidovudine were evaluated in ten patients receiving zidovudine alone or with intravenous cidofovir (without probenecid). There was no evidence of an effect of cidofovir on the pharmacokinetics of zidovudine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Cidofovir was embryotoxic (reduced fetal body weights) in rats at 1.5 mg/kg/day and in rabbits at 1.0 mg/kg/day, doses which were also maternally toxic, following daily intravenous dosing during the period of organogenesis. The no-observable-effect levels for embryotoxicity in rats (0.5 mg/kg/day) and in rabbits (0.25 mg/kg/day) were approximately 0.04 and 0.05 times the clinical dose (5 mg/kg every other week) based on AUC, respectively. An increased incidence of fetal external, soft tissue and skeletal anomalies (meningocele, short snout, and short maxillary bones) occurred in rabbits at the high dose (1.0 mg/kg/day) which was also maternally toxic. There are no adequate and well-controlled studies in pregnant women. Cidofovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cidofovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cidofovir during labor and delivery.
### Nursing Mothers
- It is not known whether cidofovir is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for adverse reactions as well as the potential for tumorigenicity shown for cidofovir in animal studies, Cidofovir should not be administered to nursing mothers. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid postnatal transmission of HIV to a child who may not yet be infected.
### Pediatric Use
- Safety and effectiveness in children have not been studied. The use of Cidofovir in children with AIDS warrants extreme caution due to the risk of long-term carcinogenicity and reproductive toxicity. Administration of Cidofovir to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh the risks.
### Geriatic Use
- No studies of the safety or efficacy of Cidofovir in patients over the age of 60 have been conducted. Since elderly individuals frequently have reduced glomerular filtration, particular attention should be paid to assessing renal function before and during Cidofovir administration
### Gender
There is no FDA guidance on the use of Cidofovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cidofovir with respect to specific racial populations.
### Renal Impairment
- Cidofovir is contraindicated in patients with a serum creatinine concentration > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
### Hepatic Impairment
There is no FDA guidance on the use of Cidofovir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Chronic, two-year carcinogenicity studies in rats and mice have not been carried out to evaluate the carcinogenic potential of cidofovir. However, a 26-week toxicology study evaluating once weekly subscapular subcutaneous injections of cidofovir in rats was terminated at 19 weeks because of the induction, in females, of palpable masses, the first of which was detected after six doses. The masses were diagnosed as mammary adenocarcinomas which developed at doses as low as 0.6 mg/kg/week, equivalent to 0.04 times the human systemic exposure at the recommended intravenous Cidofovir dose based on AUC comparisons.
- In a 26-week intravenous toxicology study in which rats received 0.6, 3, or 15 mg/kg cidofovir once weekly, a significant increase in mammary adenocarcinomas in female rats as well as a significant incidence of Zymbal's gland carcinomas in male and female rats were seen at the high dose but not at the lower two doses. The high dose was equivalent to 1.1 times the human systemic exposure at the recommended dose of Cidofovir, based on comparisons of AUC measurements. In light of the results of these studies, cidofovir should be considered to be a carcinogen in rats as well as a potential carcinogen in humans.
- Cynomolgus monkeys received intravenous cidofovir, alone and in conjunction with concomitant oral probenecid, intravenously once weekly for 52 weeks at doses resulting in exposures of approximately 0.7 times the human systemic exposure at the recommended dose of Cidofovir No tumors were detected. However, the study was not designed as a carcinogenicity study due to the small number of animals at each dose and the short duration of treatment.
- No mutagenic response was observed in microbial mutagenicity assays involving Salmonella typhimurium (Ames) and ] in the presence and absence of metabolic activation. An increase in micro nucleated polychromatic erythrocytes in vivo was seen in mice receiving ≥ 2000 mg/kg, a dosage approximately 65-fold higher than the maximum recommended clinical intravenous Cidofovir dose based on body surface area estimations. Cidofovir induced chromosomal aberrations in human peripheral blood lymphocytes in vitro without metabolic activation. At the 4 cidofovir levels tested, the percentage of damaged metaphases and number of aberrations per cell increased in a concentration-dependent manner.
- Studies showed that cidofovir caused inhibition of spermatogenesis in rats and monkeys. However, no adverse effects on fertility or reproduction were seen following once weekly intravenous injections of cidofovir in male rats for 13 consecutive weeks at doses up to 15 mg/kg/week (equivalent to 1.1 times the recommended human dose based on AUC comparisons). Female rats dosed intravenously once weekly at 1.2 mg/kg/week (equivalent to 0.09 times the recommended human dose based on AUC) or higher, for up to 6 weeks prior to mating and for 2 weeks post mating had decreased litter sizes and live births per litter and increased early resorptions per litter. Peri- and post-natal development studies in which female rats received subcutaneous injections of cidofovir once daily at doses up to 1.0 mg/kg/day from day 7 of gestation through day 21 postpartum (approximately 5 weeks) resulted in no adverse effects on viability, growth, behavior, sexual maturation or reproductive capacity in the offspring.
### Immunocompromised Patients
There is no FDA guidance one the use of Cidofovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The recommended dosage, frequency, or infusion rate must not be exceeded. Cidofovir must be diluted in 100 milliliters 0.9% (normal) saline prior to administration. to minimize potential nephrotoxicity, probenecid and intravenous saline prehydration must be administered with each VISITIDE infusion.
- Inspect vials visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is observed, the vial should not be used. With a syringe, extract the appropriate volume of Cidofovir from the vial and transfer the dose to an infusion bag containing 100 mL 0.9% (normal) saline solution. Infuse the entire volume intravenously into the patient at a constant rate over a 1 hr period. Use of a standard infusion pump for administration is recommended.
- It is recommended that Cidofovir infusion admixtures be administered within 24 hr of preparation and that refrigerator or freezer storage not be used to extend this 24 hr limit.
- If admixtures are not intended for immediate use, they may be stored under refrigeration (2–8°C) for no more than 24 hr. Refrigerated admixtures should be allowed to equilibrate to room temperature prior to use.
- The chemical stability of Cidofovir admixtures was demonstrated in polyvinyl chloride composition and ethylene/propylene copolymer composition commercial infusion bags, and in glass bottles. No data are available to support the addition of other drugs or supplements to the cidofovir admixture for concurrent administration.
- Cidofovir is supplied in single-use vials. Partially used vials should be discarded
### Monitoring
- Serum creatinine and urine protein must be monitored within 48 hours prior to each dose. White blood cell counts with differential should be monitored prior to each dose. In patients with proteinuria, intravenous hydration should be administered and the test repeated. Intraocular pressure, visual acuity and ocular symptoms should be monitored periodically.
# IV Compatibility
- Compatibility with Ringer's solution, Lactated Ringer's solution or bacteriostatic infusion fluids has not been evaluated.
# Overdosage
- Two cases of cidofovir overdose have been reported. These patients received single doses of Cidofovir at 16.3 mg/kg and 17.4 mg/kg, respectively, with concomitant oral probenecid and intravenous hydration. In both cases, the patients were hospitalized and received oral probenecid (one gram three times daily) and vigorous intravenous hydration with normal saline for 3 to 5 days. Significant changes in renal function were not observed in either patient.
# Pharmacology
## Mechanism of Action
- Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis. *Biochemical data support selective inhibition of CMV DNA polymerase by cidofovir diphosphate, the active intracellular metabolite of cidofovir. Cidofovir diphosphate inhibits herpesvirus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma1, 2, 3. Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.
## Structure
- The chemical name of cidofovir is 1-cytosine dihydrate (HPMPC), with the molecular formula of C8H14N3O6P2H2O and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is:
## Pharmacodynamics
There is limited information regarding Cidofovir Pharmacodynamics in the drug label.
## Pharmacokinetics
- Cidofovir must be administered with probenecid. The pharmacokinetics of cidofovir, administered both without and with probenecid, are described below.
- The pharmacokinetics of cidofovir without probenecid were evaluated in 27 HIV-infected patients with or without asymptomatic CMV infection. Dose-independent pharmacokinetics were demonstrated after one hr infusions of 1.0 (n = 5), 3.0 (n = 10), 5.0 (n = 2) and 10.0 (n = 8) mg/kg. There was no evidence of cidofovir accumulation after 4 weeks of repeated administration of 3 mg/kg/week (n = 5) without probenecid. In patients with normal renal function, approximately 80 to 100% of the Cidofovir dose was recovered unchanged in urine within 24 hr (n = 27). The renal clearance of cidofovir was greater than creatinine clearance, indicating renal tubular secretion contributes to the elimination of cidofovir.
- The pharmacokinetics of cidofovir administered with probenecid were evaluated in 12 HIV-infected patients with or without asymptomatic CMV infection and 10 patients with relapsing CMV retinitis. Dose-independent pharmacokinetics were observed for cidofovir, administered with probenecid, after one hr infusions of 3.0 (n = 12), 5.0 (n = 6), and 7.5 (n = 4) mg/kg (See TABLE 2). Approximately 70 to 85% of the Cidofovir dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When Cidofovir was administered with probenecid, the renal clearance of cidofovir was reduced to a level consistent with creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir.
## Nonclinical Toxicology
There is limited information regarding Cidofovir Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Cidofovir Clinical Studies in the drug label.
# How Supplied
- Cidofovir (cidofovir injection) 75 mg/mL for intravenous infusion, is supplied as a non-preserved solution in single-use clear glass vials as follows:
NDC 61958-0101-1: 375 mg in a 5 mL vial in a single-unit carton
- NDC 61958-0101-1: 375 mg in a 5 mL vial in a single-unit carton
## Storage
- Cidofovir should be stored at controlled room temperature 20–25 °C (68–77 °F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cidofovir Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Cidofovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vistide
# Look-Alike Drug Names
There is limited information regarding Cidofovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cidofovir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
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# Black Box Warning
# Overview
Cidofovir is an antiviral, cytosine nucleoside analog that is FDA approved for the treatment of Citomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). The safety and efficacy of Cidofovir have not been established for treatment of other CMV infections (such as pneumonitis or gastroenteritis), congenital or neonatal CMV disease, or CMV disease in non-HIV-infected individuals. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, rash, oral candidiasis, anemia, neutropenia, infections, asthenia, headache, iritis, uveitis, proteinuria, elevated serum creatinine, cough, dyspnea, fever, pain and shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### CMV Retinitis
- The recommended induction dose of Cidofovir for patients with a serum creatinine of ≤ 1.5 mg/dL, a calculated creatinine clearance > 55 mL/min, and a urine protein < 100 mg/dL (equivalent to < 2+ proteinuria) is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once weekly for two consecutive weeks. Because serum creatinine in patients with advanced AIDS and CMV retinitis may not provide a complete picture of the patient's underlying renal status, it is important to utilize the Cockcroft-Gault formula to more precisely estimate creatinine clearance (CrCl). As creatinine clearance is dependent on serum creatinine and patient weight, it is necessary to calculate clearance prior to initiation of Cidofovir CrCl (mL/min) should be calculated according to the following formula:
- The recommended maintenance dose of Cidofovir is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr), administered once every 2 weeks.
- Probenecid must be administered orally with each Cidofovir dose. Two grams must be administered 3 hr prior to the Cidofovir dose and one gram administered at 2 and again at 8 hr after completion of the 1 hr Cidofovir infusion (for a total of 4 grams).
- Ingestion of food prior to each dose of probenecid may reduce drug-related nausea and vomiting. Administration of an antiemetic may reduce the potential for nausea associated with probenecid ingestion. In patients who develop allergic or hypersensitivity symptoms to probenecid, the use of an appropriate prophylactic or therapeutic antihistamine and/or acetaminophen should be considered.
- Patients must receive at least one liter of 0.9% (normal) saline solution intravenously with each infusion of Cidofovir. The saline solution should be infused over a 1–2 hr period immediately before the Cidofovir infusion. Patients who can tolerate the additional fluid load should receive a second liter. If administered, the second liter of saline should be initiated either at the start of the Cidofovir infusion or immediately afterwards, and infused over a 1 to 3 hr period.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Dosage: 5 mg/kg once weekly[1]
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cidofovir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Cidofovir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cidofovir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cidofovir in pediatric patients.
# Contraindications
- Initiation of therapy with Cidofovir is contraindicated in patients with a serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
- Cidofovir is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with Cidofovir.
- Cidofovir is contraindicated in patients with hypersensitivity to cidofovir.
- Cidofovir is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications.
- Direct intraocular injection of Cidofovir is contraindicated; direct injection of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.
# Warnings
- Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to Cidofovir administration. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of Cidofovir. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of Cidofovir Dose adjustment or discontinuation is required for changes in renal function (serum creatinine and/or urine protein) while on therapy. Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indicator of Cidofovir-related nephrotoxicity. Continued administration of Cidofovir may lead to additional proximal tubule cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis. Patients with these adverse events occurring concurrently and meeting a criteria of Fanconi's syndrome have been reported. Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of Cidofovir.
- Intravenous normal saline hydration and oral probenecid must accompany each Cidofovir infusion. Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs. The safety of Cidofovir has not been evaluated in patients receiving other known potentially nephrotoxic agents, such as intravenous aminoglycosides (tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents.
- Initiation of therapy with Cidofovir is contraindicated in patients with a baseline serum creatinine > 1.5 mg/dL, a creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
- Neutropenia may occur during Cidofovir therapy. Neutrophil count should be monitored while receiving Cidofovir therapy.
- Decreased intraocular pressure may occur during Cidofovir therapy, and in some instances has been associated with decreased visual acuity. Intraocular pressure should be monitored during Cidofovir therapy.
- Decreased serum bicarbonate associated with proximal tubule injury and renal wasting syndrome (including Fanconi's syndrome) have been reported in patients receiving Cidofovir. Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving Cidofovir.
# Adverse Reactions
## Clinical Trials Experience
- Renal toxicity, as manifested by ≥ 2+ proteinuria, serum creatinine elevations of ≥ 0.4 mg/dL, or decreased creatinine clearance ≤ 55 mL/min, occurred in 79 of 135 (59%) patients receiving Cidofovir at a maintenance dose of 5 mg/kg every other week. Maintenance dose reductions from 5 mg/kg to 3 mg/kg due to proteinuria or serum creatinine elevations were made in 12 of 41 (29%) patients who had not received prior therapy for CMV retinitis (Study 106) and in 19 of 74 (26%) patients who had received prior therapy for CMV retinitis (Study 107). Prior foscarnet use has been associated with an increased risk of nephrotoxicity; therefore, such patients must be monitored closely.
- In clinical trials, at the 5 mg/kg maintenance dose, a decrease in absolute neutrophil count to ≤ 500 cells/mm 3 occurred in 24% of patients. Granulocyte colony stimulating factor (GCSF) was used in 39% of patients.
- Among the subset of patients monitored for intraocular pressure changes, a ≥ 50% decrease from baseline intraocular pressure was reported in 17 of 70 (24%) patients at the 5 mg/kg maintenance dose. Severe hypotony (intraocular pressure of 0–1 mm Hg) has been reported in 3 patients. Risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus.
- Uveitis or iritis has been reported in clinical trials and during postmarketing in patients receiving Cidofovir therapy. Uveitis or iritis was reported in 15 of 135 (11%) patients receiving 5 mg/kg maintenance dosing. Treatment with topical corticosteroids with or without topical cycloplegic agents may be considered. Patients should be monitored for signs and symptoms of uveitis/iritis during Cidofovir therapy.
- A diagnosis of Fanconi's syndrome, as manifested by multiple abnormalities of proximal renal tubular function, was reported in 1% of patients. Decreases in serum bicarbonate to ≤ 16 mEq/L occurred in 16% of cidofovir-treated patients. Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving Cidofovir In clinical trials, Cidofovir was withdrawn due to adverse events in 39% of patients treated with 5 mg/kg every other week as maintenance therapy.
- The incidence of adverse reactions reported as serious in three controlled clinical studies in patients with CMV retinitis, regardless of presumed relationship to drug, is listed in Table 4.
- The most frequently reported adverse events regardless of relationship to study drugs (cidofovir or probenecid) or severity are shown in Table 5.
The following additional list of adverse events/intercurrent illnesses have been observed in clinical studies of Cidofovir and are listed below regardless of causal relationship to Cidofovir Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medicines.
- Abdominal pain
- Accidental injury
- AIDS
- Allergic reaction
- Back pain
- Catheter blocked
- Cellulitis
- Chest pain
- Chills and fever
- Cryptococcosis
- Cyst
- Death
- Face edema
- Flu-like syndrome
- Hypothermia
- Injection site reaction
- Malaise
- Mucous membrane disorder
- Neck pain
- Overdose
- Photosensitivity reaction
- Sarcoma
- Sepsis
- Cardiomyopathy
- Cardiovascular disorder
- Congestive heart failure
- Hypertension
- hypotension
- Migraine
- Pallor
- Peripheral vascular disorder
- Phlebitis
- Postural hypotension
- Shock
- Syncope
- Tachycardia
- Vascular disorder
- Edema
- Cholangitis
- Colitis
- Constipation
- Esophagitis
- Dyspepsia
- Dysphagia
- Fecal incontinence
- Flatulence
- Gastritis
- Gastrointestinal hemorrhage
- Gingivitis
- Hepatitis
- Hepatomegaly
- Hepatosplenomegaly
- Jaundice
- Abnormal liver function
- Liver damage
- Liver necrosis
- Melena
- Pancreatitis
- Proctitis
- Rectal disorder
- Stomatitis
- Aphthous stomatitis
- Tongue discoloration
- Mouth ulceration
- Tooth caries
- Adrenal cortex insufficiency
- Hypochromic anemia
- Leukocytosis
- Leukopenia
- Lymphadenopathy
- Lymphoma like reaction
- Pancytopenia
- Splenic disorder
- Splenomegaly
- Thrombocytopenia
- Thrombocytopenic purpura
- Cachexia
- Dehydration
- Edema
- Hypercalcemia
- Hyperglycemia
- Hyperkalemia
- Hyperlipemia
- Hypocalcemia
- Hypoglycemia
- Hypoglycemic reaction
- Hypokalemia
- Hypomagnesemia
- Hyponatremia
- Hypophosphatemia
- Hypoproteinemia
- Increased alkaline phosphatase
- Increased BUN
- Increased lactic dehydrogenase
- Increased SGOT/SGPT
- Peripheral edema
- Respirator alkalosis
- Thirst
- Weight loss
- Weight gain
- Arthralgia
- Arthrosis
- Bone necrosis
- Bone pain
- Joint disorder
- Leg cramps
- Myalgia
- Myasthenia
- Pathological fracture
- Abnormal dreams
- Abnormal gait
- Acute brain syndrome
- Agitation
- Amnesia
- Anxiety
- Ataxia
- Cerebrovascular disorder
- Confusion
- Convulsion
- Delirium
- Dementia
- Depression
- Dizziness
- Drug dependence
- Dry mouth
- Encephalopathy
- Facial paralysis
- Hallucinations
- Hemiplegia
- Hyperesthesia
- Hypertonia
- Hypotony
- Incoordination
- Increased libido
- Insomnia
- Myoclonus
- Nervousness
- Neuropathy
- Paresthesia
- Personality disorder
- Somnolence
- Speech disorder
- Tremor
- Twitching
- Vasodilatation
- Vertigo
- Asthma
- Bronchitis
- Epistaxis
- Hemoptysis
- Hiccups
- Hyperventilation
- Hjypoxia
- Increased sputum
- Larynx edema
- Lung disorder
- Pharyngitis
- Pneumothorax
- Rhinitis
- Sinusitis
- Acne
- Angioedema
- Dry skin
- Eczema
- Exfoliative dermatitis
- Furunculosis
- Herpes simplex
- Nail disorder
- Pruritus
- Rash
- Seborrhea
- Skin discoloration
- Skin disorder
- Skin hypertrophy
- Skin ulcer
- Sweating
- Urticaria
- Abnormal vision
- Amblyopia
- Blindness
- Cataract
- Conjunctivitis
- Corneal lesion
- Corneal opacity
- Diplopia
- Dry eyes
- Ear disorder
- Ear pain
- Eye disorder
- Eye pain
- Hyperacusis
- Iritis
- Keratitis
- Miosis
- Otitis externa
- Otitis media
- Refraction disorder
- Retinal detachment
- Retinal disorder
- Taste perversion
- Tinnitus
- Uveitis
- Visual field defect
- Hearing loss
- Decreased creatinine clearance
- Dysuria
- Glycosuria
- Hematuria
- Kidney stone
- Mastitis
- Metorrhagia
- Nocturia
- Polyuria
- Prostatic disorder
- Toxic nephrophathy
- Urethritis
- Urinary casts
- Urinary incontinence
- Urinary retention
- Urinary tract infection
## Postmarketing Experience
There is limited information regarding Cidofovir Postmarketing Experience in the drug label.
# Drug Interactions
### Zidovudine
- The pharmacokinetics of zidovudine were evaluated in ten patients receiving zidovudine alone or with intravenous cidofovir (without probenecid). There was no evidence of an effect of cidofovir on the pharmacokinetics of zidovudine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Cidofovir was embryotoxic (reduced fetal body weights) in rats at 1.5 mg/kg/day and in rabbits at 1.0 mg/kg/day, doses which were also maternally toxic, following daily intravenous dosing during the period of organogenesis. The no-observable-effect levels for embryotoxicity in rats (0.5 mg/kg/day) and in rabbits (0.25 mg/kg/day) were approximately 0.04 and 0.05 times the clinical dose (5 mg/kg every other week) based on AUC, respectively. An increased incidence of fetal external, soft tissue and skeletal anomalies (meningocele, short snout, and short maxillary bones) occurred in rabbits at the high dose (1.0 mg/kg/day) which was also maternally toxic. There are no adequate and well-controlled studies in pregnant women. Cidofovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cidofovir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cidofovir during labor and delivery.
### Nursing Mothers
- It is not known whether cidofovir is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for adverse reactions as well as the potential for tumorigenicity shown for cidofovir in animal studies, Cidofovir should not be administered to nursing mothers. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid postnatal transmission of HIV to a child who may not yet be infected.
### Pediatric Use
- Safety and effectiveness in children have not been studied. The use of Cidofovir in children with AIDS warrants extreme caution due to the risk of long-term carcinogenicity and reproductive toxicity. Administration of Cidofovir to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh the risks.
### Geriatic Use
- No studies of the safety or efficacy of Cidofovir in patients over the age of 60 have been conducted. Since elderly individuals frequently have reduced glomerular filtration, particular attention should be paid to assessing renal function before and during Cidofovir administration
### Gender
There is no FDA guidance on the use of Cidofovir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cidofovir with respect to specific racial populations.
### Renal Impairment
- Cidofovir is contraindicated in patients with a serum creatinine concentration > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
### Hepatic Impairment
There is no FDA guidance on the use of Cidofovir in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Chronic, two-year carcinogenicity studies in rats and mice have not been carried out to evaluate the carcinogenic potential of cidofovir. However, a 26-week toxicology study evaluating once weekly subscapular subcutaneous injections of cidofovir in rats was terminated at 19 weeks because of the induction, in females, of palpable masses, the first of which was detected after six doses. The masses were diagnosed as mammary adenocarcinomas which developed at doses as low as 0.6 mg/kg/week, equivalent to 0.04 times the human systemic exposure at the recommended intravenous Cidofovir dose based on AUC comparisons.
- In a 26-week intravenous toxicology study in which rats received 0.6, 3, or 15 mg/kg cidofovir once weekly, a significant increase in mammary adenocarcinomas in female rats as well as a significant incidence of Zymbal's gland carcinomas in male and female rats were seen at the high dose but not at the lower two doses. The high dose was equivalent to 1.1 times the human systemic exposure at the recommended dose of Cidofovir, based on comparisons of AUC measurements. In light of the results of these studies, cidofovir should be considered to be a carcinogen in rats as well as a potential carcinogen in humans.
- Cynomolgus monkeys received intravenous cidofovir, alone and in conjunction with concomitant oral probenecid, intravenously once weekly for 52 weeks at doses resulting in exposures of approximately 0.7 times the human systemic exposure at the recommended dose of Cidofovir No tumors were detected. However, the study was not designed as a carcinogenicity study due to the small number of animals at each dose and the short duration of treatment.
- No mutagenic response was observed in microbial mutagenicity assays involving Salmonella typhimurium (Ames) and [Escherichia coli]] in the presence and absence of metabolic activation. An increase in micro nucleated polychromatic erythrocytes in vivo was seen in mice receiving ≥ 2000 mg/kg, a dosage approximately 65-fold higher than the maximum recommended clinical intravenous Cidofovir dose based on body surface area estimations. Cidofovir induced chromosomal aberrations in human peripheral blood lymphocytes in vitro without metabolic activation. At the 4 cidofovir levels tested, the percentage of damaged metaphases and number of aberrations per cell increased in a concentration-dependent manner.
- Studies showed that cidofovir caused inhibition of spermatogenesis in rats and monkeys. However, no adverse effects on fertility or reproduction were seen following once weekly intravenous injections of cidofovir in male rats for 13 consecutive weeks at doses up to 15 mg/kg/week (equivalent to 1.1 times the recommended human dose based on AUC comparisons). Female rats dosed intravenously once weekly at 1.2 mg/kg/week (equivalent to 0.09 times the recommended human dose based on AUC) or higher, for up to 6 weeks prior to mating and for 2 weeks post mating had decreased litter sizes and live births per litter and increased early resorptions per litter. Peri- and post-natal development studies in which female rats received subcutaneous injections of cidofovir once daily at doses up to 1.0 mg/kg/day from day 7 of gestation through day 21 postpartum (approximately 5 weeks) resulted in no adverse effects on viability, growth, behavior, sexual maturation or reproductive capacity in the offspring.
### Immunocompromised Patients
There is no FDA guidance one the use of Cidofovir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The recommended dosage, frequency, or infusion rate must not be exceeded. Cidofovir must be diluted in 100 milliliters 0.9% (normal) saline prior to administration. to minimize potential nephrotoxicity, probenecid and intravenous saline prehydration must be administered with each VISITIDE infusion.
- Inspect vials visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is observed, the vial should not be used. With a syringe, extract the appropriate volume of Cidofovir from the vial and transfer the dose to an infusion bag containing 100 mL 0.9% (normal) saline solution. Infuse the entire volume intravenously into the patient at a constant rate over a 1 hr period. Use of a standard infusion pump for administration is recommended.
- It is recommended that Cidofovir infusion admixtures be administered within 24 hr of preparation and that refrigerator or freezer storage not be used to extend this 24 hr limit.
- If admixtures are not intended for immediate use, they may be stored under refrigeration (2–8°C) for no more than 24 hr. Refrigerated admixtures should be allowed to equilibrate to room temperature prior to use.
- The chemical stability of Cidofovir admixtures was demonstrated in polyvinyl chloride composition and ethylene/propylene copolymer composition commercial infusion bags, and in glass bottles. No data are available to support the addition of other drugs or supplements to the cidofovir admixture for concurrent administration.
- Cidofovir is supplied in single-use vials. Partially used vials should be discarded
### Monitoring
- Serum creatinine and urine protein must be monitored within 48 hours prior to each dose. White blood cell counts with differential should be monitored prior to each dose. In patients with proteinuria, intravenous hydration should be administered and the test repeated. Intraocular pressure, visual acuity and ocular symptoms should be monitored periodically.
# IV Compatibility
- Compatibility with Ringer's solution, Lactated Ringer's solution or bacteriostatic infusion fluids has not been evaluated.
# Overdosage
- Two cases of cidofovir overdose have been reported. These patients received single doses of Cidofovir at 16.3 mg/kg and 17.4 mg/kg, respectively, with concomitant oral probenecid and intravenous hydration. In both cases, the patients were hospitalized and received oral probenecid (one gram three times daily) and vigorous intravenous hydration with normal saline for 3 to 5 days. Significant changes in renal function were not observed in either patient.
# Pharmacology
## Mechanism of Action
- Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis. *Biochemical data support selective inhibition of CMV DNA polymerase by cidofovir diphosphate, the active intracellular metabolite of cidofovir. Cidofovir diphosphate inhibits herpesvirus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma1, 2, 3. Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.
## Structure
- The chemical name of cidofovir is 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC), with the molecular formula of C8H14N3O6P•2H2O and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is:
## Pharmacodynamics
There is limited information regarding Cidofovir Pharmacodynamics in the drug label.
## Pharmacokinetics
- Cidofovir must be administered with probenecid. The pharmacokinetics of cidofovir, administered both without and with probenecid, are described below.
- The pharmacokinetics of cidofovir without probenecid were evaluated in 27 HIV-infected patients with or without asymptomatic CMV infection. Dose-independent pharmacokinetics were demonstrated after one hr infusions of 1.0 (n = 5), 3.0 (n = 10), 5.0 (n = 2) and 10.0 (n = 8) mg/kg. There was no evidence of cidofovir accumulation after 4 weeks of repeated administration of 3 mg/kg/week (n = 5) without probenecid. In patients with normal renal function, approximately 80 to 100% of the Cidofovir dose was recovered unchanged in urine within 24 hr (n = 27). The renal clearance of cidofovir was greater than creatinine clearance, indicating renal tubular secretion contributes to the elimination of cidofovir.
- The pharmacokinetics of cidofovir administered with probenecid were evaluated in 12 HIV-infected patients with or without asymptomatic CMV infection and 10 patients with relapsing CMV retinitis. Dose-independent pharmacokinetics were observed for cidofovir, administered with probenecid, after one hr infusions of 3.0 (n = 12), 5.0 (n = 6), and 7.5 (n = 4) mg/kg (See TABLE 2). Approximately 70 to 85% of the Cidofovir dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When Cidofovir was administered with probenecid, the renal clearance of cidofovir was reduced to a level consistent with creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir.
## Nonclinical Toxicology
There is limited information regarding Cidofovir Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Cidofovir Clinical Studies in the drug label.
# How Supplied
- Cidofovir (cidofovir injection) 75 mg/mL for intravenous infusion, is supplied as a non-preserved solution in single-use clear glass vials as follows:
NDC 61958-0101-1: 375 mg in a 5 mL vial in a single-unit carton
- NDC 61958-0101-1: 375 mg in a 5 mL vial in a single-unit carton
## Storage
- Cidofovir should be stored at controlled room temperature 20–25 °C (68–77 °F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cidofovir Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Cidofovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Vistide
# Look-Alike Drug Names
There is limited information regarding Cidofovir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cidofovir | |
c75fee80c28362ee554eaf5575522be8ca0e2d56 | wikidoc | Cigarette | Cigarette
A cigarette is a product consumed via smoking and manufactured out of cured and finely cut tobacco leaves, which are combined with other additives, then rolled or stuffed into a paper-wrapped cylinder (generally less than 120 mm in length and 10 mm in diameter). The cigarette is ignited at one end and allowed to smoulder for the purpose of inhalation of its smoke from the other (usually filtered) end, which is usually inserted in the mouth. They are sometimes smoked with a cigarette holder. The term cigarette, as commonly used, refers to a tobacco cigarette but can apply to similar devices containing other herbs, such as cannabis. They are colloquially known as "cigs", "ciggies", "smokes", "stogies", "squares", and "fags".
Cigarettes are proven to be highly addictive, as well as a cause of multiple types of cancer, heart disease, respiratory disease, circulatory disease and birth defects.
A cigarette is distinguished from a cigar by its smaller size, use of processed leaf, and white paper wrapping. Cigars are typically composed entirely of whole leaf tobacco.
# History
The earliest forms of cigarettes that have been attested in Central America around the 9th century in the form of reeds and smoking tubes. The Maya, and later the Aztecs, smoked tobacco and various psychoactive drugs in religious rituals and frequently depicted priests and deities smoking on pottery and temple engravings. The cigarette, and the cigar, were the most common method of smoking in the Caribbean, Mexico and Central and South America until recent times.
Cigarettes were largely unknown in the English-speaking world before the Crimean War, when British soldiers began emulating their Ottoman Turkish comrades, who resorted to rolling their tobacco with newsprint.
The cigarette was named some time in the 18th century: beggars in Seville began to pick from the ground the cigar ends left by the señoritos (rich young men), wrapped the tobacco remains with paper and smoked them. The first attested use in this habit can be seen in three 18th century paintings by Francisco de Goya: La cometa (The kite), La merienda en el Manzanares (Picnic by the river Manzanares) and El juego de la pelota a pala (The ball and paddle game).
In the George Bizet opera Carmen, which was set in Spain in the 1830s, the title character Carmen was at first a worker in a cigarette factory.
The use of tobacco in cigarette form became increasingly popular during and after the Crimean War. This was helped by the development of tobaccos that are suitable for cigarette use. During World War I and World War II, cigarettes were rationed to soldiers. During the second half of the 20th century, the adverse health effects of cigarettes started to become widely known and text-only health warnings became commonplace on cigarette packets. The United States has not yet implemented graphical cigarette warning labels, which is a more effective method to communicate to the public the dangers of cigarette smoking. Canada and Australia, however, have both textual warnings and graphic visual images displaying, among other things, the damaging effects tobacco use has on the human body.
The cigarette has evolved much since its conception; for example, the thin bands that travel transverse to the "axis of smoking" (thus forming circles along the length of the cigarette) are alternate sections of thin and thick paper to facilitate effective burning when being drawn, and retard burning when at rest. Synthetic particulate filters remove some of the tar before it reaches the smoker.
# Manufacturing
Commercially manufactured cigarettes are relatively simple objects consisting mainly of a tobacco blend, paper, PVA glue to bond the outer layer of paper together, and often also a cellulose acetate based filter. While the assembly of cigarettes is straightforward, much focus is given to the creation of each of the components, in particular, the tobacco blend, which often contains over one hundred ingredients.
## Paper
The paper for holding the tobacco blend may vary in porosity to allow ventilation of the burning ember or contain materials that control the burning rate of the cigarette and stability of the produced ash. The papers used in tipping the cigarette (forming the mouthpiece) and surrounding the filter stabilise the mouthpiece from saliva and moderate the burning of the cigarette as well as the delivery of smoke with the presence of one or two rows of small laser-drilled air holes.
## Tobacco blend
The process of blending, like the blending of scotch and cognac, gives the end product a consistent taste from batches of tobacco grown in different areas of a country that may change in flavour profile from year to year due to different environmental conditions.
Modern cigarettes produced after the 1950s, although composed mainly of shredded tobacco leaf, use a significant quantity of tobacco processing by-products in the blend. Each cigarette's tobacco blend is made mainly from the leaves of flue-cured brightleaf, burley tobacco, and oriental tobacco. These leaves are selected, processed, and aged prior to blending and filling. The processing of brightleaf and burley tobaccos for tobacco leaf "strips" produces several by-products such as leaf stems, tobacco dust, and tobacco leaf pieces ("small laminate"). To improve the economics of producing cigarettes, these by-products are processed separately into forms where they can then be possibly added back into the cigarette blend without an apparent or marked change in the cigarette's quality. The most common tobacco by-products include:
- Blended leaf (BL) sheet: A thin dry sheet cast from a paste made with tobacco dust collected from tobacco stemming, finely milled Burley leaf stem, and pectin
- Reconstituted leaf (RL) sheet: A paper-like material made from tobacco stems and "class tobacco", which consists of tobacco particles less than 30 mesh in size (~0.599 mm) that is collected at any stage of tobacco processing. RL is made by extracting the soluble chemicals in the tobacco by-products, processing the left-over tobacco fibres from the extraction into a paper, and then reapplying the extracted materials in concentrated form onto the paper in a fashion similar to what is done in paper sizing
- Expanded (ES) or Improved stems (IS): ES are rolled, flattened, and shredded leaf stems that are expanded by being soaked in water and rapidly heated. Improved stems follow the same process but are simply steamed after shredding. Both products are then dried. These two products look similar in appearance but are different in taste.
Whole tobacco can also be processed into a product called Expanded tobacco. The tobacco is "puffed", or expanded, by saturating it with Supercritical carbon dioxide and heating the CO2 saturated tobacco to quickly evaporate the CO2. This quick change of physical state by the CO2 causes the tobacco to expand in a similar fashion as Polystyrene foam. This is used to produce light cigarettes by reducing the density of the tobacco and thus maintain the size of a cigarette while reducing the amount of tobacco used in each cigarette.
A recipe specified combination of bright-leaf, burley and oriental leaf tobacco with be mixed with humectants such as propylene glycol or glycerol, as well as flavouring products and enhancers such as cocoa, licorice, tobacco extracts, and various sugars, which are known collectively as "casings". The leaf tobacco will then be shredded, along with a specified amount of small laminate, expanded tobacco, BL, RL, ES, and IS. A perfume-like flavour/fragrance, called "the topping" or "toppings", which is most often formulated by flavor companies, will then be blended into the tobacco mixture to improve the consistency in flavour and taste of the cigarettes associated with a certain brand name. As well, they replace lost flavours due to the repeated wetting and drying used in processing the tobacco. Finally the tobacco mixture will be filled into cigarettes tubes and packaged.
In recent years, the manufacturers' pursuit of maximum profits has led to the practice of using not just the leaves, but the plant stem also. The stem is first crushed and cut to resemble the leaf before being merged or blended into the cut leaf.
# Sale
Before the Second World War many manufacturers gave away collectible cards, one in each packet of cigarettes. This practice was discontinued to save paper during the war and was never generally reintroduced, though for a number of years Natural American Spirit cigarettes included "vignette" cards depicting endangered animals and American historical events; this series was discontinued in 2003. On April 1, 1970 President Richard Nixon signed the Public Health Cigarette Smoking Act into law, banning cigarette advertisements on television in the United States starting on January 2, 1971. However some tobacco companies attempted to circumvent the ban by marketing new brands of cigarettes as "little cigars"; examples included Tijuana Smalls, which came out almost immediately after the ban took effect, and Backwoods Smokes, which reached the market in the winter of 1973–1974 and whose ads used the slogan, "How can anything that looks so wild taste so mild."
Beginning on April 1, 1998, the sale of cigarettes and other tobacco products to people under 18 is now prohibited by law in all fifty states of the United States. The legal age of purchase has been additionally raised to 19 in Alabama, Alaska, New Jersey, Utah, and Nassau, Suffolk, and Onondaga Counties in New York. Legislation was pending as of 2004 in some other states. In Massachusetts and Virginia, parents and guardians are allowed to give cigarettes to minors, but sales to minors are prohibited.
Similar laws exist in many other countries. In Canada, most of the provinces require smokers to be 19 years of age to purchase cigarettes (except for Quebec, Saskatchewan, Manitoba and Alberta, where the age is 18). However, the minimum age only concerns the purchase of tobacco, not use. Alberta, however, does have a law which prohibits the possession or use of tobacco products by all persons under 18, punishable by a $100 fine. Australia, and Pakistan have a nationwide ban on the selling of all tobacco products to people under the age of 18.
In the UK, beginning 1st October 2007, it will be illegal for retailers to sell tobacco in all forms to people under the age of 18 in three of the four of the UKs constituent countries (England, Wales & Scotland) (rising from 16). It will also be illegal to sell lighters, rolling papers and all other tobacco associated items to people under 18. However, it will not be illegal for people under 18 to buy (or attempt to buy) or indeed smoke tobacco, it is only illegal for the said retailer to sell the item. Northern Ireland are expected to follow suit with the age increase. In the Republic of Ireland bans on the sale of the smaller ten-packs and confectionery that resembles tobacco products came into force on May 31, 2007 in a bid to cut under-aged smoking. The UK Department of Health plans to follow suit with the ten-pack ban.
Most countries in the world have a legal smoking age of 18. Six exceptions are Austria, Belgium, Denmark, Germany, Portugal, and The Netherlands, where the age is 16. Since January 1, 2007 all cigarette machines in public places in Germany must attempt to verify a customers age by requiring the insertion of a debit card. Turkey, which has one of the highest percentage of smokers in its population, has a legal age of 18. Another curiosity is Japan, one of the highest tobacco consuming nations, which requires purchasers to be 20 years of age (Suffrage in Japan is 20 years old.) However, due to the prevalence of cigarette vending machines in the most public of places the effectiveness of an underage ban is in doubt. In other countries, such as Egypt or India (especially Kerala) it is legal to use and purchase tobacco products regardless of age.
Some police departments in the United States occasionally send an underaged teenager into a store where cigarettes are sold, and have the teen attempt to purchase cigarettes, with their own or no ID. If the vendor then completes the sale, the store is issued a fine. Similar enforcement practices are regularly performed by Trading Standards Officers in the UK.
# Consumption
Approximately 5.5 trillion cigarettes are produced globally each year by the tobacco industry, smoked by over 1.1 billion people, which is more than 1/6 of the world's total population.
# Smoking bans
Many governments impose restrictions on smoking tobacco, especially in public areas. The primary justification has been the negative health effects of secondhand smoke. Laws vary by country and locality. See:
- Smoking bans
- Smoking bans by country
# Cigarette litter
Cigarette butts are the most littered item in the world. Discarded butts can be found almost any place accessible to people, including streets, sidewalks, parks and beaches. The butts of filtered cigarettes are not biodegradable. The filters, made of cellulose acetate, take many years to decompose. Many of the filters end up in waterways, where the toxic chemicals that they are designed to filter out are leached into the water supply.
# Cigarette advertising
In many parts of the world tobacco advertising and even sponsorship of sporting events has been outlawed. The ban on tobacco advertising and sponsorship in the EU in 2005 has prompted Formula One Management to look for races in areas that allow the tobacco sponsored teams to display their livery. As of 2007, only Ferrari retains tobacco sponsorship, continuing their relationship with Marlboro until 2011.
# Footnotes
- ↑ "Smoking While Pregnant Causes Finger, Toe Deformities". Science Daily. Retrieved March 6. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ List of health effects by CDC
- ↑ Robicsek, Francis Smoke; Ritual Smoking in Central America pp. 30-37
- ↑ Clean Virginia Waterways, Cigarette Butt Litter - Cigarette Filters, Longwood University, Retrieved October 31 2006
- ↑ Philip Morris USA, Product Information -Cigarette ingredients, Retrieved March 5 2007
- ↑ JTI, ""Composite List of Ingredients in Non-Tobacco Materials"". www.jti.com, Retrieved November 2 2006
- ↑ Jump up to: 9.0 9.1 9.2 9.3 9.4 David E. Merrill, (1994), "How cigarettes are made". Video presentation at Philip Morris USA, Richmond offices. Retrieved October 31 2006
- ↑ ""PCL Sheet Tobacco Cigarettes""., Retrieved November 2 2006
- ↑ Grant Gellatly, "" Method and apparatus for coating reconstituted tobacco""., Retrieved November 2 2006
- ↑ @btinternet.com/polonium210radiationpoisoning.htm
- ↑ News 10 Now (19 December 2006), "Lawmakers raise minimum age on purchasing tobacco products". Retrieved December 19 2006
- ↑ Massachusetts General Laws, Chapter 270 (Crimes Against Public Health), Section 6 (Tobacco; sale or gift to minors)
- ↑ BBC News, "Retailers sell tobacco to youths", September 2005. Retrieved 9 November 2006.
- ↑ WHO Framework Convention on Tobacco Control; First international treaty on public health, adopted by 192 countries and signed by 168. Its Article 8.1 states "Parties recognize that scientific evidence has unequivocally established that exposure to tobacco causes death, disease and disability."
- ↑ "CigaretteLitter.org". CigaretteLitter.org. Retrieved 2007-05-28. | Cigarette
Template:Pp-semi-vandalism
A cigarette is a product consumed via smoking and manufactured out of cured and finely cut tobacco leaves, which are combined with other additives, then rolled or stuffed into a paper-wrapped cylinder (generally less than 120 mm in length and 10 mm in diameter). The cigarette is ignited at one end and allowed to smoulder for the purpose of inhalation of its smoke from the other (usually filtered) end, which is usually inserted in the mouth. They are sometimes smoked with a cigarette holder. The term cigarette, as commonly used, refers to a tobacco cigarette but can apply to similar devices containing other herbs, such as cannabis. They are colloquially known as "cigs", "ciggies", "smokes", "stogies", "squares", and "fags".
Cigarettes are proven to be highly addictive, as well as a cause of multiple types of cancer, heart disease, respiratory disease, circulatory disease and birth defects.[1][2]
A cigarette is distinguished from a cigar by its smaller size, use of processed leaf, and white paper wrapping. Cigars are typically composed entirely of whole leaf tobacco.
# History
The earliest forms of cigarettes that have been attested in Central America around the 9th century in the form of reeds and smoking tubes. The Maya, and later the Aztecs, smoked tobacco and various psychoactive drugs in religious rituals and frequently depicted priests and deities smoking on pottery and temple engravings. The cigarette, and the cigar, were the most common method of smoking in the Caribbean, Mexico and Central and South America until recent times.[3]
Cigarettes were largely unknown in the English-speaking world before the Crimean War, when British soldiers began emulating their Ottoman Turkish comrades, who resorted to rolling their tobacco with newsprint.[4]
The cigarette was named some time in the 18th century: beggars in Seville began to pick from the ground the cigar ends left by the señoritos (rich young men), wrapped the tobacco remains with paper and smoked them. The first attested use in this habit can be seen in three 18th century paintings by Francisco de Goya: La cometa (The kite), La merienda en el Manzanares (Picnic by the river Manzanares) and El juego de la pelota a pala (The ball and paddle game).
In the George Bizet opera Carmen, which was set in Spain in the 1830s, the title character Carmen was at first a worker in a cigarette factory.
The use of tobacco in cigarette form became increasingly popular during and after the Crimean War. This was helped by the development of tobaccos that are suitable for cigarette use. During World War I and World War II, cigarettes were rationed to soldiers. During the second half of the 20th century, the adverse health effects of cigarettes started to become widely known and text-only health warnings became commonplace on cigarette packets. The United States has not yet implemented graphical cigarette warning labels, which is a more effective method to communicate to the public the dangers of cigarette smoking.[5] Canada and Australia, however, have both textual warnings and graphic visual images displaying, among other things, the damaging effects tobacco use has on the human body.
The cigarette has evolved much since its conception; for example, the thin bands that travel transverse to the "axis of smoking" (thus forming circles along the length of the cigarette) are alternate sections of thin and thick paper to facilitate effective burning when being drawn, and retard burning when at rest. Synthetic particulate filters remove some of the tar before it reaches the smoker.
# Manufacturing
Commercially manufactured cigarettes are relatively simple objects consisting mainly of a tobacco blend, paper, PVA glue to bond the outer layer of paper together, and often also a cellulose acetate based filter.[6] While the assembly of cigarettes is straightforward, much focus is given to the creation of each of the components, in particular, the tobacco blend, which often contains over one hundred ingredients.[7]
## Paper
The paper for holding the tobacco blend may vary in porosity to allow ventilation of the burning ember or contain materials that control the burning rate of the cigarette and stability of the produced ash. The papers used in tipping the cigarette (forming the mouthpiece) and surrounding the filter stabilise the mouthpiece from saliva and moderate the burning of the cigarette as well as the delivery of smoke with the presence of one or two rows of small laser-drilled air holes.[8]
## Tobacco blend
The process of blending, like the blending of scotch and cognac, gives the end product a consistent taste from batches of tobacco grown in different areas of a country that may change in flavour profile from year to year due to different environmental conditions.[9]
Modern cigarettes produced after the 1950s, although composed mainly of shredded tobacco leaf, use a significant quantity of tobacco processing by-products in the blend. Each cigarette's tobacco blend is made mainly from the leaves of flue-cured brightleaf, burley tobacco, and oriental tobacco. These leaves are selected, processed, and aged prior to blending and filling. The processing of brightleaf and burley tobaccos for tobacco leaf "strips" produces several by-products such as leaf stems, tobacco dust, and tobacco leaf pieces ("small laminate").[9] To improve the economics of producing cigarettes, these by-products are processed separately into forms where they can then be possibly added back into the cigarette blend without an apparent or marked change in the cigarette's quality. The most common tobacco by-products include:
- Blended leaf (BL) sheet: A thin dry sheet cast from a paste made with tobacco dust collected from tobacco stemming, finely milled Burley leaf stem, and pectin[10]
- Reconstituted leaf (RL) sheet: A paper-like material made from tobacco stems and "class tobacco", which consists of tobacco particles less than 30 mesh in size (~0.599 mm) that is collected at any stage of tobacco processing.[11] RL is made by extracting the soluble chemicals in the tobacco by-products, processing the left-over tobacco fibres from the extraction into a paper, and then reapplying the extracted materials in concentrated form onto the paper in a fashion similar to what is done in paper sizing
- Expanded (ES) or Improved stems (IS): ES are rolled, flattened, and shredded leaf stems that are expanded by being soaked in water and rapidly heated. Improved stems follow the same process but are simply steamed after shredding. Both products are then dried. These two products look similar in appearance but are different in taste.[9]
Whole tobacco can also be processed into a product called Expanded tobacco. The tobacco is "puffed", or expanded, by saturating it with Supercritical carbon dioxide and heating the CO2 saturated tobacco to quickly evaporate the CO2. This quick change of physical state by the CO2 causes the tobacco to expand in a similar fashion as Polystyrene foam. This is used to produce light cigarettes by reducing the density of the tobacco and thus maintain the size of a cigarette while reducing the amount of tobacco used in each cigarette.[9]
A recipe specified combination of bright-leaf, burley and oriental leaf tobacco with be mixed with humectants such as propylene glycol or glycerol, as well as flavouring products and enhancers such as cocoa, licorice, tobacco extracts, and various sugars, which are known collectively as "casings". The leaf tobacco will then be shredded, along with a specified amount of small laminate, expanded tobacco, BL, RL, ES, and IS. A perfume-like flavour/fragrance, called "the topping" or "toppings", which is most often formulated by flavor companies, will then be blended into the tobacco mixture to improve the consistency in flavour and taste of the cigarettes associated with a certain brand name.[9] As well, they replace lost flavours due to the repeated wetting and drying used in processing the tobacco. Finally the tobacco mixture will be filled into cigarettes tubes and packaged.
In recent years, the manufacturers' pursuit of maximum profits has led to the practice of using not just the leaves, but the plant stem also.[12] The stem is first crushed and cut to resemble the leaf before being merged or blended into the cut leaf.[13]
# Sale
Before the Second World War many manufacturers gave away collectible cards, one in each packet of cigarettes. This practice was discontinued to save paper during the war and was never generally reintroduced, though for a number of years Natural American Spirit cigarettes included "vignette" cards depicting endangered animals and American historical events; this series was discontinued in 2003. On April 1, 1970 President Richard Nixon signed the Public Health Cigarette Smoking Act into law, banning cigarette advertisements on television in the United States starting on January 2, 1971. However some tobacco companies attempted to circumvent the ban by marketing new brands of cigarettes as "little cigars"; examples included Tijuana Smalls, which came out almost immediately after the ban took effect, and Backwoods Smokes, which reached the market in the winter of 1973–1974 and whose ads used the slogan, "How can anything that looks so wild taste so mild."
Beginning on April 1, 1998, the sale of cigarettes and other tobacco products to people under 18 is now prohibited by law in all fifty states of the United States. The legal age of purchase has been additionally raised to 19 in Alabama, Alaska, New Jersey, Utah, and Nassau, Suffolk, and Onondaga Counties in New York.[14] Legislation was pending as of 2004 in some other states. In Massachusetts[15] and Virginia[citation needed], parents and guardians are allowed to give cigarettes to minors, but sales to minors are prohibited.
Similar laws exist in many other countries. In Canada, most of the provinces require smokers to be 19 years of age to purchase cigarettes (except for Quebec, Saskatchewan, Manitoba and Alberta, where the age is 18). However, the minimum age only concerns the purchase of tobacco, not use. Alberta, however, does have a law which prohibits the possession or use of tobacco products by all persons under 18, punishable by a $100 fine. Australia, and Pakistan have a nationwide ban on the selling of all tobacco products to people under the age of 18.
In the UK, beginning 1st October 2007, it will be illegal for retailers to sell tobacco in all forms to people under the age of 18 in three of the four of the UKs constituent countries (England, Wales & Scotland) (rising from 16). It will also be illegal to sell lighters, rolling papers and all other tobacco associated items to people under 18. However, it will not be illegal for people under 18 to buy (or attempt to buy) or indeed smoke tobacco, it is only illegal for the said retailer to sell the item. Northern Ireland are expected to follow suit with the age increase. In the Republic of Ireland bans on the sale of the smaller ten-packs and confectionery that resembles tobacco products came into force on May 31, 2007 in a bid to cut under-aged smoking. The UK Department of Health plans to follow suit with the ten-pack ban.
Most countries in the world have a legal smoking age of 18. Six exceptions are Austria, Belgium, Denmark, Germany, Portugal, and The Netherlands, where the age is 16. Since January 1, 2007 all cigarette machines in public places in Germany must attempt to verify a customers age by requiring the insertion of a debit card. Turkey, which has one of the highest percentage of smokers in its population,[citation needed] has a legal age of 18. Another curiosity is Japan, one of the highest tobacco consuming nations, which requires purchasers to be 20 years of age (Suffrage in Japan is 20 years old.[16]) However, due to the prevalence of cigarette vending machines in the most public of places the effectiveness of an underage ban is in doubt.[citation needed] In other countries, such as Egypt or India (especially Kerala) it is legal to use and purchase tobacco products regardless of age.
Some police departments in the United States occasionally send an underaged teenager into a store where cigarettes are sold, and have the teen attempt to purchase cigarettes, with their own or no ID. If the vendor then completes the sale, the store is issued a fine.[17] Similar enforcement practices are regularly performed by Trading Standards Officers in the UK.[18]
# Consumption
Approximately 5.5 trillion cigarettes are produced globally each year by the tobacco industry, smoked by over 1.1 billion people, which is more than 1/6 of the world's total population.
# Smoking bans
Many governments impose restrictions on smoking tobacco, especially in public areas. The primary justification has been the negative health effects of secondhand smoke.[19] Laws vary by country and locality. See:
- Smoking bans
- Smoking bans by country
# Cigarette litter
Cigarette butts are the most littered item in the world. Discarded butts can be found almost any place accessible to people, including streets, sidewalks, parks and beaches. The butts of filtered cigarettes are not biodegradable. The filters, made of cellulose acetate, take many years to decompose. Many of the filters end up in waterways, where the toxic chemicals that they are designed to filter out are leached into the water supply.[20]
# Cigarette advertising
In many parts of the world tobacco advertising and even sponsorship of sporting events has been outlawed. The ban on tobacco advertising and sponsorship in the EU in 2005 has prompted Formula One Management to look for races in areas that allow the tobacco sponsored teams to display their livery. As of 2007, only Ferrari retains tobacco sponsorship, continuing their relationship with Marlboro until 2011.
# Footnotes
- ↑ "Smoking While Pregnant Causes Finger, Toe Deformities". Science Daily. Retrieved March 6. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ List of health effects by CDC
- ↑ Robicsek, Francis Smoke; Ritual Smoking in Central America pp. 30-37
- ↑ http://www.diggerhistory.info/pages-conflicts-periods/other/crimea.htm
- ↑ http://tobaccocontrol.bmj.com/cgi/content/full/15/suppl_3/iii19
- ↑ Clean Virginia Waterways, Cigarette Butt Litter - Cigarette Filters, Longwood University, Retrieved October 31 2006
- ↑ Philip Morris USA, Product Information -Cigarette ingredients, Retrieved March 5 2007
- ↑ JTI, ""Composite List of Ingredients in Non-Tobacco Materials"". www.jti.com, Retrieved November 2 2006
- ↑ Jump up to: 9.0 9.1 9.2 9.3 9.4 David E. Merrill, (1994), "How cigarettes are made". Video presentation at Philip Morris USA, Richmond offices. Retrieved October 31 2006
- ↑ ""PCL Sheet Tobacco Cigarettes""., Retrieved November 2 2006
- ↑ Grant Gellatly, "" Method and apparatus for coating reconstituted tobacco""., Retrieved November 2 2006
- ↑ http://uk.geocities.com/[email protected]/polonium210radiationpoisoning.htm
- ↑ http://www.dickinsonlegg.com/STS/STSframeset.htm
- ↑ News 10 Now (19 December 2006), "Lawmakers raise minimum age on purchasing tobacco products". Retrieved December 19 2006
- ↑ Massachusetts General Laws, Chapter 270 (Crimes Against Public Health), Section 6 (Tobacco; sale or gift to minors) [1]
- ↑ https://www.cia.gov/library/publications/the-world-factbook/geos/ja.html
- ↑ http://www.abc.state.va.us/licensing/downloads/underagebuyer.pdf
- ↑ BBC News, "Retailers sell tobacco to youths", September 2005. Retrieved 9 November 2006.
- ↑ WHO Framework Convention on Tobacco Control; First international treaty on public health, adopted by 192 countries and signed by 168. Its Article 8.1 states "Parties recognize that scientific evidence has unequivocally established that exposure to tobacco causes death, disease and disability."
- ↑ "CigaretteLitter.org". CigaretteLitter.org. Retrieved 2007-05-28. | https://www.wikidoc.org/index.php/Cigarette | |
37f583887103060b95dcca9fed8c738c0fc70cfa | wikidoc | Cigarillo | Cigarillo
A cigarillo (Spanish for "cigarette", pronounced "see-gah-ree-yoh" in Spanish and "see-gah-ree-loh" in English) is a short, narrow cigar. Unlike cigarettes, cigarillos are wrapped not in paper but in whole-leaf tobacco. Cigarillos also usually contain fewer additives (though often more than real cigars). Cigarillos can be found for purchase alone or in packs, and are sometimes made without filters. The filtered cigarillos are sometimes called "little cigars". Unlike a cigarette, they are not meant to be inhaled but rather smoked like a cigar.
Generally, a cigarillo usually contains about 3 grams of tobacco, the length varies from between 7 to 10 cm (70 to 100 mm) and the diameter is between 0.5 to 0.8 cm (or 5 to 8 mm). Comparatively, a cigarette contains less than 1 gram of tobacco and is less than 12 cm in length and 1cm in diameter.
Cigarillos are often machine made. This allows the price to be lower than if they were hand made. They are not produced in as large a quantity as cigarettes but cigarillos are often seen by passionate cigar smokers as a lower quality product. As cigarillos are often smoked in quantities similar to cigarettes (between 5 and 10 per day), storage of them in humidors is not usually necessary.
Cigarillos are also known in Europe as a 'Seven Minute Cigar'. This due to the fact that they can be smoked in seven minutes and are often seen as an alternative not only to cigarettes but also where someone does not have enough time to smoke a full cigar.
To improve their image, cigarillos can often be found in ornamentally designed tins. Manufacturers explain this offers more protection for the product against crushing but it also gives a better image and allows better targeted advertising to people who are conscious of other people seeing what they are smoking.
In the United States popular consumer brands include Swisher Sweets, Black and Mild, White Owl, Optimo, and Winchester, while in the United Kingdom they include Hamlets and Café Crème. Inexpensive cigarillos are often identified using a brand name rather than the term cigarillo.
In Europe, cigarillos and thin panatelas (a long slender cigar) are relatively more popular with female smokers. One reason may be that it is still socially unacceptable, or at least surprising, to see women smoke larger cigars.
# Health concerns
As is the case with other tobacco products, cigarillos are a health risk to those who smoke them. In Europe, they are subject to the same laws which require manufacturers to place a health warning on a percentage of the packaging.
As cigarillos are not meant to be inhaled, they are seen as a healthier alternative to cigarettes. Health authorities around the world still warn smokers of the risk they pose due to smoke being in the mouth.
# Taxation
In the United States, cigarillos (and cigars) are taxed at a lower rate than cigarettes. The federal tax on cigarettes is 39 cents a pack where as cigarillos are 4 cents per pack of 20. Large cigars have a federal tax of 5 cents maximum per cigar. . Some states have no tax on cigarillos. | Cigarillo
Template:Tfd
A cigarillo (Spanish for "cigarette", pronounced "see-gah-ree-yoh" in Spanish and "see-gah-ree-loh" in English) is a short, narrow cigar. Unlike cigarettes, cigarillos are wrapped not in paper but in whole-leaf tobacco. Cigarillos also usually contain fewer additives (though often more than real cigars).[citation needed] Cigarillos can be found for purchase alone or in packs, and are sometimes made without filters. The filtered cigarillos are sometimes called "little cigars". Unlike a cigarette, they are not meant to be inhaled but rather smoked like a cigar.
Generally, a cigarillo usually contains about 3 grams of tobacco, the length varies from between 7 to 10 cm (70 to 100 mm) and the diameter is between 0.5 to 0.8 cm (or 5 to 8 mm). Comparatively, a cigarette contains less than 1 gram of tobacco [1] and is less than 12 cm in length and 1cm in diameter.
Cigarillos are often machine made. This allows the price to be lower than if they were hand made. They are not produced in as large a quantity as cigarettes but cigarillos are often seen by passionate cigar smokers as a lower quality product. As cigarillos are often smoked in quantities similar to cigarettes (between 5 and 10 per day), storage of them in humidors is not usually necessary.
Cigarillos are also known in Europe as a 'Seven Minute Cigar'. This due to the fact that they can be smoked in seven minutes and are often seen as an alternative not only to cigarettes but also where someone does not have enough time to smoke a full cigar.
To improve their image, cigarillos can often be found in ornamentally designed tins. Manufacturers explain this offers more protection for the product against crushing but it also gives a better image and allows better targeted advertising to people who are conscious of other people seeing what they are smoking.
In the United States popular consumer brands include Swisher Sweets, Black and Mild, White Owl, Optimo, and Winchester, while in the United Kingdom they include Hamlets and Café Crème. Inexpensive cigarillos are often identified using a brand name rather than the term cigarillo.
In Europe, cigarillos and thin panatelas (a long slender cigar) are relatively more popular with female smokers.[citation needed] One reason may be that it is still socially unacceptable, or at least surprising, to see women smoke larger cigars.
# Health concerns
As is the case with other tobacco products, cigarillos are a health risk to those who smoke them. In Europe, they are subject to the same laws which require manufacturers to place a health warning on a percentage of the packaging.
As cigarillos are not meant to be inhaled, they are seen as a healthier alternative to cigarettes. Health authorities around the world still warn smokers of the risk they pose due to smoke being in the mouth.
# Taxation
In the United States, cigarillos (and cigars) are taxed at a lower rate than cigarettes. The federal tax on cigarettes is 39 cents a pack where as cigarillos are 4 cents per pack of 20. Large cigars have a federal tax of 5 cents maximum per cigar. [2]. Some states have no tax on cigarillos.[citation needed] | https://www.wikidoc.org/index.php/Cigarillo | |
82b38f3a8e2449cc94f529c654130b6d1fa542f9 | wikidoc | Ciguatera | Ciguatera
# Overview
Ciguatera is a foodborne illness poisoning in humans caused by eating marine species whose flesh is contaminated with a toxin known as ciguatoxin, which is present in many microorganisms (particularly the micro-algae Gambierdiscus toxicus) living in tropical waters. Like many naturally and artificially occurring toxins, ciguatoxin bioaccumulates in lower-level organisms, resulting in higher concentration of the toxin at higher levels of the food chain, an example of biomagnification. Predator species near the top of the food chain in tropical waters, such as barracuda, moray eel, parrotfish, grouper, triggerfish, and amberjack, are most likely to cause ciguatera poisoning, although many other species have been found to cause occasional outbreaks of ciguatera. Ciguatoxin is very heat-resistant, so ciguatoxin-laden fish cannot be detoxified by cooking.
# History
Originally, ciguatoxin was linked to poison passed to tropical fish through consumption. However, the exact source of the toxin was unknown, and many sources were identified as the culprit. Some of these included the manchineel fruit, cocculus berries, palolo worms, compounds containing copper, pumice, and corallina opuntia.
In Northern Australia, where ciguatera is a common problem, two different methods are widely believed to be available for determining that fish harbors significant levels of ciguatoxin. The first method is that if a piece of fish is contaminated with the toxin, flies will not land on it. The second is that the toxin can be detected by feeding a piece of fish to a cat, as cats are allegedly highly sensitive to ciguatoxin and will display symptoms. It is not known whether there is any veracity to either belief.
# Etymological Roots
It is a generally held theory that ciguatera, as a poisonous substance, was named and identified in Cuba, circa the early 1800s. Local folklore has identified that the etymology stems from a story of an Englishman who caught a barracuda on the Isla de Pinos. After consuming the barracuda, the Englishman became terribly ill. When queried about the origins of his illness, the Englishman claimed to have caught and eaten “a fish, from the seawater”. This gave rise to the name of the ailment as ciguatera, a transliteration into Spanish of the English word seawater.
# Distribution
Due to the localized nature of the ciguatoxin-producing microorganisms, ciguatera illness is only common in tropical waters, particularly the Pacific and Caribbean, and usually is associated with fish caught in tropical reef waters. Ciguatoxin is found in over 400 species of reef fish, and therefore avoidance of consumption of all reef fish (any fish living in warm tropical waters) is the only sure way to avoid exposure to the toxin. Imported fish served in restaurants have been found to contain the toxin and to produce illness which often goes unexplained by physicians unfamiliar with a tropical toxin and its characteristic symptoms. In addition, ciguatoxin has been found in farm-raised salmon.
In February 2008, the FDA reported that several outbreaks of the disease had been traced to fish harvested near the Flower Garden Banks National Marine Sanctuary in the northern Gulf of Mexico, near the Texas-Louisiana shoreline. The FDA advised seafood processors that ciguatera poisoning was "reasonably likely" to occur from consuming any of several species of fish caught as far as 50 miles (80.4672 km) from the sanctuary.
# Symptoms
Hallmark symptoms of ciguatera include gastrointestinal and neurological effects. Gastrointestinal symptoms include nausea, vomiting, and diarrhea usually followed by neurological symptoms such as headaches, muscle aches, paresthesia, numbness, ataxia, and hallucinations. Severe cases of ciguatera can also result in cold allodynia, which is a burning sensation on contact with cold (commonly incorrectly referred to as reversal of hot/cold temperature sensation). Doctors are often at a loss to explain these symptoms and ciguatera poisoning is frequently misdiagnosed as Multiple Sclerosis.
Dyspareunia and other ciguatera symptoms have developed in otherwise-healthy males and females following sexual intercourse with partners suffering ciguatera poisoning, signifying that the toxin that produces ciguatera poisoning may be sexually transmitted. As diarrhea and facial rashes have been reported in breastfed infants of mothers with ciguatera poisoning, it is likely that ciguatera toxins are also transferred into the breast milk.
The symptoms can last from weeks to years, and in extreme cases as long as 20 years, often leading to long term disability. Most people do recover slowly over time. Often patients recover but redevelop symptoms in the future. Such relapses can be triggered by consumption of nuts, alcohol, fish or fish-containing products, chicken or eggs, or by exposure to fumes such as those of bleach and other chemicals. Exercise is also a possible trigger.
# Treatment
There is no effective treatment or antidote for ciguatera poisoning. The mainstay of treatment is supportive care. Some medications such as the use of Amitriptyline may reduce some symptoms of ciguatera, such as fatigue and paresthesia, although benefit does not occur in every case. Also used are steroids and vitamin supplements, but these merely support the body's recovery rather than directly reducing the toxic effects.
Previously mannitol was used for poisoning after one study reported the reversal of symptoms following its use. Followup studies in animals and case reports in humans also found benefit from mannitol. However, a randomized, controlled, double-blind clinical trial of mannitol for ciguatera poisoning did not find any difference between mannitol and normal saline, and based on this result mannitol is no longer recommended.
There are a number of antiquated Caribbean naturopathic and ritualistic treatments, most of which originated in Cuba and nearby islands. The most common old-time remedy involves bed rest subsequent to a Guanabana juice enema. Other folk treatments range from directly porting and bleeding the gastrointestinal tract to "cleansing" the diseased with a dove during a Santeria ritual. The efficacy of these treatments has never been studied or substantiated; nevertheless they are purportedly still used to this day. | Ciguatera
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ciguatera is a foodborne illness poisoning in humans caused by eating marine species whose flesh is contaminated with a toxin known as ciguatoxin, which is present in many microorganisms (particularly the micro-algae Gambierdiscus toxicus) living in tropical waters. Like many naturally and artificially occurring toxins, ciguatoxin bioaccumulates in lower-level organisms, resulting in higher concentration of the toxin at higher levels of the food chain, an example of biomagnification.[1] Predator species near the top of the food chain in tropical waters, such as barracuda, moray eel, parrotfish, grouper, triggerfish, and amberjack, are most likely to cause ciguatera poisoning, although many other species have been found to cause occasional outbreaks of ciguatera. Ciguatoxin is very heat-resistant, so ciguatoxin-laden fish cannot be detoxified by cooking.[2]
# History
Originally, ciguatoxin was linked to poison passed to tropical fish through consumption. However, the exact source of the toxin was unknown, and many sources were identified as the culprit. Some of these included the manchineel fruit, cocculus berries, palolo worms, compounds containing copper, pumice, and corallina opuntia.
In Northern Australia, where ciguatera is a common problem, two different methods are widely believed to be available for determining that fish harbors significant levels of ciguatoxin. The first method is that if a piece of fish is contaminated with the toxin, flies will not land on it. The second is that the toxin can be detected by feeding a piece of fish to a cat, as cats are allegedly highly sensitive to ciguatoxin and will display symptoms. It is not known whether there is any veracity to either belief.
# Etymological Roots
It is a generally held theory that ciguatera, as a poisonous substance, was named and identified in Cuba, circa the early 1800s. Local folklore has identified that the etymology stems from a story of an Englishman who caught a barracuda on the Isla de Pinos. After consuming the barracuda, the Englishman became terribly ill. When queried about the origins of his illness, the Englishman claimed to have caught and eaten “a fish, from the seawater”. This gave rise to the name of the ailment as ciguatera, a transliteration into Spanish of the English word seawater.
# Distribution
Due to the localized nature of the ciguatoxin-producing microorganisms, ciguatera illness is only common in tropical waters, particularly the Pacific and Caribbean, and usually is associated with fish caught in tropical reef waters. Ciguatoxin is found in over 400 species of reef fish, and therefore avoidance of consumption of all reef fish (any fish living in warm tropical waters) is the only sure way to avoid exposure to the toxin. Imported fish served in restaurants have been found to contain the toxin and to produce illness which often goes unexplained by physicians unfamiliar with a tropical toxin and its characteristic symptoms.[3] In addition, ciguatoxin has been found in farm-raised salmon.[4]
In February 2008, the FDA reported that several outbreaks of the disease had been traced to fish harvested near the Flower Garden Banks National Marine Sanctuary in the northern Gulf of Mexico, near the Texas-Louisiana shoreline. The FDA advised seafood processors that ciguatera poisoning was "reasonably likely" to occur from consuming any of several species of fish caught as far as 50 miles (80.4672 km) from the sanctuary.[5]
# Symptoms
Hallmark symptoms of ciguatera include gastrointestinal and neurological effects.[6] Gastrointestinal symptoms include nausea, vomiting, and diarrhea usually followed by neurological symptoms such as headaches, muscle aches, paresthesia, numbness, ataxia, and hallucinations.[2] Severe cases of ciguatera can also result in cold allodynia, which is a burning sensation on contact with cold (commonly incorrectly referred to as reversal of hot/cold temperature sensation).[6] Doctors are often at a loss to explain these symptoms and ciguatera poisoning is frequently misdiagnosed as Multiple Sclerosis.[7]
Dyspareunia and other ciguatera symptoms have developed in otherwise-healthy males and females following sexual intercourse with partners suffering ciguatera poisoning, signifying that the toxin that produces ciguatera poisoning may be sexually transmitted.[8] As diarrhea and facial rashes have been reported in breastfed infants of mothers with ciguatera poisoning, it is likely that ciguatera toxins are also transferred into the breast milk.[9]
The symptoms can last from weeks to years, and in extreme cases as long as 20 years, often leading to long term disability.[10] Most people do recover slowly over time.[11] Often patients recover but redevelop symptoms in the future. Such relapses can be triggered by consumption of nuts, alcohol, fish or fish-containing products, chicken or eggs, or by exposure to fumes such as those of bleach and other chemicals. Exercise is also a possible trigger.[2]
# Treatment
There is no effective treatment or antidote for ciguatera poisoning. The mainstay of treatment is supportive care. Some medications such as the use of Amitriptyline may reduce some symptoms of ciguatera, such as fatigue and paresthesia,[12] although benefit does not occur in every case.[13] Also used are steroids and vitamin supplements, but these merely support the body's recovery rather than directly reducing the toxic effects.
Previously mannitol was used for poisoning after one study reported the reversal of symptoms following its use.[14] Followup studies in animals[15] and case reports in humans[16] also found benefit from mannitol. However, a randomized, controlled, double-blind clinical trial of mannitol for ciguatera poisoning did not find any difference between mannitol and normal saline,[17] and based on this result mannitol is no longer recommended.[6]
There are a number of antiquated Caribbean naturopathic and ritualistic treatments, most of which originated in Cuba and nearby islands. The most common old-time remedy involves bed rest subsequent to a Guanabana juice enema. Other folk treatments range from directly porting and bleeding the gastrointestinal tract to "cleansing" the diseased with a dove during a Santeria ritual. The efficacy of these treatments has never been studied or substantiated; nevertheless they are purportedly still used to this day. | https://www.wikidoc.org/index.php/Ciguatera | |
931e02ad160945f5ffaec462089c47676bd19bba | wikidoc | Coriander | Coriander
Coriander, Coriandrum sativum is an annual herb in the family Apiaceae. The name 'coriander' in a culinary context may refer to either the seeds of the plant (used as a spice), or to its leaves (used as a herb); however, in North American countries, for example, the name Cilantro is given to the leaves. Coriander is native to southwestern Asia and west to north Africa. It is a soft, hairless plant growing to 50 cm tall. The leaves are variable in shape, broadly lobed at the base of the plant, and slender and feathery higher on the flowering stems. The flowers are borne in small umbels, white or very pale pink, asymmetrical, and with the petals that point away from the centre of the umbel being longer (5-6 mm) than those pointing to the middle of the umbel (only 1-3 mm long). The fruit is a globular dry schizocarp 3-5 mm diameter.
The name coriander derives from French coriandre through Latin coriandrum in turn from Greek “Template:Polytonic”. John Chadwick notes the Mycenaean Greek form of the word, koriadnon, "has a pattern curiously similar to the name of Minos' daughter Ariadne, and it is plain how this might be corrupted later to koriannon or koriandron."
# Uses
All parts of the plant are edible, but the fresh leaves and the dried seeds are the most commonly used in cooking. Coriander is commonly used in Middle Eastern, Mediterranean, Indian, South Asian, Latin American, Chinese, African and Southeast Asian cuisine.
## Leaves and stems
The leaves are variously referred to as coriander leaves in Britain; cilantro (from the Spanish name for the plant) in the United States, and dhania in the Indian subcontinent. The leaves, and especially the stems, have a very different taste from the seeds, similar to parsley but "juicier" and with citrus-like overtones. Some people instead perceive an unpleasant "soapy" taste and/or a rank smell. This is believed to be a result of an enzyme that changes the way they taste coriander leaves, a genetic trait, but has yet to be fully researched.
The fresh leaves and stems are an essential ingredient in many Vietnamese foods, Asian chutneys, Mexican salsas and guacamole, and occasionally is used in sushi rolls. Chopped coriander leaves are also used as a garnish on cooked dishes such as dal and many curries. As heat diminishes their flavor quickly, coriander leaves are often used raw or added to the dish right before serving. In some Indian and Central Asian recipes, coriander leaves are used in huge amounts and cooked till they dissolve into sauce and their flavour mellows. Another factor that dictates the quality of flavor is the time when coriander is harvested. If its roots consistently stay at a temperature above 75 degrees Fahrenheit, the herb will quickly bolt, causing its leaves and stems to yield a bitter flavor and become quite chewy. At this point, made evident by the thinner and finer leaves, it is practical to harvest only the coriander seeds, since the stems and leaves are no longer usable as food.
Coriander leaves were formerly common in European cuisine but nearly disappeared before the modern period. Today Europeans usually eat the leaves and stems only in dishes that originated in foreign cuisines; in Portugal, however, it is still an essential ingredient in many traditional dishes. To use the stems, separate cilantro leaves from stems. Chop stems finely and add them to your dish a minute or two before serving, just giving them time to warm up and disperse their flavor. The leaves will remain beautiful and fresh if you use them to garnish individual plates.
The fresh coriander herb is best stored in the refrigerator in airtight containers, after chopping off the roots. The leaves do not keep well and should be eaten quickly, as they lose their aroma when dried or frozen.
## Fruit
The dry fruits are known as coriander seeds or coriandi seeds. In some regions, the use of the word coriander in food preparation always refers to these seeds (as a spice), rather than to the plant itself. The seeds have a lemony citrus flavour when crushed, due to the presence of the terpenes linalool and pinene. It is also described as warm, nutty, spicy, and orange-flavoured. They are usually dried but can be eaten green.
If the fruit is obtained in its natural form, it can later be dried in the sun. Most commonly, it is bought as whole dried seeds, but it can also be found as a powder. When grinding at home, it can be roasted or heated on a dry pan briefly to enhance the aroma before grinding it in an electric grinder or with a mortar and pestle; ground coriander seeds lose their flavour quickly in storage and are best ground as only needed. For optimum flavour, whole coriander seed should be used within six months, or stored for no more than a year in a tightly sealed container away from sunlight and heat.
Coriander seed is a key spice (Hindi name: धनिया dhania) in garam masala and Indian curries, which often employ the ground fruits in generous amounts together with cumin. It also acts as a thickener. Roasted coriander seeds, called dhana dal, are also eaten as a snack. It is also the main ingredient of the two south Indian gravies: sambhar and rasam.
Outside of Asia, coriander seed is an important spice for sausages in Germany and South Africa (see boerewors). In Russia and Central Europe coriander seed is an occasional ingredient in rye bread as an alternative to caraway. Apart from the uses just noted, coriander seeds are rarely used in European cuisine today, though they were more important in former centuries.
Coriander seeds are also used in brewing certain styles of beer, particularly some Belgian wheat beers. The coriander seeds are typically used in conjunction with orange peel to add a sultry citrus character to these styles of beer.
## Roots
Coriander roots are used in a variety of Asian cuisine. They are commonly used in Thai dishes.
# History
Coriander grows wild over a wide area of the Near East and southern Europe, which forced Zohary and Hopf to admit that "it is hard to define exactly where this plant is wild and where it only recently established itself." Fifteen desiccated mericarps were found in the Pre-Pottery Neolithic B level of the Nahal Hemel Cave in Israel, which may be the oldest archeological find of coriander. About half a litre of coriander mericarps were recovered from the tomb of Tutankhamun, and because this plant does not grow wild in Egypt, Zohary and Hopf interpret this find as proof that coriander was cultivated by the ancient Egyptians. The Bible mentions coriander in Exodus 16:31: "And the house of Israel began to call its name Manna: and it was white like coriander seed, and its taste was like that of flat cakes made with honey."
Coriander seems to have been cultivated in Greece since at least the second millennium BC. One of the Linear B tablets recovered from Pylos refers to the species as being cultivated for the manufacture of perfumes, and it appears that it was used in two forms: as a spice for its seeds and as a herb for the flavour of its leaves. This appears to be confirmed by archaeological evidence from the same period: the large quantities of the species retrieved from an Early Bronze Age layer at Sitagroi in Macedonia could point to cultivation of the species at that time . Coriander is thought to have been introduced to Britain by the Romans as a meat preserver.
Coriander seed and leaf was very widely used in medieval cuisine. Even today, coriander seed is an important ingredient in many sausage products.
Coriander was brought to the British colonies in North America in 1670 and was one of the first spices cultivated by early settlers.
# Similar plants
- Eryngium foetidum has a very similar taste to coriander and is also known as culantro.
- Vietnamese coriander leaves have a similar odour and flavour to coriander.
- Bolivian Coriander, or quillquiña, has been described as "somewhere between arugula, cilantro and rue".
# Potential medical uses
Coriander has been used as a folk medicine for the relief of anxiety and insomnia in Iranian folk medicine. Experiments in mice support its use as an anxiolytic. Coriander seeds are also used in traditional Indian medicine as a diuretic by boiling equal amounts of coriander seeds and cumin seeds, then cooling and consuming the resulting liquid. In holistic and some traditional medicine, it is used as a carminative and for general digestive aid. | Coriander
Template:Nutritionalvalue
Coriander, Coriandrum sativum is an annual herb in the family Apiaceae. The name 'coriander' in a culinary context may refer to either the seeds of the plant (used as a spice), or to its leaves (used as a herb); however, in North American countries, for example, the name Cilantro is given to the leaves. Coriander is native to southwestern Asia and west to north Africa. It is a soft, hairless plant growing to 50 cm [20 in.] tall. The leaves are variable in shape, broadly lobed at the base of the plant, and slender and feathery higher on the flowering stems. The flowers are borne in small umbels, white or very pale pink, asymmetrical, and with the petals that point away from the centre of the umbel being longer (5-6 mm) than those pointing to the middle of the umbel (only 1-3 mm long). The fruit is a globular dry schizocarp 3-5 mm diameter.
The name coriander derives from French coriandre through Latin coriandrum in turn from Greek “Template:Polytonic”.[1] John Chadwick notes the Mycenaean Greek form of the word, koriadnon, "has a pattern curiously similar to the name of Minos' daughter Ariadne, and it is plain how this might be corrupted later to koriannon or koriandron."[2]
# Uses
All parts of the plant are edible, but the fresh leaves and the dried seeds are the most commonly used in cooking. Coriander is commonly used in Middle Eastern, Mediterranean, Indian, South Asian, Latin American, Chinese, African and Southeast Asian cuisine.
## Leaves and stems
The leaves are variously referred to as coriander leaves in Britain; cilantro (from the Spanish name for the plant) in the United States, and dhania in the Indian subcontinent. The leaves, and especially the stems, have a very different taste from the seeds, similar to parsley but "juicier" and with citrus-like overtones. Some people instead perceive an unpleasant "soapy" taste and/or a rank smell. This is believed to be a result of an enzyme that changes the way they taste coriander leaves, a genetic trait, but has yet to be fully researched.[3]
The fresh leaves and stems are an essential ingredient in many Vietnamese foods, Asian chutneys, Mexican salsas and guacamole, and occasionally is used in sushi rolls. Chopped coriander leaves are also used as a garnish on cooked dishes such as dal and many curries. As heat diminishes their flavor quickly, coriander leaves are often used raw or added to the dish right before serving. In some Indian and Central Asian recipes, coriander leaves are used in huge amounts and cooked till they dissolve into sauce and their flavour mellows.[1] Another factor that dictates the quality of flavor is the time when coriander is harvested. If its roots consistently stay at a temperature above 75 degrees Fahrenheit, the herb will quickly bolt, causing its leaves and stems to yield a bitter flavor and become quite chewy. At this point, made evident by the thinner and finer leaves, it is practical to harvest only the coriander seeds, since the stems and leaves are no longer usable as food.
Coriander leaves were formerly common in European cuisine but nearly disappeared before the modern period. Today Europeans usually eat the leaves and stems only in dishes that originated in foreign cuisines; in Portugal, however, it is still an essential ingredient in many traditional dishes. To use the stems, separate cilantro leaves from stems. Chop stems finely and add them to your dish a minute or two before serving, just giving them time to warm up and disperse their flavor. The leaves will remain beautiful and fresh if you use them to garnish individual plates.
The fresh coriander herb is best stored in the refrigerator in airtight containers, after chopping off the roots. The leaves do not keep well and should be eaten quickly, as they lose their aroma when dried or frozen.
## Fruit
The dry fruits are known as coriander seeds or coriandi seeds. In some regions, the use of the word coriander in food preparation always refers to these seeds (as a spice), rather than to the plant itself. The seeds have a lemony citrus flavour when crushed, due to the presence of the terpenes linalool and pinene. It is also described as warm, nutty, spicy, and orange-flavoured. They are usually dried but can be eaten green.
If the fruit is obtained in its natural form, it can later be dried in the sun. Most commonly, it is bought as whole dried seeds, but it can also be found as a powder. When grinding at home, it can be roasted or heated on a dry pan briefly to enhance the aroma before grinding it in an electric grinder or with a mortar and pestle; ground coriander seeds lose their flavour quickly in storage and are best ground as only needed. For optimum flavour, whole coriander seed should be used within six months, or stored for no more than a year in a tightly sealed container away from sunlight and heat.
Coriander seed is a key spice (Hindi name: धनिया dhania) in garam masala and Indian curries, which often employ the ground fruits in generous amounts together with cumin. It also acts as a thickener. Roasted coriander seeds, called dhana dal, are also eaten as a snack. It is also the main ingredient of the two south Indian gravies: sambhar and rasam.
Outside of Asia, coriander seed is an important spice for sausages in Germany and South Africa (see boerewors). In Russia and Central Europe coriander seed is an occasional ingredient in rye bread as an alternative to caraway. Apart from the uses just noted, coriander seeds are rarely used in European cuisine today, though they were more important in former centuries.
Coriander seeds are also used in brewing certain styles of beer, particularly some Belgian wheat beers. The coriander seeds are typically used in conjunction with orange peel to add a sultry citrus character to these styles of beer.
## Roots
Coriander roots are used in a variety of Asian cuisine. They are commonly used in Thai dishes.
# History
Coriander grows wild over a wide area of the Near East and southern Europe, which forced Zohary and Hopf to admit that "it is hard to define exactly where this plant is wild and where it only recently established itself."[4] Fifteen desiccated mericarps were found in the Pre-Pottery Neolithic B level of the Nahal Hemel Cave in Israel, which may be the oldest archeological find of coriander. About half a litre of coriander mericarps were recovered from the tomb of Tutankhamun, and because this plant does not grow wild in Egypt, Zohary and Hopf interpret this find as proof that coriander was cultivated by the ancient Egyptians.[5] The Bible mentions coriander in Exodus 16:31: "And the house of Israel began to call its name Manna: and it was white like coriander seed, and its taste was like that of flat cakes made with honey."
Coriander seems to have been cultivated in Greece since at least the second millennium BC. One of the Linear B tablets recovered from Pylos refers to the species as being cultivated for the manufacture of perfumes, and it appears that it was used in two forms: as a spice for its seeds and as a herb for the flavour of its leaves.[6] This appears to be confirmed by archaeological evidence from the same period: the large quantities of the species retrieved from an Early Bronze Age layer at Sitagroi in Macedonia could point to cultivation of the species at that time [7]. Coriander is thought to have been introduced to Britain by the Romans as a meat preserver.[citation needed]
Coriander seed and leaf was very widely used in medieval cuisine. Even today, coriander seed is an important ingredient in many sausage products.
Coriander was brought to the British colonies in North America in 1670 and was one of the first spices cultivated by early settlers.
# Similar plants
- Eryngium foetidum has a very similar taste to coriander and is also known as culantro.
- Vietnamese coriander leaves have a similar odour and flavour to coriander.
- Bolivian Coriander, or quillquiña, has been described as "somewhere between arugula, cilantro and rue".
# Potential medical uses
Coriander has been used as a folk medicine for the relief of anxiety and insomnia in Iranian folk medicine. Experiments in mice support its use as an anxiolytic.[8] Coriander seeds are also used in traditional Indian medicine as a diuretic by boiling equal amounts of coriander seeds and cumin seeds, then cooling and consuming the resulting liquid.[9] In holistic and some traditional medicine, it is used as a carminative and for general digestive aid.[10][11] | https://www.wikidoc.org/index.php/Cilantro | |
acf641ebf62ea81b21f7745ba35e8a4a43d58970 | wikidoc | Cinnoline | Cinnoline
Cinnoline is an aromatic heterocyclic compound with the formula C8H6N2 (CAS# ). It is isomeric with phthalazine. Alternative name: benzopyridazine.
# Properties
The free base can be obtained as an oil by treatment of the hydrochloride with base. It co-crystallizes with one molecule of ether as white silky needles, (m.p. 24-25 °C) upon cooling etherial solutions. The free base melts at 39°C. It has a taste resembling that of chloral hydrate and leaves a sharp irritation for some time. Cinnoline derivatives are obtained from oxycinnolin carboxylic acid, which is formed by digesting orthophenyl propiolic acid diazo chloride with water. Oxycinnolin carboxylic acid on heating gives oxycinnoline, melting at 225 °C, which with phosphorus pentachloride gives chlorcinnolin. This substance is reduced by iron filings and sulfuric acid to dihydrocinnolin.
# Discovery and synthesis
The compound was first obtained in impure form by cyclization of the alkyne o-C6H4(NH2)C≡CCO2H in water to give 4-hydroxycinnoline-3-carboxylic acid. This material could be decarboxylated and the hydroxyl group reductively removed to give the parent heterocycle. This reaction is called the Richter cinnoline synthesis Improved methods exist for its synthesis. It can be prepared by dehydrogenation of dihydrocinnoline with freshly precipitated mercuric oxide. It can be isolated as the hydrochloride.
Cinnolines are cinnoline derivatives. A classic organic reaction for synthesizing cinnolines is the Widman-Stoermer synthesis , a ring-closing reaction of an α-vinyl- aniline with hydrochloric acid and sodium nitrite:
The sodium nitrite is first converted to nitrous acid which then forms the electrophilic intermediate dinitrogen trioxide. The next intermediate is the stable Nitrosamine with goes on to lose water forming the diazonium salt which then reacts with the vinyl group in the ring-closing step. A conceptually related reaction is the Bamberger triazine synthesis towards triazines.
Another cinnoline method is the Borsche cinnoline synthesis. | Cinnoline
Cinnoline is an aromatic heterocyclic compound with the formula C8H6N2 (CAS# [253-66-7]). It is isomeric with phthalazine. Alternative name: benzopyridazine.
# Properties
The free base can be obtained as an oil by treatment of the hydrochloride with base. It co-crystallizes with one molecule of ether as white silky needles, (m.p. 24-25 °C) upon cooling etherial solutions. The free base melts at 39°C. It has a taste resembling that of chloral hydrate and leaves a sharp irritation for some time. Cinnoline derivatives are obtained from oxycinnolin carboxylic acid, which is formed by digesting orthophenyl propiolic acid diazo chloride with water. Oxycinnolin carboxylic acid on heating gives oxycinnoline, melting at 225 °C, which with phosphorus pentachloride gives chlorcinnolin. This substance is reduced by iron filings and sulfuric acid to dihydrocinnolin.
# Discovery and synthesis
The compound was first obtained in impure form by cyclization of the alkyne o-C6H4(NH2)C≡CCO2H in water to give 4-hydroxycinnoline-3-carboxylic acid. This material could be decarboxylated and the hydroxyl group reductively removed to give the parent heterocycle. This reaction is called the Richter cinnoline synthesis [1] Improved methods exist for its synthesis. It can be prepared by dehydrogenation of dihydrocinnoline with freshly precipitated mercuric oxide. It can be isolated as the hydrochloride. [2]
Cinnolines are cinnoline derivatives. A classic organic reaction for synthesizing cinnolines is the Widman-Stoermer synthesis [3], a ring-closing reaction of an α-vinyl- aniline with hydrochloric acid and sodium nitrite:
The sodium nitrite is first converted to nitrous acid which then forms the electrophilic intermediate dinitrogen trioxide. The next intermediate is the stable Nitrosamine with goes on to lose water forming the diazonium salt which then reacts with the vinyl group in the ring-closing step. A conceptually related reaction is the Bamberger triazine synthesis towards triazines.
Another cinnoline method is the Borsche cinnoline synthesis. | https://www.wikidoc.org/index.php/Cinnoline | |
6cfde15d6ec3e35f8fa837ddb414b5841d70529e | wikidoc | Cinoxacin | Cinoxacin
# Overview
Cinoxacin is a quinolone antibiotic that has been discontinued in the U.K. as well the United States, both as a branded drug or a generic.
Cinoxacin was an older synthetic antimicrobial related to the quinolone class of antibiotics with activity similar to oxolinic acid and nalidixic acid. It was commonly used thirty years ago to treat urinary tract infections in adults. There are reports that cinoxacin had also been used to treat initial and recurrent urinary tract infections and bacterial prostatitis in dogs. however this veterinary use was never approved by the United States Food and Drug Administration (FDA). In complicated UTI, the older gyrase-inhibitors such as cinoxacin are no longer indicated.
# History
Cinoxacin is one of the original quinolone drugs, which were introduced in the 1970s. Commonly referred to as the first generation quinolones. This first generation also included other quinolone drugs such as pipemidic acid, and oxolinic acid, but this first generation proved to be only marginal improvements over nalidixic acid. Cinoxacin is similar chemically (and in antimicrobial activity) to oxolonic acid and nalidixic acid. Relative to nalidixic acid, cinoxacin was found to have a slightly greater inhibitory and bactericidal activity. Cinoxacin was patented in 1972 and assigned to Eli Lilly. Eli Lilly obtained approval from the FDA to market cinoxacin in the United States as Cinobac on June 13, 1980. Prior to this cinobac was marketed in the U.K. and Switzerland in 1979.
Oclassen Pharmaceuticals (Oclassen Dermatologics) commenced sales of Cinobac in the United States and Canada back in September 1992, under an agreement with Eli Lilly which granted Oclassen exclusive United States and Canadian distribution rights. Oclassen promoted Cinobac primarily to urologists for the outpatient treatment of initial and recurrent urinary tract infections and prophylaxis. Oclassen Pharmaceuticals was a privately held pharmaceutical company founded in 1985 until acquired by Watson Pharmaceuticals, Inc., in 1997. Watson Pharmaceuticals, Inc., (also incorporated in 1985), having acquired Oclassen Pharmaceuticals (Oclassen Dermatologics) also acquired the marketing rights contained within the agreement with Eli Lilly to market Cinobac.
# Licensed uses
Urinary tract infections only
# Availability
250 mg, capsules (prescription only)
# Mode of action
Cinoxacin mode of action involves the inhibiting of DNA gyrase, a type II topoisomerase, and topoisomerase iv, which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division.
# Contraindications
Within the most recent package insert (circa 1999) Cinobac is listed as being contraindicated in patients with a history of hypersensitivity to cinoxacin or other quinolones.
# Adverse reactions
The safety profile of cinoxacin appears to be rather unremarkable. Adverse drug reactions appear to be limited to the gastrointestinal system and the central nervous system. Hypersensitivity resulting in an anaphylactic reactions (as seen with all drugs found within this class) has also been reported in association with cinoxacin. Animal studies have shown that Cinoxacin is associated with renal damage. Such damage appears to be due to the physical trauma resulting from deposition of cinoxacin crystals in the urinary tract. Such crystaluria has also been reported with other drugs in this class. A review of the literature indicates that patients treated with cinoxacin reported fewer adverse drug reactions than those treated with nalidixic acid, furadantin, amoxicillin, or trimethoprim-sulfamethoxazole.
Although phototoxicity and photoallergenicity is well demonstrated experimentally, phototoxicity does not appear to be an issue with cinoxacin. As a result of this safety profile the manufacturer, Eli Lilley states that "cinoxacin perhaps should be reserved only for those patients with organisms resistant to usual first-line agents or those who fail to respond to therapy with these agents."
# Overdose
Symptoms following an overdose of cinoxacin may include anorexia, nausea, vomiting, epigastric distress, and diarrhea. The severity of the epigastric distress and the diarrhea are dose related. Patients who have ingested an overdose of cinoxacin should be kept well hydrated to prevent crystalluria. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cinoxacin.
# Pharmacokinetics
Biotransformation is mainly hepatic, with approximately 30-40% metabolized to inactive metabolites. Protein Binding ranges from 60 to 80%. Cinoxacin is rapidly absorbed after oral administration. The presence of food delays absorption but does not affect total absorption. The mean serum half-life is 1.5 hours. Half-life in patients with impaired renal function may exceed 10 hours.
# Dosing
The usual adult dosage for the treatment of urinary tract infections is 1 g daily, administered orally in 2 or 4 divided doses (500 mg b.i.d. or 250 mg q.i.d. respectively) for 7 to 14 days.
## Impaired renal function
When renal function is impaired, a reduced dosage must be employed.
# Susceptible bacteria
Gram-negative aerobes:
- Enterobacter species
- Escherichia coli
- Klebsiella species
- Proteus mirabilis
- Proteus vulgaris
Enterococcus species, Pseudomonas species, and Staphylococcus species are resistant. | Cinoxacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cinoxacin is a quinolone antibiotic that has been discontinued in the U.K.[1] as well the United States, both as a branded drug or a generic.
Cinoxacin was an older synthetic antimicrobial related to the quinolone class of antibiotics with activity similar to oxolinic acid and nalidixic acid. It was commonly used thirty years ago to treat urinary tract infections in adults. There are reports that cinoxacin had also been used to treat initial and recurrent urinary tract infections and bacterial prostatitis in dogs.[2] however this veterinary use was never approved by the United States Food and Drug Administration (FDA). In complicated UTI, the older gyrase-inhibitors such as cinoxacin are no longer indicated.[3]
# History
Cinoxacin is one of the original quinolone drugs, which were introduced in the 1970s. Commonly referred to as the first generation quinolones. This first generation also included other quinolone drugs such as pipemidic acid, and oxolinic acid, but this first generation proved to be only marginal improvements over nalidixic acid. Cinoxacin is similar chemically (and in antimicrobial activity) to oxolonic acid and nalidixic acid. Relative to nalidixic acid, cinoxacin was found to have a slightly greater inhibitory and bactericidal activity. Cinoxacin was patented in 1972 and assigned to Eli Lilly.[4] Eli Lilly obtained approval from the FDA to market cinoxacin in the United States as Cinobac on June 13, 1980. Prior to this cinobac was marketed in the U.K. and Switzerland in 1979.
Oclassen Pharmaceuticals (Oclassen Dermatologics) commenced sales of Cinobac in the United States and Canada back in September 1992, under an agreement with Eli Lilly which granted Oclassen exclusive United States and Canadian distribution rights.[5] Oclassen promoted Cinobac primarily to urologists for the outpatient treatment of initial and recurrent urinary tract infections and prophylaxis. Oclassen Pharmaceuticals was a privately held pharmaceutical company founded in 1985 until acquired by Watson Pharmaceuticals, Inc., in 1997. Watson Pharmaceuticals, Inc., (also incorporated in 1985), having acquired Oclassen Pharmaceuticals (Oclassen Dermatologics) also acquired the marketing rights contained within the agreement with Eli Lilly to market Cinobac.[6]
# Licensed uses
Urinary tract infections only
# Availability
250 mg, capsules (prescription only)
# Mode of action
Cinoxacin mode of action involves the inhibiting of DNA gyrase, a type II topoisomerase, and topoisomerase iv,[7] which is an enzyme necessary to separate replicated DNA, thereby inhibiting cell division.
# Contraindications
Within the most recent package insert (circa 1999) Cinobac is listed as being contraindicated in patients with a history of hypersensitivity to cinoxacin or other quinolones.
# Adverse reactions
The safety profile of cinoxacin appears to be rather unremarkable. Adverse drug reactions appear to be limited to the gastrointestinal system and the central nervous system.[8] Hypersensitivity resulting in an anaphylactic reactions (as seen with all drugs found within this class) has also been reported in association with cinoxacin.[9][10] Animal studies have shown that Cinoxacin is associated with renal damage. Such damage appears to be due to the physical trauma resulting from deposition of cinoxacin crystals in the urinary tract.[11] Such crystaluria has also been reported with other drugs in this class.[12] A review of the literature indicates that patients treated with cinoxacin reported fewer adverse drug reactions than those treated with nalidixic acid, furadantin, amoxicillin, or trimethoprim-sulfamethoxazole.[13]
Although phototoxicity and photoallergenicity is well demonstrated experimentally, phototoxicity does not appear to be an issue with cinoxacin.[14] As a result of this safety profile the manufacturer, Eli Lilley states that "cinoxacin perhaps should be reserved only for those patients with organisms resistant to usual first-line agents or those who fail to respond to therapy with these agents."[15]
# Overdose
Symptoms following an overdose of cinoxacin may include anorexia, nausea, vomiting, epigastric distress, and diarrhea. The severity of the epigastric distress and the diarrhea are dose related.[16] Patients who have ingested an overdose of cinoxacin should be kept well hydrated to prevent crystalluria. Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cinoxacin.[17]
# Pharmacokinetics
Biotransformation is mainly hepatic, with approximately 30-40% metabolized to inactive metabolites. Protein Binding ranges from 60 to 80%. Cinoxacin is rapidly absorbed after oral administration. The presence of food delays absorption but does not affect total absorption. The mean serum half-life is 1.5 hours. Half-life in patients with impaired renal function may exceed 10 hours.[18]
# Dosing
The usual adult dosage for the treatment of urinary tract infections is 1 g daily, administered orally in 2 or 4 divided doses (500 mg b.i.d. or 250 mg q.i.d. respectively) for 7 to 14 days.
## Impaired renal function
When renal function is impaired, a reduced dosage must be employed.
# Susceptible bacteria
Gram-negative aerobes:
- Enterobacter species
- Escherichia coli
- Klebsiella species
- Proteus mirabilis
- Proteus vulgaris
Enterococcus species, Pseudomonas species, and Staphylococcus species are resistant. | https://www.wikidoc.org/index.php/Cinoxacin | |
a787ec146dc438f05fe18f99b173b8a8723cfc92 | wikidoc | Cisplatin | Cisplatin
# Disclaimer
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# Black Box Warning
# Overview
Cisplatin is an antineoplastic agent that is FDA approved for the treatment of metastatic testicular tumors, metastatic ovarian tumors, and advanced bladder cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, leukopenia, and thrombocytopenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The usual Cisplatin Injection dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.
- The usual Cisplatin Injection dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every four weeks (DAY 1).
- The dose of cyclophosphamide when used in combination with Cisplatin Injection is 600 mg/m2 IV once every 4 weeks (DAY 1).
- For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.
- In combination therapy, Cisplatin Injection and cyclophosphamide are administered sequentially.
- As a single agent, Cisplatin Injection should be administered at a dose of 100 mg/m2 IV per cycle once every four weeks.
- Cisplatin Injection should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended.
- Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a Cisplatin Injection dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute Cisplatin Injection in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours.
- A repeat course of Cisplatin Injection should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥100,000/mm3, WBC ≥4000/mm3). Subsequent doses of Cisplatin Injection should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cisplatin in adult patients.
### Non–Guideline-Supported Use
- Intravenous cisplatin 30 mg/m(2)/day for 4 days every 3 weeks for a maximum of 6 courses.
- Paclitaxel 175 mg/m(2) on day 1, cisplatin 20 mg/m(2) on days 1 through 5 (attenuated to 15 mg/m(2) after cycle 3), and a continuous infusion of ] on days 1 through 5 at a dose of 1000 mg/m(2).
- Doxorubicin 60 mg/m(2) followed immediately by cisplatin 50 mg/m(2) (the latter infused over 1 hour).
- Docetaxel 75 mg/m(2) and cisplatin 75 mg/m (2) every three weeks for 6 cycles.
- The COB (cisplatin 100 mg/m(2), vincristine 1 mg, bleomycin 30 units) regimen.
- Epirubicin 50 mg/m(2) and cisplatin 60 mg/m(2) on day 1, each given every 21 days and 5-fluorouracil 200 mg/m(2)/day given as a continuous 24-hour infusion throughout the treatment course.
- Vincristine 1.4 mg/m(2), methotrexate 8 g/m(2) with leucovorin rescue 15 mg every 6 hours for 12 doses administered 24 hours after initial dose of methotrexate. Following a 4- to 5-day interval, cisplatin 120 mg/m(2) was administered.
- Cisplatin continuous infusion 20 mg/m(2) days 1 to 5.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cisplatin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cisplatin in pediatric patients.
### Non–Guideline-Supported Use
- Intravenous doxorubicin 90 mg/m(2) over a period of 4 days. On day 5, patients received cisplatin 150 mg/m(2) over a 2 hour period with hydration.
- 1 cycle of cisplatin 80 mg/m(2) as a continuous 24-hour IV infusion within 7 days of diagnosis.
# Contraindications
- Cisplatin is contraindicated in patients with preexisting renal impairment. Cisplatin should not be employed in myelosuppressed patients, or in patients with hearing impairment.
- Cisplatin is contraindicated in patients with a history of allergic reactions to cisplatin or other platinum-containing compounds.
# Warnings
- Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and magnesium, sodium, potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, cisplatin should not be given more frequently than once every 3 to 4 weeks. Elderly patients may be more susceptible to nephrotoxicity.
- There are reports of severe neuropathies in patients in whom regimens are employed using higher doses of cisplatin or greater dose frequencies than those recommended. These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients may be more susceptible to peripheral neuropathy.
- Loss of motor function has also been reported.
- Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines.
- Cisplatin can commonly cause ototoxicity which is cumulative and may be severe. Audiometric testing should be performed prior to initiating therapy and prior to each subsequent dose of drug.
- Certain genetic variants in the thiopurine S-methyltransferase (TPMT) gene are associated with increased risk of ototoxicity in children administered conventional doses of cisplatin. Children who do not have one of these TPMT gene variants remain at risk for ototoxicity. All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose, of drug and for several years post therapy.
- Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant.
- The carcinogenic effect of cisplatin was studied in BD IX rats. Cisplatin was administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body weight per week. Four hundred and fifty-five days after the first application, 33 animals died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma.
- The development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents.
- Injection site reactions may occur during the administration of cisplatin. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.
### Precautions
- Peripheral blood counts should be monitored weekly. Liver function should be monitored periodically. Neurologic examination should also be performed regularly.
# Adverse Reactions
## Clinical Trials Experience
- Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of cisplatin. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m2. It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of cisplatin can be given. Elderly patients may be more susceptible to nephrotoxicity.
- Impairment of renal function has been associated with renal tubular damage. The administration of cisplatin using a 6- to 8-hour infusion with intravenous hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of these procedures.
- Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000 Hz). The prevelance of hearing loss in children is particularly high and is estimated to be 40-60%. Decreased ability to hear normal conversational tones may occur. Deafness after the initial dose of cisplatin has been reported. Ototoxic effects may be more severe in children receiving cisplatin.
- Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It is unclear whether cisplatin-induced ototoxicity is reversible. Vestibular toxicity has also been reported. Ototoxic effects may be related to the peak plasma concentration of cisplatin. Ototoxicity can occur during treatment or be delayed. Audiometric monitoring should be performed prior to initiation of therapy, prior to each subsequent dose, and for several years post therapy.
- The risk of ototoxicity may increased by prior or simultaneous cranial irradiation, and may be more severe in patients less than 5 years of age, patients being treated with other ototoxic drugs (e.g. aminoglycosides and vancomycin), and in patients with renal impairment. Variants in the thiopurine S-methyltransferase gene (TPMT) have been reported to be associated with an increased risk of ototoxicity in children treated with cisplatin.
- Other genetic factors may also contribute to the cisplatin-induced ototoxicity.
- Myelosuppression occurs in 25% to 30% of patients treated with cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infection have also been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Elderly patients may be more susceptible to myelosuppression.
- In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician.
- The development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents.
- Marked nausea and vomiting occur in almost all patients treated with cisplatin, and may be so severe that the drug must be discontinued. Nausea and vomiting may begin within 1 to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after treatment.
- Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of cisplatin therapy.
- Diarrhea has also been reported.
- Vascular toxicities coincident with the use of cisplatin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome ), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud's phenomenon occurring in patients treated with the combination of bleomycin, vinblastine with or without cisplatin. It has been suggested that hypomagnesemia developing coincident with the use of cisplatin may be an added, although not essential, factor associated with this event. However, it is currently unknown if the cause of Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.
- Serum Electrolyte Disturbances
- Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been reported to occur in patients treated with cisplatin and are probably related to renal tubular damage. Tetany has been reported in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing cisplatin.
- Inappropriate antidiuretic hormone syndrome has also been reported.
- Hyperuricemia
- Hyperuricemia has been reported to occur at approximately the same frequency as the increases in BUN and serum creatinine.
- It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels.
- Neurotoxicity
- Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of cisplatin. Cisplatin therapy should be discontinued when the symptoms are first observed. The neuropathy, however, may progress further even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. Elderly patients may be more susceptible to peripheral neuropathy.
- Lhermitte's sign, dorsal column myelopathy, and autonomic neuropathy have also been reported.
- Loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported.
- Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and were usually associated in patients receiving a relatively high cumulative dose of cisplatin and with a relatively advanced symptomatic stage of peripheral neuropathy.
- Ocular Toxicity
- Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving standard recommended doses of cisplatin. Improvement and/or total recovery usually occurs after discontinuing cisplatin. Steroids with or without mannitol have been used; however, efficacy has not been established.
- Blurred vision and altered color perception have been reported after the use of regimens with higher doses of cisplatin or greater dose frequencies than recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area.
- Anaphylactic-Like Reactions
- Anaphylactic-like reactions have been reported in patients previously exposed to cisplatin. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving cisplatin should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication.
- Hepatotoxicity
- Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with cisplatin administration at the recommended doses.
- Other Events
- Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and dehydration have been reported.
- Local soft tissue toxicity has been reported following extravasation of cisplatin. Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin solution. Infusion of solutions with a cisplatin concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Cisplatin in the drug label.
# Drug Interactions
- Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy.
- In a randomized trial in advanced ovarian cancer, response duration was adversely affected when pyridoxine was used in combination with altretamine (hexamethylmelamine) and cisplatin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cisplatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cisplatin during labor and delivery.
### Nursing Mothers
- Cisplatin has been reported to be found in human milk; patients receiving cisplatin should not breast-feed.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Variants in the thiopurine S-methyltransferase (TPMT) gene are associated with an increased risk of ototoxicity in children treated with cisplatin.
- All children should have audiometric monitoring performed prior to initiation of therapy prior to each subsequent dose, and for several years post therapy. Advanced testing methods may allow for earlier detection of hearing loss in an attempt to facilitate the rapid initiation of interventions that can limit the potential adverse impact of hearing impairment on a child's cognitive and social development.
### Geriatic Use
- Insufficient data are available from clinical trials of cisplatin in the treatment of metastatic testicular tumors or advanced bladder cancer to determine whether elderly patients respond differently than younger patients. In four clinical trials of combination chemotherapy for advanced ovarian carcinoma, 1484 patients received cisplatin either in combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than 65 years. In these trials, age was not found to be a prognostic factor for survival. However, in a later secondary analysis for one of these trials, elderly patients were found to have shorter survival compared with younger patients. In all four trials, elderly patients experienced more severe neutropenia than younger patients. Higher incidences of severe thrombocytopenia and leukopenia were also seen in elderly compared with younger patients, although not in all cisplatin-containing treatment arms. In the two trials where nonhematologic toxicity was evaluated according to age, elderly patients had a numerically higher incidence of peripheral neuropathy than younger patients. Other reported clinical experience suggests that elderly patients may be more susceptible to myelosuppression, infectious complications, and nephrotoxicity than younger patients.
- Cisplatin is known to be substantially excreted by the kidney and is contraindicated in patients with preexisting renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.
### Gender
There is no FDA guidance on the use of Cisplatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cisplatin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cisplatin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cisplatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cisplatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cisplatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Peripheral blood counts should be monitored weekly. Liver function should be monitored periodically. Neurologic examination should also be performed regularly.
# IV Compatibility
- Preparation Precautions
- Caution should be exercised in handling the aqueous solution. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and IV sets containing cisplatin.
- Skin reactions associated with accidental exposure to cisplatin may occur. The use of gloves is recommended. If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water. More information is available in the references listed below.
- Instructions for Preparation
- The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6- to 8-hour period.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- NOTE TO PHARMACIST: Exercise caution to prevent inadvertent cisplatin overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum and flip-off seal of vial have been imprinted with the following statement:
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Caution should be exercised to prevent inadvertent overdosage with cisplatin. Acute overdosage with this drug may result in kidney failure, liver failure, deafness, ocular toxicity (including detachment of the retina), significant myelosuppression, intractable nausea and vomiting and/or neuritis. In addition, death can occur following overdosage.
### Management
- No proven antidotes have been established for cisplatin overdosage. Hemodialysis, even when initiated four hours after the overdosage, appears to have little effect on removing platinum from the body because of cisplatin's rapid and high degree of protein binding. Management of overdosage should include general supportive measures to sustain the patient through any period of toxicity that may occur.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cisplatin in the drug label.
# Pharmacology
## Mechanism of Action
- Cisplatin possibly acts through cross-linking and by interference with the function of DNA. It is an alkylating agent and it is cell cycle phase- nonspecific.
## Structure
- Cisplatin Injection infusion concentrate is a clear, colorless, sterile aqueous solution available in amber vials. Each 50 mL or 100 mL amber vial of infusion concentrate contains: 1 mg/mL cisplatin, 9 mg/mL sodium chloride, hydrochloric acid and sodium hydroxide to approximate pH of 4.0, and water for injection to a final volume of 50 mL or 100 mL, respectively.
- Cisplatin Injection infusion concentrate must be further diluted prior to administration.
- The active ingredient, cisplatin, is a yellow to orange crystalline powder with the molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. It is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207° C.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cisplatin in the drug label.
## Pharmacokinetics
- Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2 doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total-body clearances and volumes of distribution at steady-state for cisplatin are about 15 to 16 L/h/m2 and 11 to 12 L/m2.
- Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. At physiological pH in the presence of 0.1M NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis-diammine platinum (II) in nearly equal concentrations. The latter, combined with the possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the instability of cisplatin in biological matrices. The ratios of cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.
- Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more.
- Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days after the last administration. With the exception of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower than the concentrations in the organ where the tumor is located. Different metastatic sites in the same patient may have different platinum concentrations. Hepatic metastases have the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. Maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after a 100 mg/m2 dose of cisplatin and decline in a biphasic manner with a terminal half-life of 36 to 47 days.
- Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over five days following administration of 40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following five daily administrations of 20, 30, or 40 mg/m2/day. Only a small percentage of the administered platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is excreted within the first few hours. Platinum-containing species excreted in the urine are the same as those found following the incubation of cisplatin with urine from healthy subjects, except that the proportions are different.
- The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within one hour after administration of 50 mg/m2. The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively.
- The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption.
- There is a potential for accumulation of ultrafilterable platinum plasma concentrations whenever cisplatin is administered on a daily basis but not when dosed on an intermittent basis.
- No significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance.
- Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Cisplatin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Cisplatin in the drug label.
# How Supplied
- Cisplatin Injection is available as follows:
- NDC 44567-509-01 Each multidose vial contains 50 mg of cisplatin
- NDC 44567-510-01 Each multidose vial contains 100 mg of cisplatin
## Storage
There is limited information regarding Cisplatin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Cisplatin in the drug label.
# Precautions with Alcohol
- Alcohol-Cisplatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CISPLATIN®
# Look-Alike Drug Names
- CISplatin® — CARBOplatin®
- Platinol® — Patanol®
# Drug Shortage Status
# Price | Cisplatin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]; Sree Teja Yelamanchili, MBBS [3]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Cisplatin is an antineoplastic agent that is FDA approved for the treatment of metastatic testicular tumors, metastatic ovarian tumors, and advanced bladder cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, leukopenia, and thrombocytopenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The usual Cisplatin Injection dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.
- The usual Cisplatin Injection dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every four weeks (DAY 1).
- The dose of cyclophosphamide when used in combination with Cisplatin Injection is 600 mg/m2 IV once every 4 weeks (DAY 1).
- For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.
- In combination therapy, Cisplatin Injection and cyclophosphamide are administered sequentially.
- As a single agent, Cisplatin Injection should be administered at a dose of 100 mg/m2 IV per cycle once every four weeks.
- Cisplatin Injection should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended.
- Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a Cisplatin Injection dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute Cisplatin Injection in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours.
- A repeat course of Cisplatin Injection should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥100,000/mm3, WBC ≥4000/mm3). Subsequent doses of Cisplatin Injection should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cisplatin in adult patients.
### Non–Guideline-Supported Use
- Intravenous cisplatin 30 mg/m(2)/day for 4 days every 3 weeks for a maximum of 6 courses.[1]
- Paclitaxel 175 mg/m(2) on day 1, cisplatin 20 mg/m(2) on days 1 through 5 (attenuated to 15 mg/m(2) after cycle 3), and a continuous infusion of [[|5-FC|fluorouracil]] on days 1 through 5 at a dose of 1000 mg/m(2).[2]
- Doxorubicin 60 mg/m(2) followed immediately by cisplatin 50 mg/m(2) (the latter infused over 1 hour).[3]
- Docetaxel 75 mg/m(2) and cisplatin 75 mg/m (2) every three weeks for 6 cycles.[4]
- The COB (cisplatin 100 mg/m(2), vincristine 1 mg, bleomycin 30 units) regimen.[5]
- Epirubicin 50 mg/m(2) and cisplatin 60 mg/m(2) on day 1, each given every 21 days and 5-fluorouracil 200 mg/m(2)/day given as a continuous 24-hour infusion throughout the treatment course.[6]
- Vincristine 1.4 mg/m(2), methotrexate 8 g/m(2) with leucovorin rescue 15 mg every 6 hours for 12 doses administered 24 hours after initial dose of methotrexate. Following a 4- to 5-day interval, cisplatin 120 mg/m(2) was administered.[7]
- Cisplatin continuous infusion 20 mg/m(2) days 1 to 5.[8]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cisplatin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cisplatin in pediatric patients.
### Non–Guideline-Supported Use
- Intravenous doxorubicin 90 mg/m(2) over a period of 4 days. On day 5, patients received cisplatin 150 mg/m(2) over a 2 hour period with hydration.[9]
- 1 cycle of cisplatin 80 mg/m(2) as a continuous 24-hour IV infusion within 7 days of diagnosis.[10]
# Contraindications
- Cisplatin is contraindicated in patients with preexisting renal impairment. Cisplatin should not be employed in myelosuppressed patients, or in patients with hearing impairment.
- Cisplatin is contraindicated in patients with a history of allergic reactions to cisplatin or other platinum-containing compounds.
# Warnings
- Cisplatin produces cumulative nephrotoxicity which is potentiated by aminoglycoside antibiotics. The serum creatinine, blood urea nitrogen (BUN), creatinine clearance, and magnesium, sodium, potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course. At the recommended dosage, cisplatin should not be given more frequently than once every 3 to 4 weeks. Elderly patients may be more susceptible to nephrotoxicity.
- There are reports of severe neuropathies in patients in whom regimens are employed using higher doses of cisplatin or greater dose frequencies than those recommended. These neuropathies may be irreversible and are seen as paresthesias in a stocking-glove distribution, areflexia, and loss of proprioception and vibratory sensation. Elderly patients may be more susceptible to peripheral neuropathy.
- Loss of motor function has also been reported.
- Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to cisplatin, and have been alleviated by administration of epinephrine, corticosteroids, and antihistamines.
- Cisplatin can commonly cause ototoxicity which is cumulative and may be severe. Audiometric testing should be performed prior to initiating therapy and prior to each subsequent dose of drug.
- Certain genetic variants in the thiopurine S-methyltransferase (TPMT) gene are associated with increased risk of ototoxicity in children administered conventional doses of cisplatin. Children who do not have one of these TPMT gene variants remain at risk for ototoxicity. All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose, of drug and for several years post therapy.
- Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant.
- The carcinogenic effect of cisplatin was studied in BD IX rats. Cisplatin was administered intraperitoneally (i.p.) to 50 BD IX rats for 3 weeks, 3 X 1 mg/kg body weight per week. Four hundred and fifty-five days after the first application, 33 animals died, 13 of them related to malignancies: 12 leukemias and 1 renal fibrosarcoma.
- The development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents.
- Injection site reactions may occur during the administration of cisplatin. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.
### Precautions
- Peripheral blood counts should be monitored weekly. Liver function should be monitored periodically. Neurologic examination should also be performed regularly.
# Adverse Reactions
## Clinical Trials Experience
- Dose-related and cumulative renal insufficiency, including acute renal failure, is the major dose-limiting toxicity of cisplatin. Renal toxicity has been noted in 28% to 36% of patients treated with a single dose of 50 mg/m2. It is first noted during the second week after a dose and is manifested by elevations in BUN and creatinine, serum uric acid and/or a decrease in creatinine clearance. Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal function must return to normal before another dose of cisplatin can be given. Elderly patients may be more susceptible to nephrotoxicity.
- Impairment of renal function has been associated with renal tubular damage. The administration of cisplatin using a 6- to 8-hour infusion with intravenous hydration, and mannitol has been used to reduce nephrotoxicity. However, renal toxicity still can occur after utilization of these procedures.
- Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000 Hz). The prevelance of hearing loss in children is particularly high and is estimated to be 40-60%. Decreased ability to hear normal conversational tones may occur. Deafness after the initial dose of cisplatin has been reported. Ototoxic effects may be more severe in children receiving cisplatin.
- Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated cisplatin doses. It is unclear whether cisplatin-induced ototoxicity is reversible. Vestibular toxicity has also been reported. Ototoxic effects may be related to the peak plasma concentration of cisplatin. Ototoxicity can occur during treatment or be delayed. Audiometric monitoring should be performed prior to initiation of therapy, prior to each subsequent dose, and for several years post therapy.
- The risk of ototoxicity may increased by prior or simultaneous cranial irradiation, and may be more severe in patients less than 5 years of age, patients being treated with other ototoxic drugs (e.g. aminoglycosides and vancomycin), and in patients with renal impairment. Variants in the thiopurine S-methyltransferase gene (TPMT) have been reported to be associated with an increased risk of ototoxicity in children treated with cisplatin.
- Other genetic factors may also contribute to the cisplatin-induced ototoxicity.
- Myelosuppression occurs in 25% to 30% of patients treated with cisplatin. The nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia are more pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same timing as leukopenia and thrombocytopenia. Fever and infection have also been reported in patients with neutropenia. Potential fatalities due to infection (secondary to myelosuppression) have been reported. Elderly patients may be more susceptible to myelosuppression.
- In addition to anemia secondary to myelosuppression, a Coombs' positive hemolytic anemia has been reported. In the presence of cisplatin hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis and this risk should be weighed by the treating physician.
- The development of acute leukemia coincident with the use of cisplatin has been reported. In these reports, cisplatin was generally given in combination with other leukemogenic agents.
- Marked nausea and vomiting occur in almost all patients treated with cisplatin, and may be so severe that the drug must be discontinued. Nausea and vomiting may begin within 1 to 4 hours after treatment and last up to 24 hours. Various degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after treatment.
- Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in patients attaining complete emetic control on the day of cisplatin therapy.
- Diarrhea has also been reported.
- Vascular toxicities coincident with the use of cisplatin in combination with other antineoplastic agents have been reported. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic-uremic syndrome [HUS]), or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud's phenomenon occurring in patients treated with the combination of bleomycin, vinblastine with or without cisplatin. It has been suggested that hypomagnesemia developing coincident with the use of cisplatin may be an added, although not essential, factor associated with this event. However, it is currently unknown if the cause of Raynaud's phenomenon in these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these factors.
- Serum Electrolyte Disturbances
- Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia have been reported to occur in patients treated with cisplatin and are probably related to renal tubular damage. Tetany has been reported in those patients with hypocalcemia and hypomagnesemia. Generally, normal serum electrolyte levels are restored by administering supplemental electrolytes and discontinuing cisplatin.
- Inappropriate antidiuretic hormone syndrome has also been reported.
- Hyperuricemia
- Hyperuricemia has been reported to occur at approximately the same frequency as the increases in BUN and serum creatinine.
- It is more pronounced after doses greater than 50 mg/m2, and peak levels of uric acid generally occur between 3 to 5 days after the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels.
- Neurotoxicity
- Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, neurologic symptoms have been reported to occur after a single dose. Although symptoms and signs of cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may begin 3 to 8 weeks after the last dose of cisplatin. Cisplatin therapy should be discontinued when the symptoms are first observed. The neuropathy, however, may progress further even after stopping treatment. Preliminary evidence suggests peripheral neuropathy may be irreversible in some patients. Elderly patients may be more susceptible to peripheral neuropathy.
- Lhermitte's sign, dorsal column myelopathy, and autonomic neuropathy have also been reported.
- Loss of taste, seizures, leukoencephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS) have also been reported.
- Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and were usually associated in patients receiving a relatively high cumulative dose of cisplatin and with a relatively advanced symptomatic stage of peripheral neuropathy.
- Ocular Toxicity
- Optic neuritis, papilledema, and cerebral blindness have been reported in patients receiving standard recommended doses of cisplatin. Improvement and/or total recovery usually occurs after discontinuing cisplatin. Steroids with or without mannitol have been used; however, efficacy has not been established.
- Blurred vision and altered color perception have been reported after the use of regimens with higher doses of cisplatin or greater dose frequencies than recommended in the package insert. The altered color perception manifests as a loss of color discrimination, particularly in the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation of the macular area.
- Anaphylactic-Like Reactions
- Anaphylactic-like reactions have been reported in patients previously exposed to cisplatin. The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. Reactions may be controlled by intravenous epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving cisplatin should be observed carefully for possible anaphylactic-like reactions and supportive equipment and medication should be available to treat such a complication.
- Hepatotoxicity
- Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, have been reported to be associated with cisplatin administration at the recommended doses.
- Other Events
- Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, asthenia, and dehydration have been reported.
- Local soft tissue toxicity has been reported following extravasation of cisplatin. Severity of the local tissue toxicity appears to be related to the concentration of the cisplatin solution. Infusion of solutions with a cisplatin concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Cisplatin in the drug label.
# Drug Interactions
- Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy.
- In a randomized trial in advanced ovarian cancer, response duration was adversely affected when pyridoxine was used in combination with altretamine (hexamethylmelamine) and cisplatin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. In mice cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cisplatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cisplatin during labor and delivery.
### Nursing Mothers
- Cisplatin has been reported to be found in human milk; patients receiving cisplatin should not breast-feed.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Variants in the thiopurine S-methyltransferase (TPMT) gene are associated with an increased risk of ototoxicity in children treated with cisplatin.
- All children should have audiometric monitoring performed prior to initiation of therapy prior to each subsequent dose, and for several years post therapy. Advanced testing methods may allow for earlier detection of hearing loss in an attempt to facilitate the rapid initiation of interventions that can limit the potential adverse impact of hearing impairment on a child's cognitive and social development.
### Geriatic Use
- Insufficient data are available from clinical trials of cisplatin in the treatment of metastatic testicular tumors or advanced bladder cancer to determine whether elderly patients respond differently than younger patients. In four clinical trials of combination chemotherapy for advanced ovarian carcinoma, 1484 patients received cisplatin either in combination with cyclophosphamide or paclitaxel. Of these, 426 (29%) were older than 65 years. In these trials, age was not found to be a prognostic factor for survival. However, in a later secondary analysis for one of these trials, elderly patients were found to have shorter survival compared with younger patients. In all four trials, elderly patients experienced more severe neutropenia than younger patients. Higher incidences of severe thrombocytopenia and leukopenia were also seen in elderly compared with younger patients, although not in all cisplatin-containing treatment arms. In the two trials where nonhematologic toxicity was evaluated according to age, elderly patients had a numerically higher incidence of peripheral neuropathy than younger patients. Other reported clinical experience suggests that elderly patients may be more susceptible to myelosuppression, infectious complications, and nephrotoxicity than younger patients.
- Cisplatin is known to be substantially excreted by the kidney and is contraindicated in patients with preexisting renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.
### Gender
There is no FDA guidance on the use of Cisplatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cisplatin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cisplatin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cisplatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cisplatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cisplatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Peripheral blood counts should be monitored weekly. Liver function should be monitored periodically. Neurologic examination should also be performed regularly.
# IV Compatibility
- Preparation Precautions
- Caution should be exercised in handling the aqueous solution. Procedures for proper handling and disposal of anticancer drugs should be utilized. Several guidelines on this subject have been published. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and IV sets containing cisplatin.
- Skin reactions associated with accidental exposure to cisplatin may occur. The use of gloves is recommended. If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water. More information is available in the references listed below.
- Instructions for Preparation
- The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6- to 8-hour period.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- NOTE TO PHARMACIST: Exercise caution to prevent inadvertent cisplatin overdosage. Please call prescriber if dose is greater than 100 mg/m2 per cycle. Aluminum and flip-off seal of vial have been imprinted with the following statement:
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Caution should be exercised to prevent inadvertent overdosage with cisplatin. Acute overdosage with this drug may result in kidney failure, liver failure, deafness, ocular toxicity (including detachment of the retina), significant myelosuppression, intractable nausea and vomiting and/or neuritis. In addition, death can occur following overdosage.
### Management
- No proven antidotes have been established for cisplatin overdosage. Hemodialysis, even when initiated four hours after the overdosage, appears to have little effect on removing platinum from the body because of cisplatin's rapid and high degree of protein binding. Management of overdosage should include general supportive measures to sustain the patient through any period of toxicity that may occur.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cisplatin in the drug label.
# Pharmacology
## Mechanism of Action
- Cisplatin possibly acts through cross-linking and by interference with the function of DNA. It is an alkylating agent and it is cell cycle phase- nonspecific.
## Structure
- Cisplatin Injection infusion concentrate is a clear, colorless, sterile aqueous solution available in amber vials. Each 50 mL or 100 mL amber vial of infusion concentrate contains: 1 mg/mL cisplatin, 9 mg/mL sodium chloride, hydrochloric acid and sodium hydroxide to approximate pH of 4.0, and water for injection to a final volume of 50 mL or 100 mL, respectively.
- Cisplatin Injection infusion concentrate must be further diluted prior to administration.
- The active ingredient, cisplatin, is a yellow to orange crystalline powder with the molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy metal complex containing a central atom of platinum surrounded by two chloride atoms and two ammonia molecules in the cis position. It is soluble in water or saline at 1 mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207° C.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cisplatin in the drug label.
## Pharmacokinetics
- Plasma concentrations of the parent compound, cisplatin, decay monoexponentially with a half-life of about 20 to 30 minutes following bolus administrations of 50 or 100 mg/m2 doses. Monoexponential decay and plasma half-lives of about 0.5 hour are also seen following 2-hour or 7-hour infusions of 100 mg/m2. After the latter, the total-body clearances and volumes of distribution at steady-state for cisplatin are about 15 to 16 L/h/m2 and 11 to 12 L/m2.
- Due to its unique chemical structure, the chlorine atoms of cisplatin are more subject to chemical displacement reactions by nucleophiles, such as water or sulfhydryl groups, than to enzyme-catalyzed metabolism. At physiological pH in the presence of 0.1M NaCl, the predominant molecular species are cisplatin and monohydroxymonochloro cis-diammine platinum (II) in nearly equal concentrations. The latter, combined with the possible direct displacement of the chlorine atoms by sulfhydryl groups of amino acids or proteins, accounts for the instability of cisplatin in biological matrices. The ratios of cisplatin to total free (ultrafilterable) platinum in the plasma vary considerably between patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.
- Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of normal drug-protein binding. However, the platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more.
- Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days after the last administration. With the exception of intracerebral tumors, platinum concentrations in tumors are generally somewhat lower than the concentrations in the organ where the tumor is located. Different metastatic sites in the same patient may have different platinum concentrations. Hepatic metastases have the highest platinum concentrations, but these are similar to the platinum concentrations in normal liver. Maximum red blood cell concentrations of platinum are reached within 90 to 150 minutes after a 100 mg/m2 dose of cisplatin and decline in a biphasic manner with a terminal half-life of 36 to 47 days.
- Over a dose range of 40 to 140 mg cisplatin/m2 given as a bolus injection or as infusions varying in length from 1 hour to 24 hours, from 10% to about 40% of the administered platinum is excreted in the urine in 24 hours. Over five days following administration of 40 to 100 mg/m2 doses given as rapid, 2- to 3-hour, or 6- to 8-hour infusions, a mean of 35% to 51% of the dosed platinum is excreted in the urine. Similar mean urinary recoveries of platinum of about 14% to 30% of the dose are found following five daily administrations of 20, 30, or 40 mg/m2/day. Only a small percentage of the administered platinum is excreted beyond 24 hours post-infusion and most of the platinum excreted in the urine in 24 hours is excreted within the first few hours. Platinum-containing species excreted in the urine are the same as those found following the incubation of cisplatin with urine from healthy subjects, except that the proportions are different.
- The parent compound, cisplatin, is excreted in the urine and accounts for 13% to 17% of the dose excreted within one hour after administration of 50 mg/m2. The mean renal clearance of cisplatin exceeds creatinine clearance and is 62 and 50 mL/min/m2 following administration of 100 mg/m2 as 2-hour or 6- to 7-hour infusions, respectively.
- The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption.
- There is a potential for accumulation of ultrafilterable platinum plasma concentrations whenever cisplatin is administered on a daily basis but not when dosed on an intermittent basis.
- No significant relationships exist between the renal clearance of either free platinum or cisplatin and creatinine clearance.
- Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Cisplatin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Cisplatin in the drug label.
# How Supplied
- Cisplatin Injection is available as follows:
- NDC 44567-509-01 Each multidose vial contains 50 mg of cisplatin
- NDC 44567-510-01 Each multidose vial contains 100 mg of cisplatin
## Storage
There is limited information regarding Cisplatin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Cisplatin in the drug label.
# Precautions with Alcohol
- Alcohol-Cisplatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CISPLATIN®[11]
# Look-Alike Drug Names
- CISplatin® — CARBOplatin®[12]
- Platinol® — Patanol®[12]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cis-diamminedichloroplatinum(II) | |
c2e13f38d4a315105cd59a2900c5048fb2289fb0 | wikidoc | Cisternae | Cisternae
# Overview
A cisterna (plural cisternae) comprises a flattened membrane disk that makes up the Golgi apparatus. A typical Golgi has anywhere from 3 to 7 cisternae stacked upon each other like a stack of dinner plates, but there are usually around 6. The cisternae carry Golgi enzymes to help or to modify cargo proteins traveling through them destined for other parts of the cell.
The cisternae also carry structural proteins important for its maintenance as a flattened membrane and its stacking upon each other.
The earliest cisternae are called the cis-cisternae, followed by the medial cisternae, then the trans-cisternae (as they move away from the endoplasmic reticulum).
The formation of new cisternae is often called the cis-Golgi network and at the end of the Golgi where transport to other parts of the cell occurs is called the trans-Golgi network. Both are thought to be specialized cisternae leading in and out of the Golgi apparatus.
Cisternae may also refer to flattened regions of the rough endoplasmic reticulum.
nl:Cistern | Cisternae
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A cisterna (plural cisternae) comprises a flattened membrane disk that makes up the Golgi apparatus. A typical Golgi has anywhere from 3 to 7 cisternae stacked upon each other like a stack of dinner plates, but there are usually around 6. The cisternae carry Golgi enzymes to help or to modify cargo proteins traveling through them destined for other parts of the cell.
The cisternae also carry structural proteins important for its maintenance as a flattened membrane and its stacking upon each other.
The earliest cisternae are called the cis-cisternae, followed by the medial cisternae, then the trans-cisternae (as they move away from the endoplasmic reticulum).
The formation of new cisternae is often called the cis-Golgi network and at the end of the Golgi where transport to other parts of the cell occurs is called the trans-Golgi network. Both are thought to be specialized cisternae leading in and out of the Golgi apparatus.
Cisternae may also refer to flattened regions of the rough endoplasmic reticulum.
Template:Organelles
nl:Cistern
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cisternae | |
7ca8ca860186c4861b1935c822a6662dee8ffba5 | wikidoc | Claw hand | Claw hand
# Overview
Claw hand is a condition that causes curved or bent fingers. This makes the hand appear like the claw of an animal. Claw hand can be something that someone is born with (congenital) or that they develop because of certain disorders, such as nerve injury.
# Causes
- Congenital abnormality
- Leprosy
- Nerve damage in the arm
- Scarring after a severe burn of the hand or forearm
# Diagnosis
The following tests may be performed:
- Electromyography (EMG)
- Nerve conduction studies
# Treatment
Treatment depends on the cause. It may include:
- Splinting
- Surgery to fix problems that may be contributing to the claw hand, such as nerve problems, tendon abnormalities, or scar tissue
- Therapy to straighten the fingers
# Source
Medline Plus | Claw hand
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Claw hand is a condition that causes curved or bent fingers. This makes the hand appear like the claw of an animal. Claw hand can be something that someone is born with (congenital) or that they develop because of certain disorders, such as nerve injury.
# Causes
- Congenital abnormality
- Leprosy
- Nerve damage in the arm
- Scarring after a severe burn of the hand or forearm
# Diagnosis
The following tests may be performed:
- Electromyography (EMG)
- Nerve conduction studies
# Treatment
Treatment depends on the cause. It may include:
- Splinting
- Surgery to fix problems that may be contributing to the claw hand, such as nerve problems, tendon abnormalities, or scar tissue
- Therapy to straighten the fingers
# Source
Medline Plus [2] | https://www.wikidoc.org/index.php/Claw_hand | |
3be7d40210bd05481bc92100f2188a410534e288 | wikidoc | Pes cavus | Pes cavus
Pes cavus is a medical term for a somewhat unusual condition of the foot, or pes, due to a fixed plantar flexion of the foot. The resulting configuration is a highly arched foot—giving the condition its more common name, high arches—which is the opposite of a flat foot and somewhat less common.
As with certain cases of flat feet, pes cavus may be painful due to metatarsal compression; however, high arches— particularly if they are flexible or properly cared-for—may be an asymptomatic condition and in fact beneficial to the person.
People with pes cavus sometimes—though not always—have difficulty finding shoes that fit and may require support in their shoes. Children with high arches who have difficulty walking may wear specially-designed insoles, which are available in various sizes and can be made to order.
High arches may be hereditary or acquired, and the underlying cause may be neurological, orthopedic or neuromuscular. Pes cavus is oftentimes—but not always—connected through Hereditary Motor and Sensory Neuropathy Type 1 (Charcot-Marie-Tooth disease) and Friedreich's Ataxia; many other cases of pes cavus are natural.
# Treatment
Surgical treatment is only initiated if there is severe pain, as the available operations can be difficult. Otherwise, high arches may be handled with care and proper treatment.
de:Knickfuß
nl:Holvoet | Pes cavus
Pes cavus is a medical term for a somewhat unusual condition of the foot, or pes, due to a fixed plantar flexion of the foot. The resulting configuration is a highly arched foot—giving the condition its more common name, high arches—which is the opposite of a flat foot and somewhat less common.
As with certain cases of flat feet, pes cavus may be painful due to metatarsal compression; however, high arches— particularly if they are flexible or properly cared-for—may be an asymptomatic condition and in fact beneficial to the person.
People with pes cavus sometimes—though not always—have difficulty finding shoes that fit and may require support in their shoes. Children with high arches who have difficulty walking may wear specially-designed insoles, which are available in various sizes and can be made to order.
High arches may be hereditary or acquired, and the underlying cause may be neurological, orthopedic or neuromuscular. Pes cavus is oftentimes—but not always—connected through Hereditary Motor and Sensory Neuropathy Type 1 (Charcot-Marie-Tooth disease) and Friedreich's Ataxia; many other cases of pes cavus are natural.
# Treatment
Surgical treatment is only initiated if there is severe pain, as the available operations can be difficult. Otherwise, high arches may be handled with care and proper treatment.
de:Knickfuß
nl:Holvoet
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Clawfoot | |
5e0328b65e5fcf03fce2bb662b5e7073cc3fde52 | wikidoc | Cleanroom | Cleanroom
A cleanroom is an environment, typically used in manufacturing or scientific research, that has a low level of environmental pollutants such as dust, airborne microbes, aerosol particles and chemical vapors. More accurately, a cleanroom has a controlled level of contamination that is specified by the number of particles per cubic meter at a specified particle size. To give perspective, the ambient air outside in a typical urban environment might contain as many as 35,000,000 particles per cubic meter, 0.5 μm and larger in diameter, corresponding to an ISO 9 cleanroom.
# Overview
Cleanrooms can be very large. Entire manufacturing facilities can be contained within a cleanroom with factory floors covering thousands of square meters. They are used extensively in semiconductor manufacturing, biotechnology, the life sciences and other fields that are very sensitive to environmental contamination.
The air entering a cleanroom from outside is filtered to exclude dust, and the air inside is constantly recirculated through high efficiency particulate air (HEPA) and ultra low penetration air (ULPA) filters to remove internally generated contaminants.
Staff enter and leave through airlocks (sometimes including an air shower stage), and wear protective clothing such as hats, face masks, gloves, boots and cover-alls.
Equipment inside the cleanroom is designed to generate minimal air contamination. There are even specialised mops and buckets. Cleanroom furniture is also designed to produce a low amount of particles and to be easy to clean.
Common materials such as paper, pencils, and fabrics made from natural fibers are often excluded; however, alternatives are available. Cleanrooms are not sterile (i.e., free of uncontrolled microbes) and more attention is given to airborne particles. Particle levels are usually tested using a particle counter.
Some cleanrooms are kept at a positive pressure so that if there are any leaks, air leaks out of the chamber instead of unfiltered air coming in.
Some cleanroom HVAC systems control the humidity to relatively low levels, such that extra precautions are necessary to prevent ESD electrostatic discharge problems. These ESD controls ("ionizers") are also used in rooms where ESD sensitive products are produced or handled.
Low-level cleanrooms may only require special shoes, ones with completely smooth soles that do not track in dust or dirt. However, shoe bottoms must not create slipping hazards (safety always takes precedence). Entering a cleanroom usually requires wearing a cleanroom suit.
In cheaper cleanrooms, in which the standards of air contamination are less rigorous, the entrance to the cleanroom may not have an air shower. There is an anteroom, in which the special suits must be put on, but then a person can walk in directly to the room (as seen in the photograph on the right).
Some manufacturing facilities do not use fully classified cleanrooms, but use some cleanroom practices together to maintain their cleanliness requirements.
# Cleanroom classifications
The following is adapted from Rockwell Automation and from FILT AIR
Cleanrooms are classified according to the number and size of particles permitted per volume of air. Large numbers like "class 100" or "class 1000" refer to US FED STD 209E, and denote the number of particles of size 0.5 µm or larger permitted per cubic foot of air. The standard also allows interpolation, so it is possible to describe e.g. "class 2000".
Small numbers refer to ISO 14644-1 standards, which specify the decimal logarithm of the number of particles 0.1 µm or larger permitted per cubic metre of air. So, for example, an ISO class 5 clean room has at most 105 = 100,000 particles per m³.
Note that both FS 209E and ISO 14644-1 are based on assumed log-log relationships between particle size and particle concentration. For that reason, there are no "zero" particle concentrations listed. The table locations without entries are N/A ("not applicable") combinations of particle sizes and cleanliness classes. They should not be read as zero.
Because 1 m³ is approximately 35 ft³, the two standards are mostly equivalent when measuring 0.5 µm particles, although the testing standards differ. Ordinary room air is approximately class 1,000,000 or ISO 9.
## US FED STD 209E cleanroom standards
NOTE: US FED STD 209E was officially cancelled by the General Services Administration of the US Department of Commerce November 29, 2001, but is still widely used.
## ISO 14644-1 cleanroom standards
## BS 5295 cleanroom standards
BS 5295 Class 1 also requires that the greatest particle present in any sample does not exceed 5 μm. | Cleanroom
A cleanroom is an environment, typically used in manufacturing or scientific research, that has a low level of environmental pollutants such as dust, airborne microbes, aerosol particles and chemical vapors. More accurately, a cleanroom has a controlled level of contamination that is specified by the number of particles per cubic meter at a specified particle size. To give perspective, the ambient air outside in a typical urban environment might contain as many as 35,000,000 particles per cubic meter, 0.5 μm and larger in diameter, corresponding to an ISO 9 cleanroom.
# Overview
Cleanrooms can be very large. Entire manufacturing facilities can be contained within a cleanroom with factory floors covering thousands of square meters. They are used extensively in semiconductor manufacturing, biotechnology, the life sciences and other fields that are very sensitive to environmental contamination.
The air entering a cleanroom from outside is filtered to exclude dust, and the air inside is constantly recirculated through high efficiency particulate air (HEPA) and ultra low penetration air (ULPA) filters to remove internally generated contaminants.
Staff enter and leave through airlocks (sometimes including an air shower stage), and wear protective clothing such as hats, face masks, gloves, boots and cover-alls.
Equipment inside the cleanroom is designed to generate minimal air contamination. There are even specialised mops and buckets. Cleanroom furniture is also designed to produce a low amount of particles and to be easy to clean.
Common materials such as paper, pencils, and fabrics made from natural fibers are often excluded; however, alternatives are available. Cleanrooms are not sterile (i.e., free of uncontrolled microbes) [1]and more attention is given to airborne particles. Particle levels are usually tested using a particle counter.
Some cleanrooms are kept at a positive pressure so that if there are any leaks, air leaks out of the chamber instead of unfiltered air coming in.
Some cleanroom HVAC systems control the humidity to relatively low levels, such that extra precautions are necessary to prevent ESD electrostatic discharge problems. These ESD controls ("ionizers") are also used in rooms where ESD sensitive products are produced or handled.
Low-level cleanrooms may only require special shoes, ones with completely smooth soles that do not track in dust or dirt. However, shoe bottoms must not create slipping hazards (safety always takes precedence). Entering a cleanroom usually requires wearing a cleanroom suit.
In cheaper cleanrooms, in which the standards of air contamination are less rigorous, the entrance to the cleanroom may not have an air shower. There is an anteroom, in which the special suits must be put on, but then a person can walk in directly to the room (as seen in the photograph on the right).
Some manufacturing facilities do not use fully classified cleanrooms, but use some cleanroom practices together to maintain their cleanliness requirements.[1]
# Cleanroom classifications
The following is adapted from Rockwell Automation[2] and from FILT AIR[3]
Cleanrooms are classified according to the number and size of particles permitted per volume of air. Large numbers like "class 100" or "class 1000" refer to US FED STD 209E, and denote the number of particles of size 0.5 µm or larger permitted per cubic foot of air. The standard also allows interpolation, so it is possible to describe e.g. "class 2000".
Small numbers refer to ISO 14644-1 standards, which specify the decimal logarithm of the number of particles 0.1 µm or larger permitted per cubic metre of air. So, for example, an ISO class 5 clean room has at most 105 = 100,000 particles per m³.
Note that both FS 209E and ISO 14644-1 are based on assumed log-log relationships between particle size and particle concentration. For that reason, there are no "zero" particle concentrations listed. The table locations without entries are N/A ("not applicable") combinations of particle sizes and cleanliness classes. They should not be read as zero.
Because 1 m³ is approximately 35 ft³, the two standards are mostly equivalent when measuring 0.5 µm particles, although the testing standards differ. Ordinary room air is approximately class 1,000,000 or ISO 9.[2]
## US FED STD 209E cleanroom standards
NOTE: US FED STD 209E was officially cancelled by the General Services Administration of the US Department of Commerce November 29, 2001,[4][5] but is still widely used.
## ISO 14644-1 cleanroom standards
## BS 5295 cleanroom standards
BS 5295 Class 1 also requires that the greatest particle present in any sample does not exceed 5 μm.[6] | https://www.wikidoc.org/index.php/Cleanroom | |
d5a4346c6088a6d07ff879b296201dbb7a079cc6 | wikidoc | Syringoma | Syringoma
Synonyms and keywords: Clear cell syringoma
# Overview
Syringomas are eccrine sweat duct tumors, typically found clustered on eyelids. However, they may also be found in the axilla, abdomen, chest, neck, scalp or groin area. Syringomas are symmetrically distributed, usually multiple, and sometimes arranged in clusters. Syringoma is a benign adnexal neoplasm which is formed by well-differentiated ductal elements.
# Historical Perspective
The name syringoma is derived from the Greek word syrinx, which means pipe or tube.
# Classification
Syringoma may be classified according to Friedman and Butler's classification into four subtypes:
- A localized form
- A form associated with Down syndrome
- A generalized form that encompasses multiple and eruptive syringomas
- A familial form
## Location
The majority of syringomas are located on the upper parts of the cheeks and lower eyelids. Other common sites for syringomas include:
- Axilla
- Chest
- Abdomen
- Penis
- Vulva
Syringomas limited to the dorsa of the hands have also been described. In the variant of eruptive syringoma, multiple lesions appear simultaneously on the chest and lower abdomen. However, rarely syringomas may appear as unilateral, linear, or nevoid lesions. The eruptive variant may involve the intertriginous areas and penis.
# Pathophysiology
## Pathogenesis
The pathophysiology of syringomas is largely unknown. However, it is hypothesized that syringomas are benign hyperplastic growths that arise from the intraepidermal portion of eccrine ducts in response to an inflammatory reaction rather than a true adnexal neoplasm. It has also been suggested that a hamartoma of pluripotent stem cells could precede the pathological process of eruptive syringomas. Additionally, syringomas may be under hormonal influence, which may explain its female predominance. An alternate hypothesis suggests that phosphorylase deficiency, resulting from hyperglycemia seen in diabetes leads to an accumulation of glycogen in the skin and within the clear cells of syringomas.
## Genetics
A mutation in chromosome 16q22 has been associated with the development of familial autosomal dominant syringoma.
## Gross Pathology
On gross pathology, syringoma may have the following appearance:
- Syringoma From Public Health Image Library (PHIL).
- Syringoma From Public Health Image Library (PHIL).
- Syringoma From Public Health Image Library (PHIL).
- Syringoma From Public Health Image Library (PHIL).
- Syringoma From Public Health Image Library (PHIL).
- Syringoma From Public Health Image Library (PHIL).
- Syringoma From Public Health Image Library (PHIL).
## Microscopic Pathology
- On immunohistochemical tests, the presence of eccrine enzymes such as leucine aminopeptidase, succinic dehydrogenase, and phosphorylase and the immunohistochemical pattern of cytokeratin expression which indicates differentiation toward both the uppermost part of the dermal duct and the lower intraepidermal duct are characteristic findings of syringoma.
- On microscopic histopathological analysis, the histogenesis of syringomas is most likely related to eccrine or pluripotential stem cells.
- On electron microscopy, ductal cells with numerous short microvilli, desmosomes, luminal tonofilaments, and lysosomes are characteristic findings of syringoma.
## Associated Conditions
Syringomas may be found in association with other disorders such as:
- Hailey-Hailey disease also known as chronicfamilial benign pemphigus
- Diabetes mellitus
- Down syndrome
- Brooke-Spiegler
- Nicolau-Balus
# Causes
- Syringoma may be caused by either sporadic mutation or occur in the setting of certain genetic disorders.
- A mutation in chromosome 16q22 has been associated with the development of familial autosomal dominant syringoma..
- Usually, syringomas are sporadic. Familial syringomas are usually inherited as an autosomal dominant trait, tend to occur in adolescence or preadolescence, and most commonly affect the face.
- If the syringoma is associated with Down syndrome, it is usually located in the periorbital region. However, some rare cases of eruptive syringomas associated withDown syndrome have also been reported. Clear-cell syringoma may be associated with diabetes mellitus.
# Differentiating Syringoma from other Diseases
- Syringoma must be differentiated from other diseases such as:
- Acne Vulgaris
- Apocrine Hydrocystoma
- Basal Cell Carcinoma
- Colloid Milium
- Cowden Disease (Multiple hamartoma syndrome)
- Favre-Racouchot syndrome (Nodular Elastosis With Cysts and Comedones)
- Granuloma annulare
- Microcystic Adnexal Carcinoma
- Milia
- Sebaceous hyperplasia
- Steatocystoma multiplex
- Trichoepithelioma
- Tuberculosis
- Xanthelasma
# Epidemiology and Demographics
Syringomas affect approximately 1% of the population.
## Age
Syringomas are more commonly observed at puberty. However, patients of all ages may be affected by syringomas.
## Gender
Females are more commonly affected with syringoma than males.
## Race
There is no racial predilection for syringoma.
# Risk Factors
There are no established risk factors for syringoma.
# Natural History, Complications and Prognosis
The majority of patients with syringomas remain asymptomatic and suffer no sequelae or complications. Prognosis is generally excellent and with treatment, syringomas usually resolve with minimal scarring and no recurrence.
# Diagnosis
## History
A positive family history of syringoma may be present.
## Symptoms
Syringomas are most commonly asymptomatic. In some cases, patients with syringoma may present with pruritis.
## Physical Examination
Physical examination may be remarkable for:
- Skin-colored or yellowish, small dermal papules
- Eruptive syringomas appear as hyperpigmented papules on the chest, penile shaft, or vulva
- Lesions may appear translucent or cystic
- Syringomas are commonly smaller than 3mm in diameter
## Laboratory Findings
There are no specific laboratory findings associated with syringoma.
## Imaging Findings
There are no imaging findings associated with syringoma.
## Other Diagnostic Studies
- Syringoma may be diagnosed by skin biopsy.
- An adequate deep biopsy is usually required to rule out microcystic adnexal carcinoma.
- Consideration of rebiopsy for persistent or recurrent lesions is indicated.
# Treatment
## Medical Therapy
The mainstay of medical therapy for syringoma is oral isotretinoin, topical atropine, topical tretinoin, and oral tranilast.
## Surgery
Surgery is the mainstay of therapy for syringomas. The main reason for treatment is cosmetic; patients commonly seek treatment for syringomas of the cheeks and eyelids. The goal of surgical therapy for syringomas should be the destruction of the tumor with minimal scarring and no recurrence. However, complete removal of syringomas is often unsuccessful and recurrence is common because syringomas are embedded within the dermis. Possible surgical treatment options available for syringomas include:
- Surgical excision with primary suturing
- Scissor excision with secondary intention healing
- Electrocautery
- Electrodesiccation and curettage
- Carbon dioxide laser using the pinhole method of application or Er:YAG laser ablation
- Fractionated carbon dioxide laser ablation
- Cryotherapy
- Dermabrasion
- Trichloroacetic acid
## Prevention
There are no primary preventive measures available for syringoma. However, clinical follow-up with consideration of repeat biopsy for persistent or recurrent lesions is indicated. | Syringoma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]; Tarek Nafee, M.D. [3]
Synonyms and keywords: Clear cell syringoma
# Overview
Syringomas are eccrine sweat duct tumors, typically found clustered on eyelids. However, they may also be found in the axilla, abdomen, chest, neck, scalp or groin area. Syringomas are symmetrically distributed, usually multiple, and sometimes arranged in clusters. Syringoma is a benign adnexal neoplasm which is formed by well-differentiated ductal elements.[1]
# Historical Perspective
The name syringoma is derived from the Greek word syrinx, which means pipe or tube.
# Classification
Syringoma may be classified according to Friedman and Butler's classification into four subtypes:
- A localized form
- A form associated with Down syndrome
- A generalized form that encompasses multiple and eruptive syringomas
- A familial form
## Location
The majority of syringomas are located on the upper parts of the cheeks and lower eyelids. Other common sites for syringomas include:
- Axilla
- Chest
- Abdomen
- Penis
- Vulva
Syringomas limited to the dorsa of the hands have also been described. In the variant of eruptive syringoma, multiple lesions appear simultaneously on the chest and lower abdomen. However, rarely syringomas may appear as unilateral, linear, or nevoid lesions. The eruptive variant may involve the intertriginous areas and penis.[2][3][4]
# Pathophysiology
## Pathogenesis
The pathophysiology of syringomas is largely unknown. However, it is hypothesized that syringomas are benign hyperplastic growths that arise from the intraepidermal portion of eccrine ducts in response to an inflammatory reaction rather than a true adnexal neoplasm. It has also been suggested that a hamartoma of pluripotent stem cells could precede the pathological process of eruptive syringomas. Additionally, syringomas may be under hormonal influence, which may explain its female predominance. An alternate hypothesis suggests that phosphorylase deficiency, resulting from hyperglycemia seen in diabetes leads to an accumulation of glycogen in the skin and within the clear cells of syringomas.[5][6]
## Genetics
A mutation in chromosome 16q22 has been associated with the development of familial autosomal dominant syringoma.
## Gross Pathology
On gross pathology, syringoma may have the following appearance:
- Syringoma From Public Health Image Library (PHIL). [7]
- Syringoma From Public Health Image Library (PHIL). [7]
- Syringoma From Public Health Image Library (PHIL). [7]
- Syringoma From Public Health Image Library (PHIL). [7]
- Syringoma From Public Health Image Library (PHIL). [7]
- Syringoma From Public Health Image Library (PHIL). [7]
- Syringoma From Public Health Image Library (PHIL). [7]
## Microscopic Pathology
- On immunohistochemical tests, the presence of eccrine enzymes such as leucine aminopeptidase, succinic dehydrogenase, and phosphorylase and the immunohistochemical pattern of cytokeratin expression which indicates differentiation toward both the uppermost part of the dermal duct and the lower intraepidermal duct are characteristic findings of syringoma.
- On microscopic histopathological analysis, the histogenesis of syringomas is most likely related to eccrine or pluripotential stem cells.
- On electron microscopy, ductal cells with numerous short microvilli, desmosomes, luminal tonofilaments, and lysosomes are characteristic findings of syringoma.
## Associated Conditions
Syringomas may be found in association with other disorders such as:
- Hailey-Hailey disease also known as chronicfamilial benign pemphigus
- Diabetes mellitus
- Down syndrome
- Brooke-Spiegler
- Nicolau-Balus
# Causes
- Syringoma may be caused by either sporadic mutation or occur in the setting of certain genetic disorders.
- A mutation in chromosome 16q22 has been associated with the development of familial autosomal dominant syringoma..
- Usually, syringomas are sporadic. Familial syringomas are usually inherited as an autosomal dominant trait, tend to occur in adolescence or preadolescence, and most commonly affect the face.[8][9][10][11][12]
- If the syringoma is associated with Down syndrome, it is usually located in the periorbital region. However, some rare cases of eruptive syringomas associated withDown syndrome have also been reported. Clear-cell syringoma may be associated with diabetes mellitus.
# Differentiating Syringoma from other Diseases
- Syringoma must be differentiated from other diseases such as:
- Acne Vulgaris
- Apocrine Hydrocystoma
- Basal Cell Carcinoma
- Colloid Milium
- Cowden Disease (Multiple hamartoma syndrome)
- Favre-Racouchot syndrome (Nodular Elastosis With Cysts and Comedones)
- Granuloma annulare
- Microcystic Adnexal Carcinoma
- Milia
- Sebaceous hyperplasia
- Steatocystoma multiplex
- Trichoepithelioma
- Tuberculosis
- Xanthelasma
# Epidemiology and Demographics
Syringomas affect approximately 1% of the population.
## Age
Syringomas are more commonly observed at puberty. However, patients of all ages may be affected by syringomas.
## Gender
Females are more commonly affected with syringoma than males.
## Race
There is no racial predilection for syringoma.
# Risk Factors
There are no established risk factors for syringoma.
# Natural History, Complications and Prognosis
The majority of patients with syringomas remain asymptomatic and suffer no sequelae or complications. Prognosis is generally excellent and with treatment, syringomas usually resolve with minimal scarring and no recurrence.
# Diagnosis
## History
A positive family history of syringoma may be present.
## Symptoms
Syringomas are most commonly asymptomatic. In some cases, patients with syringoma may present with pruritis.
## Physical Examination
Physical examination may be remarkable for:
- Skin-colored or yellowish, small dermal papules
- Eruptive syringomas appear as hyperpigmented papules on the chest, penile shaft, or vulva
- Lesions may appear translucent or cystic
- Syringomas are commonly smaller than 3mm in diameter[13]
## Laboratory Findings
There are no specific laboratory findings associated with syringoma.
## Imaging Findings
There are no imaging findings associated with syringoma.
## Other Diagnostic Studies
- Syringoma may be diagnosed by skin biopsy.
- An adequate deep biopsy is usually required to rule out microcystic adnexal carcinoma.
- Consideration of rebiopsy for persistent or recurrent lesions is indicated.
# Treatment
## Medical Therapy
The mainstay of medical therapy for syringoma is oral isotretinoin, topical atropine, topical tretinoin, and oral tranilast.
## Surgery
Surgery is the mainstay of therapy for syringomas. The main reason for treatment is cosmetic; patients commonly seek treatment for syringomas of the cheeks and eyelids. The goal of surgical therapy for syringomas should be the destruction of the tumor with minimal scarring and no recurrence. However, complete removal of syringomas is often unsuccessful and recurrence is common because syringomas are embedded within the dermis. Possible surgical treatment options available for syringomas include:[14][15][16][17][18][19]
- Surgical excision with primary suturing
- Scissor excision with secondary intention healing
- Electrocautery
- Electrodesiccation and curettage
- Carbon dioxide laser using the pinhole method of application or Er:YAG laser ablation
- Fractionated carbon dioxide laser ablation
- Cryotherapy
- Dermabrasion
- Trichloroacetic acid
## Prevention
There are no primary preventive measures available for syringoma. However, clinical follow-up with consideration of repeat biopsy for persistent or recurrent lesions is indicated. | https://www.wikidoc.org/index.php/Clear_cell_syringoma | |
ad4addbe52069200495b6872474bf9419ad8639f | wikidoc | Clidinium | Clidinium
Clidinium (generally found as the bromide salt, clidinium bromide) is an anticholinergic drug. It may help symptoms of cramping and abdominal/stomach pain by decreasing stomach acid, and slowing the intestines. It is commonly prescribed in combination with chlordiazepoxide using the brand name Librax.
Clidinium is an effective anticholinergic agent with activity approximating that of atropine sulfate against spasms induced by acetylcholine in isolated intestinal strips. On oral administration in mice it proved an effective antisialagogue in preventing salivation induced by pilocarpine. Spontaneous intestinal motility in both rats and dogs is reduced following oral dosing with 0.1 to 0.25 mg/kg. Potent cholinergic ganglionic blocking effects (vagal) are produced with intravenous usage in anesthetized dogs.
Oral doses of 23 mg/kg to dogs produced signs of nasal dryness and slight pupillary dilation. In two other species, monkeys and rabbits, doses of 5 mg/kg, po, given three times daily for 5 days did not produce apparent secretory or visual changes.
# Toxicity
The oral LD50 of a single dose of clidinium bromide is 860 + 57 mg/kg, as determined in mice observed over a period of 5 days following dosage. | Clidinium
Clidinium (generally found as the bromide salt, clidinium bromide) is an anticholinergic drug. It may help symptoms of cramping and abdominal/stomach pain by decreasing stomach acid, and slowing the intestines. It is commonly prescribed in combination with chlordiazepoxide using the brand name Librax.
Clidinium is an effective anticholinergic agent with activity approximating that of atropine sulfate against spasms induced by acetylcholine in isolated intestinal strips. On oral administration in mice it proved an effective antisialagogue in preventing salivation induced by pilocarpine. Spontaneous intestinal motility in both rats and dogs is reduced following oral dosing with 0.1 to 0.25 mg/kg. Potent cholinergic ganglionic blocking effects (vagal) are produced with intravenous usage in anesthetized dogs.
Oral doses of 23 mg/kg to dogs produced signs of nasal dryness and slight pupillary dilation. In two other species, monkeys and rabbits, doses of 5 mg/kg, po, given three times daily for 5 days did not produce apparent secretory or visual changes.
# Toxicity
The oral LD50 of a single dose of clidinium bromide is 860 + 57 mg/kg, as determined in mice observed over a period of 5 days following dosage.
# External links
- RxList.com - Librax
Template:Pharma-stub | https://www.wikidoc.org/index.php/Clidinium | |
46070d424e2effaac51f72832d9c02d32092e199 | wikidoc | Clinomics | Clinomics
Clinomics is the study of -omics data along with its associated clinical data. The term -omics generally refers to a study of biology. As an example, genomics is the study of the entire genome of an organism and was the first -omics term.
As personalized medicine advances, clinomics will be a bridge between basic biological data and its effect on human health. As an example, there have been studies of the genes expressed in certain cancer tissues as a way of classification of the cancer and the putative best form of treatment.
Already we know that certain genes such as BRCA1 are associated with a higher probability of developing breast cancer. Clinomics takes the next step by looking at not only the genetics of the patient, but also such data as mRNA, metabolites, and proteins associated with a patient and a disease. | Clinomics
Clinomics is the study of -omics data along with its associated clinical data. The term -omics generally refers to a study of biology. As an example, genomics is the study of the entire genome of an organism and was the first -omics term.
As personalized medicine advances, clinomics will be a bridge between basic biological data and its effect on human health. As an example, there have been studies of the genes expressed in certain cancer tissues as a way of classification of the cancer and the putative best form of treatment.
Already we know that certain genes such as BRCA1 are associated with a higher probability of developing breast cancer. Clinomics takes the next step by looking at not only the genetics of the patient, but also such data as mRNA, metabolites, and proteins associated with a patient and a disease. | https://www.wikidoc.org/index.php/Clinomics | |
c55cbb8aec39f7f634c7330a208501e3aeaaf763 | wikidoc | Clitorism | Clitorism
# Overview
Clitorism (/Template:IPA/), from the German "Clitorismus", in turn from the Greek kleitoris + ismos, is the female counterpart of priapism. A long continued, painful condition in the female with recurring erection of the clitoris. The word is also used to describe an abnormal enlargement of the clitoris.
# Signs and symptoms
'Clitorism is painful, much like priapism is for men. Men and women alike may feel ashamed of seeking medical attention; especially men, since the condition is much more visible.
# Treatment
Clitorism is nearly impossible to treat since the female genitals are mostly on the inside.
# See Also
Vaginismus | Clitorism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Clitorism (/Template:IPA/), from the German "Clitorismus", in turn from the Greek kleitoris + ismos, is the female counterpart of priapism. A long continued, painful condition in the female with recurring erection of the clitoris. The word is also used to describe an abnormal enlargement of the clitoris.
# Signs and symptoms
'Clitorism is painful, much like priapism is for men. Men and women alike may feel ashamed of seeking medical attention; especially men, since the condition is much more visible.
# Treatment
Clitorism is nearly impossible to treat since the female genitals are mostly on the inside.
# See Also
Vaginismus
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Clitorism | |
7d1ad4a25bd2133fab9a2931d688d236190ff186 | wikidoc | Clomifene | Clomifene
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Clomifene is a gonadotropin that is FDA approved for the treatment of ovulatory dysfunction in women desiring pregnancy. Common adverse reactions include flushing, abdominal bloating, abdominal discomfort, abdominal distension, nausea, vomiting, headache, visual disturbance, and breast pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Treatment of the selected patient should begin with a low dose, 50 mg daily (1 tablet) for 5 days. The dose should be increased only in those patients who do not ovulate in response to cyclic 50 mg clomiphene citrate tablets USP. A low dosage or duration of treatment course is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, such as in patients with polycystic ovary syndrome.
- The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle.
- If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs prior to therapy, the regimen of 50 mg daily for 5 days should be started on or about the 5th day of the cycle. Therapy may be started at any time in the patient who has had no recent uterine bleeding. When ovulation occurs at this dosage, there is no advantage to increasing the dose in subsequent cycles of treatment.
- If ovulation does not appear to occur after the first course of therapy, a second course of 100 mg daily (two 50 mg tablets given as a single daily dose) for 5 days should be given. This course may be started as early as 30 days after the previous one after precautions are taken to exclude the presence of pregnancy. Increasing the dosage or duration of therapy beyond 100 mg/day for 5 days is not recommended.
- The majority of patients who are going to ovulate will do so after the first course of therapy. If ovulation does not occur after three courses of therapy, further treatment with clomiphene citrate tablets USP is not recommended and the patient should be reevaluated. If three ovulatory responses occur, but pregnancy has not been achieved, further treatment is not recommended. If menses does not occur after an ovulatory response, the patient should be reevaluated. Long-term cyclic therapy is not recommended beyond a total of about 6 cycles.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clomifene in adult patients.
### Non–Guideline-Supported Use
- ClomiPHENE 100 mg daily given on days 5 through 9.
- ClomiPHENE 100 mg daily for 5 days.
- ClomiPHENE citrate 100 milligrams/day on cycle days 3 to 7.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Clomifene in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clomifene in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clomifene in pediatric patients.
# Contraindications
- Hypersensitivity
- Clomiphene citrate tablets USP is contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients.
- Pregnancy
- Pregnancy Category X. Clomiphene citrate tablets USP use in pregnant women is contraindicated, as clomiphene citrate does not offer benefit in this population.
- Available human data do not suggest an increased risk for congenital anomalies above the background population risk when used as indicated. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus.
- Liver Disease
- Clomiphene citrate tablets USP therapy is contraindicated in patients with liver disease or a history of liver dysfunction.
- Abnormal Uterine Bleeding
- Clomiphene citrate tablets USP is contraindicated in patients with abnormal uterine bleeding of undetermined origin.
- Ovarian Cysts
- Clomiphene citrate tablets USP is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome.
- Other
- Clomiphene citrate tablets USP is contraindicated in patients with uncontrolled thyroid or adrenal dysfunction or in the presence of an organic intracranial lesion such as pituitary tumor.
# Warnings
- Visual Symptoms
- Patients should be advised that blurring or other visual symptoms such as spots or flashes (scintillating scotomata) may occasionally occur during therapy with clomiphene citrate tablets USP. These visual symptoms increase in incidence with increasing total dose or therapy duration. These visual disturbances are usually reversible; however, cases of prolonged visual disturbance have been reported with some occurring after clomiphene citrate tablets USP discontinuation. The visual disturbances may be irreversible, especially with increased dosage or duration of therapy. Patients should be warned that these visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting.
- These visual symptoms appear to be due to intensification and prolongation of afterimages. Symptoms often first appear or are accentuated with exposure to a brightly lit environment. While measured visual acuity usually has not been affected, a study patient taking 200 mg clomiphene citrate tablets USP daily developed visual blurring on the 7th day of treatment, which progressed to severe diminution of visual acuity by the 10th day. No other abnormality was found, and the visual acuity returned to normal on the 3rd day after treatment was stopped.
- Ophthalmologically definable scotomata and retinal cell function (electroretinographic) changes have also been reported. A patient treated during clinical studies developed phosphenes and scotomata during prolonged clomiphene citrate tablets USP administration, which disappeared by the 32nd day after stopping therapy.
- Postmarketing surveillance of adverse events has also revealed other visual signs and symptoms during clomiphene citrate tablets USP therapy.
- While the etiology of these visual symptoms is not yet understood, patients with any visual symptoms should discontinue treatment and have a complete ophthalmological evaluation carried out promptly.
- Ovarian Hyperstimulation Syndrome
- The ovarian hyperstimulation syndrome (OHSS) has been reported to occur in patients receiving clomiphene citrate therapy for ovulation induction. OHSS may progress rapidly (within 24 hours to several days) and become a serious medical disorder. In some cases, OHSS occurred following cyclic use of clomiphene citrate therapy or when clomiphene citrate was used in combination with gonadotropins. Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with OHSS.
- OHSS is a medical event distinct from uncomplicated ovarian enlargement. The clinical signs of this syndrome in severe cases can include gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. In addition, the following symptoms have been reported in association with this syndrome: pericardial effusion, anasarca, hydrothorax, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, torsion of the ovary, and acute respiratory distress. The early warning signs of OHSS are abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain. Elevated urinary steroid levels, varying degrees of electrolyte imbalance, hypovolemia, hemoconcentration, and hypoproteinemia may occur. Death due to hypovolemic shock, hemoconcentration, or thromboembolism has occurred. Due to fragility of enlarged ovaries in severe cases, abdominal and pelvic examination should be performed very cautiously. If conception results, rapid progression to the severe form of the syndrome may occur.
- To minimize the hazard associated with occasional abnormal ovarian enlargement associated with clomiphene citrate tablets USP therapy, the lowest dose consistent with expected clinical results should be used. Maximal enlargement of the ovary, whether physiologic or abnormal, may not occur until several days after discontinuation of the recommended dose of clomiphene citrate tablets USP. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiphene citrate tablets USP. Therefore, patients with polycystic ovary syndrome should be started on the lowest recommended dose and shortest treatment duration for the first course of therapy
- If enlargement of the ovary occurs, additional clomiphene citrate tablets USP therapy should not be given until the ovaries have returned to pretreatment size, and the dosage or duration of the next course should be reduced. Ovarian enlargement and cyst formation associated with clomiphene citrate tablets USP therapy usually regress spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent clomiphene citrate tablets USP therapy in these cases should exceed the risk. Unless surgical indication for laparotomy exists, such cystic enlargement should always be managed conservatively.
- A causal relationship between ovarian hyperstimulation and ovarian cancer has not been determined. However, because a correlation between ovarian cancer and nulliparity, infertility, and age has been suggested, if ovarian cysts do not regress spontaneously, a thorough evaluation should be performed to rule out the presence of ovarian neoplasia.
### Precautions
- General
- Careful attention should be given to the selection of candidates for clomiphene citrate tablets USP therapy. Pelvic examination is necessary prior to clomiphene citrate tablets USP treatment and before each subsequent course.
# Adverse Reactions
## Clinical Trials Experience
- Clomiphene citrate tablets USP, at recommended dosages, is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Adverse experiences reported in patients treated with clomiphene citrate during clinical studies are shown in Table 2.
- The following adverse events have been reported in fewer than 1% of patients in clinical trails: Acute abdomen, appetite increase, constipation, dermatitis or rash, depression, diarrhea, dizziness, fatigue, hair loss/dry hair, increased urinary frequency/volume, insomnia, light-headedness, nervous tension, vaginal dryness, vertigo, weight gain/loss.
- Patients on prolonged clomiphene citrate tablets USP therapy may show elevated serum levels of desmosterol. This is most likely due to a direct interference with cholesterol synthesis. However, the serum sterols in patients receiving the recommended dose of clomiphene citrate tablets USP are not significantly altered. Ovarian cancer has been infrequently reported in patients who have received fertility drugs. Infertility is a primary risk factor for ovarian cancer; however, epidemiology data suggest that prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of clomiphene citrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Fever, tinnitus, weakness
Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis
Migraine headache, paresthesia, seizure, stroke, syncope
Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus, urticaria
- Abnormal bone development: skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia), foot (clubfoot), spine, and joints
- Cardiac abnormalities: septal heart defects, muscular ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, and coarctation of the aorta
- Chromosomal disorders: Downs syndrome
- Ear abnormalities and deafness
- Gastrointestinal tract abnormalities: cleft lip and palate, imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, omphalocele
- Genitalia abnormalities: hypospadias, cloacal exstrophy
- Lung tissue malformations
- Malformations of the eye and lens (cataract)
- Neoplasms: neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic leukemia
- Nervous system abnormalities: neural tube defects (anencephaly, meningomyelocele), microcephaly, and hydrocephalus
- Renal abnormalities: renal agenesis and renal dysgenesis
- Others: dwarfism, mental retardation
Pancreatitis
Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage, reduced endometrial thickness
Transaminases increased, hepatitis
Hypertriglyceridemia, in some cases with pancreatitis
Arthralgia, back pain, myalgia
Liver (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular carcinoma); breast (fibrocystic disease, breast carcinoma); endometrium (endometrial carcinoma); nervous system (astrocytoma, pituitary tumor, prolactinoma, neurofibromatosis, glioblastoma multiforme, brain abcess); ovary (luteoma of pregnancy, dermoid cyst of the ovary, ovarian carcinoma); trophoblastic (hydatiform mole, choriocarcinoma); miscellaneous (melanoma, myeloma, perianal cysts, renal cell carcinoma, Hodgkin's lymphoma, tongue carcinoma, bladder carcinoma)
Anxiety, irritability, mood changes, psychosis
Abnormal accommodation, cataract, eye pain, macular edema, optic neuritis, photopsia, posterior vitreous detachment, retinal hemorrhage, retinal thrombosis, retinal vascular spasm, temporary or prolonged loss of vision, possibly irreversible
Leukocytosis, thyroid disorder
# Drug Interactions
- Drug interactions with clomiphene citrate tablets USP have not been documented.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Clomiphene citrate use in pregnant women is contraindicated, as clomiphene citrate tablets USP treatment does not offer benefit in this population.
- Available human data do not suggest an increased risk for congenital anomalies above the background population risk. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus.
- Clinical Considerations
- To avoid inadvertent clomiphene citrate tablets USP administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation and/or pregnancy occurs. Patients should be evaluated carefully to exclude ovarian enlargement or ovarian cyst formation between each treatment cycle. The next course of clomiphene citrate tablets USP therapy should be delayed until these conditions have been excluded.
- Human data
- The available human data from epidemiologic studies do not show any apparent cause and effect relationship between clomiphene citrate periconceptual exposure and an increased risk of overall birth defects, or any specific anomaly. However, due to the small number of cases of congenital anomalies occurring in clomiphene citrate treated women, these epidemiologic studies were only able to rule out large differences in risk. The studies did not consider factors associated with female subfertility and were unable to adjust for other important confounders.
- In addition, available data do not support an increased rate of spontaneous abortion among subfertile women treated with clomiphene citrate for ovulation induction.
- Animal data
- Oral administration of clomiphene citrate to pregnant rats during organogenesis at doses of 1 to 2 mg/kg/day resulted in hydramnion and weak, edematous fetuses with wavy ribs and other temporary bone changes. Doses of 8 mg/kg/day or more also caused increased resorptions and dead fetuses, dystocia, and delayed parturition, and 40 mg/kg/day resulted in increased maternal mortality. Single doses of 50 mg/kg caused fetal cataracts, while 200 mg/kg caused cleft palate. Following injection of clomiphene citrate 2 mg/kg to mice and rats during pregnancy, the offspring exhibited metaplastic changes of the reproductive tract. Newborn mice and rats injected during the first few days of life also developed metaplastic changes in uterine and vaginal mucosa, as well as premature vaginal opening and anovulatory ovaries. These findings are similar to the abnormal reproductive behavior and sterility described with other estrogens and antiestrogens.
- In rabbits, some temporary bone alterations were seen in fetuses from dams given oral doses of 20 or 40 mg/kg/day during pregnancy, but not following 8 mg/kg/day. No permanent malformations were observed in those studies. Also, rhesus monkeys given oral doses of 1.5 to 4.5 mg/kg/day for various periods during pregnancy did not have any abnormal offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clomifene in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Clomifene during labor and delivery.
### Nursing Mothers
- It is not known whether clomiphene citrate tablets USP is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene citrate tablets USP is administered to a nursing woman. In some patients, clomiphene citrate tablets USP may reduce lactation.
### Pediatric Use
There is no FDA guidance on the use of Clomifene with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Clomifene with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Clomifene with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Clomifene with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Clomifene in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Clomifene in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clomifene in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Clomifene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Clomifene in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Clomifene in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Toxic effects accompanying acute overdosage of clomiphene citrate tablets USP have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomiphene citrate tablets USP therapy include nausea, vomiting, vasomotor flushes, blurred vision, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.
- Oral LD50. The acute oral LD50 of clomiphene citrate tablets USP is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known.
### Management
- In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. It is not known if clomiphene citrate tablets USP is dialyzable.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Clomifene in the drug label.
# Pharmacology
## Mechanism of Action
- Clomiphene citrate tablets USP is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, clomiphene citrate tablets USP has been demonstrated to be a useful therapy for the anovulatory patient desiring pregnancy.
- Clomiphene citrate is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Clomiphene citrate initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event in response to a course of clomiphene therapy is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis, resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle.
- Available data suggest that both the estrogenic and antiestrogenic properties of clomiphene may participate in the initiation of ovulation. The two clomiphene isomers have been found to have mixed estrogenic and antiestrogenic effects, which may vary from one species to another. Some data suggest that zuclomiphene has greater estrogenic activity than enclomiphene.
- Clomiphene citrate has no apparent progestational, androgenic, or antiandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.
- Although there is no evidence of a "carryover effect" of clomiphene citrate tablets USP, spontaneous ovulatory menses have been noted in some patients after clomiphene citrate tablets USP therapy.
## Structure
- Clomiphene citrate tablets USP is an orally administered, nonsteroidal, ovulatory stimulant designated chemically as 2- triethylamine citrate (1:1). It has the molecular formula of C26H28ClNO - C6H8O7 and a molecular weight of 598.09. It is represented structurally as:
- Clomiphene citrate is a white to pale yellow, essentially odorless, crystalline powder. It is freely soluble in methanol; soluble in ethanol; slightly soluble in acetone, water, and chloroform; and insoluble in ether.
- Clomiphene citrate tablets USP is a mixture of two geometric isomers containing between 30% and 50% of the cis-isomer.
- Each white scored tablet contains 50 mg clomiphene citrate USP. The tablet also contains the following inactive ingredients: corn starch, lactose, magnesium stearate, pregelatinized corn starch, and sucrose.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Clomifene in the drug label.
## Pharmacokinetics
- Based on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Cumulative urinary and fecal excretion of the 14C averaged about 50% of the oral dose and 37% of an intravenous dose after 5 days. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.
- Some 14C label was still present in the feces 6 weeks after administration. Subsequent single-dose studies in normal volunteers showed that zuclomiphene (cis) has a longer half-life than enclomiphene (trans). Detectable levels of zuclomiphene persisted for longer than a month in these subjects. This may be suggestive of stereo-specific enterohepatic recycling or sequestering of the zuclomiphene. Thus, it is possible that some active drug may remain in the body during early pregnancy in women who conceive in the menstrual cycle during clomiphene citrate tablets USP therapy.
## Nonclinical Toxicology
- Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential of clomiphene citrate.
- Oral administration of clomiphene citrate tablets USP to male rats at doses of 0.3 or 1 mg/kg/day caused decreased fertility, while higher doses caused temporary infertility. Oral doses of 0.1 mg/kg/day in female rats temporarily interrupted the normal cyclic vaginal smear pattern and prevented conception. Doses of 0.3 mg/kg/day slightly reduced the number of ovulated ova and corpora lutea, while 3 mg/kg/day inhibited ovulation.
# Clinical Studies
- During clinical investigations, 7578 patients received clomiphene citrate tablets USP, some of whom had impediments to ovulation other than ovulatory dysfunction. In those clinical trials, successful therapy characterized by pregnancy occurred in approximately 30% of these patients.
- There were a total of 2635 pregnancies reported during the clinical trial period. Of those pregnancies, information on outcome was only available for 2369 of the cases. Table 1 summarizes the outcome of these cases.
- Of the reported pregnancies, the incidence of multiple pregnancies was 7.98%: 6.9% twin, 0.5% triplet, 0.3% quadruplet, and 0.1% quintuplet. Of the 165 twin pregnancies for which sufficient information was available, the ratio of monozygotic to dizygotic twins was about 1:5. Table 1 reports the survival rate of the live multiple births.
- A sextuplet birth was reported after completion of original clinical studies; none of the sextuplets survived (each weighed less than 400 g), although each appeared grossly normal.
- Fetal/Neonatal Anomalies and Mortality. The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with clomiphene citrate tablets USP during clinical trials. Each of the following fetal abnormalities were reported at a rate of <1% (experiences are listed in order of decreasing frequency): Congenital heart lesions, Down syndrome, club foot, congenital gut lesions, hypospadias, microcephaly, harelip and cleft palate, congenital hip, hemangioma, undescended testicles, polydactyly, conjoined twins and teratomatous malformation, patent ductus arteriosus, amaurosis, arteriovenous fistula, inguinal hernia, umbilical hernia, syndactyly, pectus excavatum, myopathy, dermoid cyst of scalp, omphalocele, spina bifida occulta, ichthyosis, and persistent lingual frenulum. Neonatal death and fetal death/stillbirth in infants with birth defects have also been reported at a rate of <1%. The overall incidence of reported congenital anomalies from pregnancies associated with maternal clomiphene citrate tablets USP ingestion during clinical studies was within the range of that reported for the general population.
- In addition, reports of congenital anomalies have been received during postmarketing surveillance of clomiphene citrate.
# How Supplied
- NDC 0591-0781-30: 50 mg tablets in cartons of 30
- Tablets are round, white, scored, and debossed Watson over 781.
- Store tablets at controlled room temperature 59°-86°F (15°-30°C). Protect from heat, light, and excessive humidity, and store in closed containers.
## Storage
There is limited information regarding Clomifene Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The purpose and risks of clomiphene citrate tablets USP therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiphene citrate tablets USP therapy is ovulation for subsequent pregnancy. The physician should counsel the patient with special regard to the following potential risks:
- Visual Symptoms
- Advise that blurring or other visual symptoms occasionally may occur during or shortly after clomiphene citrate tablets USP therapy. It should be made clear to the patient that, in some instances, visual disturbances may be prolonged, and possibly irreversible, especially with increased dosage or duration of therapy. Warn that visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting.
- The patient should be instructed to inform the physician whenever any unusual visual symptoms occur. If the patient has any visual symptoms, treatment should be discontinued and complete ophthalmologic evaluation performed.
- Abdominal/Pelvic Pain or Distention
- Ovarian enlargement may occur during or shortly after therapy with clomiphene citrate tablets USP. To minimize the risks associated with ovarian enlargement, the patient should be instructed to inform the physician of any abdominal or pelvic pain, weight gain, discomfort, or distention after taking clomiphene citrate tablets USP.
- Metabolism Disorders
- Cases of hypertriglyceridemia have been reported. Preexisting or family history of hyperlipidemia and use of higher than recommended dose and/or longer duration of treatment with clomiphene citrate are associated with a risk of hypertriglyceridemia. Periodic monitoring of plasma triglycerides is recommended in patients with preexisting or family history of hyperlipidemia.
- Multiple Pregnancy
- Inform the patient that there is an increased chance of multiple pregnancy, including bilateral tubal pregnancy and coexisting tubal and intrauterine pregnancy, when conception occurs in relation to clomiphene citrate tablets USP therapy. The potential complications and hazards of multiple pregnancy should be explained.
- Spontaneous Abortion and Congenital Anomalies
- Inform the patient that the available data suggest no increase in the rates of spontaneous abortion (miscarriage) or congenital anomalies with maternal clomiphene citrate tablets USP use compared to rates in the general population.
- During clinical investigation, the experience from patients with known pregnancy outcome (Table 1) shows a spontaneous abortion rate of 20.4% and stillbirth rate of 1.0%. Among the birth anomalies spontaneously reported as individual cases since commercial availability of clomiphene citrate tablets USP, the proportion of neural tube defects has been high among pregnancies associated with ovulation induced by clomiphene citrate tablets USP, but this has not been supported by data from population-based studies.
# Precautions with Alcohol
- Alcohol-Clomifene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CLOMIPHENE CITRATE®
# Look-Alike Drug Names
- clomiPHENE® — clomiPRAMINE®
- Serophene® — Sarafem®
# Drug Shortage Status
# Price | Clomifene
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Overview
Clomifene is a gonadotropin that is FDA approved for the treatment of ovulatory dysfunction in women desiring pregnancy. Common adverse reactions include flushing, abdominal bloating, abdominal discomfort, abdominal distension, nausea, vomiting, headache, visual disturbance, and breast pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Treatment of the selected patient should begin with a low dose, 50 mg daily (1 tablet) for 5 days. The dose should be increased only in those patients who do not ovulate in response to cyclic 50 mg clomiphene citrate tablets USP. A low dosage or duration of treatment course is particularly recommended if unusual sensitivity to pituitary gonadotropin is suspected, such as in patients with polycystic ovary syndrome.
- The patient should be evaluated carefully to exclude pregnancy, ovarian enlargement, or ovarian cyst formation between each treatment cycle.
- If progestin-induced bleeding is planned, or if spontaneous uterine bleeding occurs prior to therapy, the regimen of 50 mg daily for 5 days should be started on or about the 5th day of the cycle. Therapy may be started at any time in the patient who has had no recent uterine bleeding. When ovulation occurs at this dosage, there is no advantage to increasing the dose in subsequent cycles of treatment.
- If ovulation does not appear to occur after the first course of therapy, a second course of 100 mg daily (two 50 mg tablets given as a single daily dose) for 5 days should be given. This course may be started as early as 30 days after the previous one after precautions are taken to exclude the presence of pregnancy. Increasing the dosage or duration of therapy beyond 100 mg/day for 5 days is not recommended.
- The majority of patients who are going to ovulate will do so after the first course of therapy. If ovulation does not occur after three courses of therapy, further treatment with clomiphene citrate tablets USP is not recommended and the patient should be reevaluated. If three ovulatory responses occur, but pregnancy has not been achieved, further treatment is not recommended. If menses does not occur after an ovulatory response, the patient should be reevaluated. Long-term cyclic therapy is not recommended beyond a total of about 6 cycles.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clomifene in adult patients.
### Non–Guideline-Supported Use
- ClomiPHENE 100 mg daily given on days 5 through 9.[1]
- ClomiPHENE 100 mg daily for 5 days.[2]
- ClomiPHENE citrate 100 milligrams/day on cycle days 3 to 7.[3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Clomifene in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clomifene in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clomifene in pediatric patients.
# Contraindications
- Hypersensitivity
- Clomiphene citrate tablets USP is contraindicated in patients with a known hypersensitivity or allergy to clomiphene citrate or to any of its ingredients.
- Pregnancy
- Pregnancy Category X. Clomiphene citrate tablets USP use in pregnant women is contraindicated, as clomiphene citrate does not offer benefit in this population.
- Available human data do not suggest an increased risk for congenital anomalies above the background population risk when used as indicated. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus.
- Liver Disease
- Clomiphene citrate tablets USP therapy is contraindicated in patients with liver disease or a history of liver dysfunction.
- Abnormal Uterine Bleeding
- Clomiphene citrate tablets USP is contraindicated in patients with abnormal uterine bleeding of undetermined origin.
- Ovarian Cysts
- Clomiphene citrate tablets USP is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome.
- Other
- Clomiphene citrate tablets USP is contraindicated in patients with uncontrolled thyroid or adrenal dysfunction or in the presence of an organic intracranial lesion such as pituitary tumor.
# Warnings
- Visual Symptoms
- Patients should be advised that blurring or other visual symptoms such as spots or flashes (scintillating scotomata) may occasionally occur during therapy with clomiphene citrate tablets USP. These visual symptoms increase in incidence with increasing total dose or therapy duration. These visual disturbances are usually reversible; however, cases of prolonged visual disturbance have been reported with some occurring after clomiphene citrate tablets USP discontinuation. The visual disturbances may be irreversible, especially with increased dosage or duration of therapy. Patients should be warned that these visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting.
- These visual symptoms appear to be due to intensification and prolongation of afterimages. Symptoms often first appear or are accentuated with exposure to a brightly lit environment. While measured visual acuity usually has not been affected, a study patient taking 200 mg clomiphene citrate tablets USP daily developed visual blurring on the 7th day of treatment, which progressed to severe diminution of visual acuity by the 10th day. No other abnormality was found, and the visual acuity returned to normal on the 3rd day after treatment was stopped.
- Ophthalmologically definable scotomata and retinal cell function (electroretinographic) changes have also been reported. A patient treated during clinical studies developed phosphenes and scotomata during prolonged clomiphene citrate tablets USP administration, which disappeared by the 32nd day after stopping therapy.
- Postmarketing surveillance of adverse events has also revealed other visual signs and symptoms during clomiphene citrate tablets USP therapy.
- While the etiology of these visual symptoms is not yet understood, patients with any visual symptoms should discontinue treatment and have a complete ophthalmological evaluation carried out promptly.
- Ovarian Hyperstimulation Syndrome
- The ovarian hyperstimulation syndrome (OHSS) has been reported to occur in patients receiving clomiphene citrate therapy for ovulation induction. OHSS may progress rapidly (within 24 hours to several days) and become a serious medical disorder. In some cases, OHSS occurred following cyclic use of clomiphene citrate therapy or when clomiphene citrate was used in combination with gonadotropins. Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with OHSS.
- OHSS is a medical event distinct from uncomplicated ovarian enlargement. The clinical signs of this syndrome in severe cases can include gross ovarian enlargement, gastrointestinal symptoms, ascites, dyspnea, oliguria, and pleural effusion. In addition, the following symptoms have been reported in association with this syndrome: pericardial effusion, anasarca, hydrothorax, acute abdomen, hypotension, renal failure, pulmonary edema, intraperitoneal and ovarian hemorrhage, deep venous thrombosis, torsion of the ovary, and acute respiratory distress. The early warning signs of OHSS are abdominal pain and distention, nausea, vomiting, diarrhea, and weight gain. Elevated urinary steroid levels, varying degrees of electrolyte imbalance, hypovolemia, hemoconcentration, and hypoproteinemia may occur. Death due to hypovolemic shock, hemoconcentration, or thromboembolism has occurred. Due to fragility of enlarged ovaries in severe cases, abdominal and pelvic examination should be performed very cautiously. If conception results, rapid progression to the severe form of the syndrome may occur.
- To minimize the hazard associated with occasional abnormal ovarian enlargement associated with clomiphene citrate tablets USP therapy, the lowest dose consistent with expected clinical results should be used. Maximal enlargement of the ovary, whether physiologic or abnormal, may not occur until several days after discontinuation of the recommended dose of clomiphene citrate tablets USP. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiphene citrate tablets USP. Therefore, patients with polycystic ovary syndrome should be started on the lowest recommended dose and shortest treatment duration for the first course of therapy
- If enlargement of the ovary occurs, additional clomiphene citrate tablets USP therapy should not be given until the ovaries have returned to pretreatment size, and the dosage or duration of the next course should be reduced. Ovarian enlargement and cyst formation associated with clomiphene citrate tablets USP therapy usually regress spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent clomiphene citrate tablets USP therapy in these cases should exceed the risk. Unless surgical indication for laparotomy exists, such cystic enlargement should always be managed conservatively.
- A causal relationship between ovarian hyperstimulation and ovarian cancer has not been determined. However, because a correlation between ovarian cancer and nulliparity, infertility, and age has been suggested, if ovarian cysts do not regress spontaneously, a thorough evaluation should be performed to rule out the presence of ovarian neoplasia.
### Precautions
- General
- Careful attention should be given to the selection of candidates for clomiphene citrate tablets USP therapy. Pelvic examination is necessary prior to clomiphene citrate tablets USP treatment and before each subsequent course.
# Adverse Reactions
## Clinical Trials Experience
- Clomiphene citrate tablets USP, at recommended dosages, is generally well tolerated. Adverse reactions usually have been mild and transient and most have disappeared promptly after treatment has been discontinued. Adverse experiences reported in patients treated with clomiphene citrate during clinical studies are shown in Table 2.
- The following adverse events have been reported in fewer than 1% of patients in clinical trails: Acute abdomen, appetite increase, constipation, dermatitis or rash, depression, diarrhea, dizziness, fatigue, hair loss/dry hair, increased urinary frequency/volume, insomnia, light-headedness, nervous tension, vaginal dryness, vertigo, weight gain/loss.
- Patients on prolonged clomiphene citrate tablets USP therapy may show elevated serum levels of desmosterol. This is most likely due to a direct interference with cholesterol synthesis. However, the serum sterols in patients receiving the recommended dose of clomiphene citrate tablets USP are not significantly altered. Ovarian cancer has been infrequently reported in patients who have received fertility drugs. Infertility is a primary risk factor for ovarian cancer; however, epidemiology data suggest that prolonged use of clomiphene may increase the risk of a borderline or invasive ovarian tumor.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of clomiphene citrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Fever, tinnitus, weakness
Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis
Migraine headache, paresthesia, seizure, stroke, syncope
Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus, urticaria
- Abnormal bone development: skeletal malformations of the skull, face, nasal passages, jaw, hand, limb (ectromelia including amelia, hemimelia, and phocomelia), foot (clubfoot), spine, and joints
- Cardiac abnormalities: septal heart defects, muscular ventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, and coarctation of the aorta
- Chromosomal disorders: Downs syndrome
- Ear abnormalities and deafness
- Gastrointestinal tract abnormalities: cleft lip and palate, imperforate anus, tracheoesophageal fistula, diaphragmatic hernia, omphalocele
- Genitalia abnormalities: hypospadias, cloacal exstrophy
- Lung tissue malformations
- Malformations of the eye and lens (cataract)
- Neoplasms: neuroectodermal tumor, thyroid tumor, hepatoblastoma, lymphocytic leukemia
- Nervous system abnormalities: neural tube defects (anencephaly, meningomyelocele), microcephaly, and hydrocephalus
- Renal abnormalities: renal agenesis and renal dysgenesis
- Others: dwarfism, mental retardation
Pancreatitis
Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage, reduced endometrial thickness
Transaminases increased, hepatitis
Hypertriglyceridemia, in some cases with pancreatitis
Arthralgia, back pain, myalgia
Liver (hepatic hemangiosarcoma, liver cell adenoma, hepatocellular carcinoma); breast (fibrocystic disease, breast carcinoma); endometrium (endometrial carcinoma); nervous system (astrocytoma, pituitary tumor, prolactinoma, neurofibromatosis, glioblastoma multiforme, brain abcess); ovary (luteoma of pregnancy, dermoid cyst of the ovary, ovarian carcinoma); trophoblastic (hydatiform mole, choriocarcinoma); miscellaneous (melanoma, myeloma, perianal cysts, renal cell carcinoma, Hodgkin's lymphoma, tongue carcinoma, bladder carcinoma)
Anxiety, irritability, mood changes, psychosis
Abnormal accommodation, cataract, eye pain, macular edema, optic neuritis, photopsia, posterior vitreous detachment, retinal hemorrhage, retinal thrombosis, retinal vascular spasm, temporary or prolonged loss of vision, possibly irreversible
Leukocytosis, thyroid disorder
# Drug Interactions
- Drug interactions with clomiphene citrate tablets USP have not been documented.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Clomiphene citrate use in pregnant women is contraindicated, as clomiphene citrate tablets USP treatment does not offer benefit in this population.
- Available human data do not suggest an increased risk for congenital anomalies above the background population risk. However, animal reproductive toxicology studies showed increased embryo-fetal loss and structural malformations in offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks to the fetus.
- Clinical Considerations
- To avoid inadvertent clomiphene citrate tablets USP administration during early pregnancy, appropriate tests should be utilized during each treatment cycle to determine whether ovulation and/or pregnancy occurs. Patients should be evaluated carefully to exclude ovarian enlargement or ovarian cyst formation between each treatment cycle. The next course of clomiphene citrate tablets USP therapy should be delayed until these conditions have been excluded.
- Human data
- The available human data from epidemiologic studies do not show any apparent cause and effect relationship between clomiphene citrate periconceptual exposure and an increased risk of overall birth defects, or any specific anomaly. However, due to the small number of cases of congenital anomalies occurring in clomiphene citrate treated women, these epidemiologic studies were only able to rule out large differences in risk. The studies did not consider factors associated with female subfertility and were unable to adjust for other important confounders.
- In addition, available data do not support an increased rate of spontaneous abortion among subfertile women treated with clomiphene citrate for ovulation induction.
- Animal data
- Oral administration of clomiphene citrate to pregnant rats during organogenesis at doses of 1 to 2 mg/kg/day resulted in hydramnion and weak, edematous fetuses with wavy ribs and other temporary bone changes. Doses of 8 mg/kg/day or more also caused increased resorptions and dead fetuses, dystocia, and delayed parturition, and 40 mg/kg/day resulted in increased maternal mortality. Single doses of 50 mg/kg caused fetal cataracts, while 200 mg/kg caused cleft palate. Following injection of clomiphene citrate 2 mg/kg to mice and rats during pregnancy, the offspring exhibited metaplastic changes of the reproductive tract. Newborn mice and rats injected during the first few days of life also developed metaplastic changes in uterine and vaginal mucosa, as well as premature vaginal opening and anovulatory ovaries. These findings are similar to the abnormal reproductive behavior and sterility described with other estrogens and antiestrogens.
- In rabbits, some temporary bone alterations were seen in fetuses from dams given oral doses of 20 or 40 mg/kg/day during pregnancy, but not following 8 mg/kg/day. No permanent malformations were observed in those studies. Also, rhesus monkeys given oral doses of 1.5 to 4.5 mg/kg/day for various periods during pregnancy did not have any abnormal offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clomifene in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Clomifene during labor and delivery.
### Nursing Mothers
- It is not known whether clomiphene citrate tablets USP is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene citrate tablets USP is administered to a nursing woman. In some patients, clomiphene citrate tablets USP may reduce lactation.
### Pediatric Use
There is no FDA guidance on the use of Clomifene with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Clomifene with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Clomifene with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Clomifene with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Clomifene in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Clomifene in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clomifene in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Clomifene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Clomifene in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Clomifene in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Toxic effects accompanying acute overdosage of clomiphene citrate tablets USP have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomiphene citrate tablets USP therapy include nausea, vomiting, vasomotor flushes, blurred vision, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.
- Oral LD50. The acute oral LD50 of clomiphene citrate tablets USP is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known.
### Management
- In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. It is not known if clomiphene citrate tablets USP is dialyzable.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Clomifene in the drug label.
# Pharmacology
## Mechanism of Action
- Clomiphene citrate tablets USP is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, clomiphene citrate tablets USP has been demonstrated to be a useful therapy for the anovulatory patient desiring pregnancy.
- Clomiphene citrate is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors. Clomiphene citrate initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event in response to a course of clomiphene therapy is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis, resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle.
- Available data suggest that both the estrogenic and antiestrogenic properties of clomiphene may participate in the initiation of ovulation. The two clomiphene isomers have been found to have mixed estrogenic and antiestrogenic effects, which may vary from one species to another. Some data suggest that zuclomiphene has greater estrogenic activity than enclomiphene.
- Clomiphene citrate has no apparent progestational, androgenic, or antiandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.
- Although there is no evidence of a "carryover effect" of clomiphene citrate tablets USP, spontaneous ovulatory menses have been noted in some patients after clomiphene citrate tablets USP therapy.
## Structure
- Clomiphene citrate tablets USP is an orally administered, nonsteroidal, ovulatory stimulant designated chemically as 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy] triethylamine citrate (1:1). It has the molecular formula of C26H28ClNO • C6H8O7 and a molecular weight of 598.09. It is represented structurally as:
- Clomiphene citrate is a white to pale yellow, essentially odorless, crystalline powder. It is freely soluble in methanol; soluble in ethanol; slightly soluble in acetone, water, and chloroform; and insoluble in ether.
- Clomiphene citrate tablets USP is a mixture of two geometric isomers [cis (zuclomiphene) and trans (enclomiphene)] containing between 30% and 50% of the cis-isomer.
- Each white scored tablet contains 50 mg clomiphene citrate USP. The tablet also contains the following inactive ingredients: corn starch, lactose, magnesium stearate, pregelatinized corn starch, and sucrose.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Clomifene in the drug label.
## Pharmacokinetics
- Based on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Cumulative urinary and fecal excretion of the 14C averaged about 50% of the oral dose and 37% of an intravenous dose after 5 days. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.
- Some 14C label was still present in the feces 6 weeks after administration. Subsequent single-dose studies in normal volunteers showed that zuclomiphene (cis) has a longer half-life than enclomiphene (trans). Detectable levels of zuclomiphene persisted for longer than a month in these subjects. This may be suggestive of stereo-specific enterohepatic recycling or sequestering of the zuclomiphene. Thus, it is possible that some active drug may remain in the body during early pregnancy in women who conceive in the menstrual cycle during clomiphene citrate tablets USP therapy.
## Nonclinical Toxicology
- Long-term toxicity studies in animals have not been performed to evaluate the carcinogenic or mutagenic potential of clomiphene citrate.
- Oral administration of clomiphene citrate tablets USP to male rats at doses of 0.3 or 1 mg/kg/day caused decreased fertility, while higher doses caused temporary infertility. Oral doses of 0.1 mg/kg/day in female rats temporarily interrupted the normal cyclic vaginal smear pattern and prevented conception. Doses of 0.3 mg/kg/day slightly reduced the number of ovulated ova and corpora lutea, while 3 mg/kg/day inhibited ovulation.
# Clinical Studies
- During clinical investigations, 7578 patients received clomiphene citrate tablets USP, some of whom had impediments to ovulation other than ovulatory dysfunction. In those clinical trials, successful therapy characterized by pregnancy occurred in approximately 30% of these patients.
- There were a total of 2635 pregnancies reported during the clinical trial period. Of those pregnancies, information on outcome was only available for 2369 of the cases. Table 1 summarizes the outcome of these cases.
- Of the reported pregnancies, the incidence of multiple pregnancies was 7.98%: 6.9% twin, 0.5% triplet, 0.3% quadruplet, and 0.1% quintuplet. Of the 165 twin pregnancies for which sufficient information was available, the ratio of monozygotic to dizygotic twins was about 1:5. Table 1 reports the survival rate of the live multiple births.
- A sextuplet birth was reported after completion of original clinical studies; none of the sextuplets survived (each weighed less than 400 g), although each appeared grossly normal.
- Fetal/Neonatal Anomalies and Mortality. The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with clomiphene citrate tablets USP during clinical trials. Each of the following fetal abnormalities were reported at a rate of <1% (experiences are listed in order of decreasing frequency): Congenital heart lesions, Down syndrome, club foot, congenital gut lesions, hypospadias, microcephaly, harelip and cleft palate, congenital hip, hemangioma, undescended testicles, polydactyly, conjoined twins and teratomatous malformation, patent ductus arteriosus, amaurosis, arteriovenous fistula, inguinal hernia, umbilical hernia, syndactyly, pectus excavatum, myopathy, dermoid cyst of scalp, omphalocele, spina bifida occulta, ichthyosis, and persistent lingual frenulum. Neonatal death and fetal death/stillbirth in infants with birth defects have also been reported at a rate of <1%. The overall incidence of reported congenital anomalies from pregnancies associated with maternal clomiphene citrate tablets USP ingestion during clinical studies was within the range of that reported for the general population.
- In addition, reports of congenital anomalies have been received during postmarketing surveillance of clomiphene citrate.
# How Supplied
- NDC 0591-0781-30: 50 mg tablets in cartons of 30
- Tablets are round, white, scored, and debossed Watson over 781.
- Store tablets at controlled room temperature 59°-86°F (15°-30°C). Protect from heat, light, and excessive humidity, and store in closed containers.
## Storage
There is limited information regarding Clomifene Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The purpose and risks of clomiphene citrate tablets USP therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiphene citrate tablets USP therapy is ovulation for subsequent pregnancy. The physician should counsel the patient with special regard to the following potential risks:
- Visual Symptoms
- Advise that blurring or other visual symptoms occasionally may occur during or shortly after clomiphene citrate tablets USP therapy. It should be made clear to the patient that, in some instances, visual disturbances may be prolonged, and possibly irreversible, especially with increased dosage or duration of therapy. Warn that visual symptoms may render such activities as driving a car or operating machinery more hazardous than usual, particularly under conditions of variable lighting.
- The patient should be instructed to inform the physician whenever any unusual visual symptoms occur. If the patient has any visual symptoms, treatment should be discontinued and complete ophthalmologic evaluation performed.
- Abdominal/Pelvic Pain or Distention
- Ovarian enlargement may occur during or shortly after therapy with clomiphene citrate tablets USP. To minimize the risks associated with ovarian enlargement, the patient should be instructed to inform the physician of any abdominal or pelvic pain, weight gain, discomfort, or distention after taking clomiphene citrate tablets USP.
- Metabolism Disorders
- Cases of hypertriglyceridemia have been reported. Preexisting or family history of hyperlipidemia and use of higher than recommended dose and/or longer duration of treatment with clomiphene citrate are associated with a risk of hypertriglyceridemia. Periodic monitoring of plasma triglycerides is recommended in patients with preexisting or family history of hyperlipidemia.
- Multiple Pregnancy
- Inform the patient that there is an increased chance of multiple pregnancy, including bilateral tubal pregnancy and coexisting tubal and intrauterine pregnancy, when conception occurs in relation to clomiphene citrate tablets USP therapy. The potential complications and hazards of multiple pregnancy should be explained.
- Spontaneous Abortion and Congenital Anomalies
- Inform the patient that the available data suggest no increase in the rates of spontaneous abortion (miscarriage) or congenital anomalies with maternal clomiphene citrate tablets USP use compared to rates in the general population.
- During clinical investigation, the experience from patients with known pregnancy outcome (Table 1) shows a spontaneous abortion rate of 20.4% and stillbirth rate of 1.0%. Among the birth anomalies spontaneously reported as individual cases since commercial availability of clomiphene citrate tablets USP, the proportion of neural tube defects has been high among pregnancies associated with ovulation induced by clomiphene citrate tablets USP, but this has not been supported by data from population-based studies.
# Precautions with Alcohol
- Alcohol-Clomifene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CLOMIPHENE CITRATE®[4]
# Look-Alike Drug Names
- clomiPHENE® — clomiPRAMINE®[5]
- Serophene® — Sarafem®[5]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Clomid | |
2b80285b2298766295667f143599a26d2b91ea5b | wikidoc | Clozapine | Clozapine
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# Black Box Warning
# Overview
Clozapine is a antipsychotic, dibenzodiazepine, central nervous system agent that is FDA approved for the treatment of treatment-resistant schizophrenia, reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders. There is a Black Box Warning for this drug as shown here. Common adverse reactions include drowsiness/sedation, dizziness/vertigo, headache, tremor; excessive salivation, sweating, Xerostomia, tachycardia, hypotension, syncope, constipation, nausea, weight increased, fever and visual disturbance..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Clozapine tablets are indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, Clozapine tablets should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs.
- The effectiveness of Clozapine in a treatment-resistant schizophrenic population was demonstrated in a 6-week study comparing Clozapine and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean BPRS total score of 61 were demonstrated to be treatment-resistant by history and by open, prospective treatment with haloperidol before entering into the double-blind phase of the study. The superiority of clozapine tablets to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect.
- Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated.
- Clozapine tablets are indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that puts him/herself at risk for death.
- The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a 2-year treatment period in the InterSePT Trial . Therefore, clozapine tablet treatment to reduce the risk of suicidal behavior should be continued for at least 2 years.
- The prescriber should be aware that a majority of patients in both treatment groups in InterSePT received other treatments as well to reduce suicide risk, such as antidepressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.
- It is generally recommended that clozapine tablets should not be used in combination with other antipsychotics. When clozapine tablet therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the dosage of other antipsychotics be reduced or discontinued by gradually tapering it downwards. Based on the clinical circumstances, the prescribing physician should judge whether or not to discontinue the other antipsychotic therapy before initiating treatment with clozapine tablets.
- Upon initiation of clozapine tablet therapy, up to a one week supply of additional clozapine tablets may be provided to the patient to be held for emergencies (e.g., weather, holidays).
- Initial Treatment
- It is recommended that treatment with clozapine tablets begin with one-half of a 25 mg tablet (12.5 mg) once or twice daily and then be continued with daily dosage increments of 25 to 50 mg/day, if well tolerated, to achieve a target dose of 300 to 450 mg/day by the end of 2 weeks. Subsequent dosage increments should be made no more than once or twice weekly, in increments not to exceed 100 mg. Cautious titration and a divided dosage schedule are necessary to minimize the risks of hypotension, seizure, and sedation.
- In the multicenter study that provides primary support for the effectiveness of clozapine in patients resistant to standard drug treatment for schizophrenia, patients were titrated during the first 2 weeks up to a maximum dose of 500 mg/day, on a t.i.d. basis, and were then dosed in a total daily dose range of 100 to 900 mg/day, on a t.i.d. basis thereafter, with clinical response and adverse effects as guides to correct dosing.
- Therapeutic Dose Adjustment
- Daily dosing should continue on a divided basis as an effective and tolerable dose level is sought. While many patients may respond adequately at doses between 300 to 600 mg/day, it may be necessary to raise the dose to the 600 to 900 mg/day range to obtain an acceptable response. (Note: In the multicenter study providing the primary support for the superiority of clozapine tablets in treatment-resistant patients, the mean and median clozapine tablet doses were both approximately 600 mg/day.)
- Because of the possibility of increased adverse reactions at higher doses, particularly seizure, patients should ordinarily be given adequate time to respond to a given dose level before escalation to a higher dose is contemplated. Clozapine tablets can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalized seizures. These symptoms may be likely to occur with rapid dose increase and in patients with preexisting epilepsy. In this case, the dose should be reduced and, if necessary, anticonvulsant treatment initiated.
- Dosing should not exceed 900 mg/day.
- Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided.
- Maintenance Treatment
- While the maintenance effectiveness of clozapine in schizophrenia is still under study, the effectiveness of maintenance treatment is well established for many other drugs used to treat schizophrenia. It is recommended that responding patients be continued on clozapine tablets, but at the lowest level needed to maintain remission. Because of the significant risk associated with the use of clozapine tablets, patients should be periodically reassessed to determine the need for maintenance treatment.
- Discontinuation of Treatment
- In the event of planned termination of clozapine tablet therapy, gradual reduction in dose is recommended over a 1 to 2 week period. However, should a patient’s medical condition require abrupt discontinuation (e.g., leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as headache, nausea, vomiting, and diarrhea.
- Reinitiation of Treatment in Patients Previously Discontinued
- When restarting patients who have had even a brief interval off clozapine tablets, i.e., 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily. If that dose is well tolerated, it may be feasible to titrate patients back to a therapeutic dose more quickly than is recommended for initial treatment. However, any patient who has previously experienced respiratory or cardiac arrest with initial dosing, but was then able to be successfully titrated to a therapeutic dose, should be retitrated with extreme caution after even 24 hours of discontinuation.
- Certain additional precautions seem prudent when reinitiating treatment. The mechanisms underlying clozapine induced adverse reactions are unknown. It is conceivable, however, that reexposure of a patient might enhance the risk of an untoward event’s occurrence and increase its severity. Such phenomena, for example, occur when immune mediated mechanisms are responsible. Consequently, during the reinitiation of treatment, additional caution is advised. Patients discontinued for WBC counts below 2000/mm3 or an ANC below 1000/mm3 must not be restarted on clozapine tablets.
- Reducing the Risk of Recurrent Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder
- The dosage and administration recommendations outlined above regarding the use of clozapine tablets in patients with treatment-resistant schizophrenia should also be followed when treating patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior.
- The InterSePT study demonstrated the efficacy of clozapine in treatment of patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior where the mean daily dose was about 300 mg (range 12.5 mg to 900 mg).
- Patients previously treated with other antipsychotics were cross-titrated to clozapine tablets over a one-month interval; the dose of the previous antipsychotic was gradually decreased simultaneous with a gradual increase in clozapine tablet dose over the first month of the study. Patients on depot antipsychotic medication began clozapine tablets after one full dosing interval since the last injection.
- Recommendations to Reduce the Risk of Recurrent suicidal Behavior in Patients Who Otherwise Previously Responded to Treatment of Schizophrenia or Schizoaffective Disorder with Another Antipsychotic Medication
- The results of the InterSePT study demonstrated that, for a 2-year treatment period, the probability of a suicide attempt or a hospitalization due to imminent suicide risk is stable at approximately 24% after one year of treatment with clozapine tablets (Figure 1 Clinical Trial Data Section). A course of treatment with clozapine tablets of at least 2 years is therefore recommended in order to maintain the reduction of risk for suicidal behavior. After 2 years, it is recommended that the patient’s risk of suicidal behavior be assessed. If the physician’s assessment indicates that a significant risk for suicidal behavior is still present, treatment with clozapine tablets should be continued. Thereafter, the decision to continue treatment with clozapine tablets should be revisited at regular intervals, based on thorough assessments of the patient’s risk for suicidal behavior during treatment. If the physician determines that the patient is no longer at risk for suicidal behavior, treatment with clozapine tablets may be discontinued (see recommendations above regarding discontinuation of treatment) and treatment of the underlying disorder with an antipsychotic medication to which the patient has previously responded may be resumed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Parkinson's disease - Psychotic disorder
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clozapine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Clozapine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clozapine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clozapine in pediatric patients.
# Contraindications
- Clozapine tablets are contraindicated in patients with a previous hypersensitivity to clozapine or any other component of this drug, in patients with myeloproliferative disorders, uncontrolled epilepsy, paralytic ileus, or a history of clozapine induced agranulocytosis or severe granulocytopenia. As with more typical antipsychotic drugs, clozapine is contraindicated in severe central nervous system depression or comatose states from any cause.
- Clozapine should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function. The mechanism of Clozapine induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.
# Warnings
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozapine is not approved for the treatment of patients with dementia-related psychosis.
- Because of the significant risk of agranulocytosis, a potentially life threatening adverse event (see following), Clozapine should be reserved for use in the following indications: 1) For treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard drug treatment for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with Clozapine; it is strongly recommended that a patient be given at least two trials, each with a different standard drug product for schizophrenia, at an adequate dose, and for an adequate duration. 2) For reducing the risk for recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of re-experiencing suicidal behavior.
- Clozapine is available only through a distribution system that ensures monitoring of white blood cell count (WBC) and absolute neutrophil count (ANC) according to the schedule described below prior to delivery of the next supply of medication.
- As described in table 1, patients who are being treated with Clozapine must have a baseline WBC count and ANC before initiation of treatment, and a WBC count and ANC every week for the first 6 months. Thereafter, if acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) have been maintained during the first 6 months of continuous therapy, WBC counts and ANC can be monitored every 2 weeks for the next 6 months. Thereafter, if acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.
- When treatment with Clozapine is discontinued (regardless of the reason), WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3.
- Background:
- Agranulocytosis, defined as an ANC of less than 500/mm3, has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 1.3%, based on the occurrence of 15 U.S. cases out of 1,743 patients exposed to clozapine during its clinical testing prior to domestic marketing. All of these cases occurred at a time when the need for close monitoring of WBC counts was already recognized. agranulocytosis could prove fatal if not detected early and therapy interrupted. Of the 149 cases of agranulocytosis reported worldwide in association with clozapine use as of December 31, 1989, 32% were fatal. However, few of these deaths occurred since 1977, at which time the knowledge of clozapine-induced agranulocytosis became more widespread, and close monitoring of WBC counts more widely practiced. In the U.S., under a weekly WBC count monitoring system with clozapine, there have been 585 cases of agranulocytosis as of August 21, 1997; 19 were fatal (3%). During this period 150,409 patients received clozapine. A hematologic risk analysis was conducted based upon the available information in the Clozapine National Registry (CNR) for U.S. patients. Based upon a cut-off date of April 30, 1995, the incidence rates of agranulocytosis based upon a weekly monitoring schedule, rose steeply during the first 2 months of therapy, peaking in the third month. Among clozapine patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell to a substantial degree. After 6 months, the weekly incidence of agranulocytosis declines still further, however, it never reaches zero. It should be noted that any type of reduction in the frequency of monitoring WBC counts may result in an increased incidence of agranulocytosis.
- Risk Factors:
- Experience from clinical development, as well as from examples in the medical literature, suggest that patients who have developed agranulocytosis during clozapine therapy are at increased risk of subsequent episodes of agranulocytosis. Analysis of WBC count data from the Clozapine National Registry also suggests that patients who have an initial episode of moderate leukopenia (3000/mm3 > WBC ≥ 2000/mm3) are at an increased risk of subsequent episodes of agranulocytosis. Except for bone marrow suppression during initial clozapine therapy, there are no other established risk factors, based on worldwide experience, for the development of agranulocytosis in association with clozapine use. However, a disproportionate number of the U.S. cases of agranulocytosis occurred in patients of Jewish background compared to the overall proportion of such patients exposed during domestic development of clozapine. Most of the U.S. cases of agranulocytosis occurred within 4 to 10 weeks of exposure but neither dose nor duration is a reliable predictor of this problem. agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in women, the elderly and in patients who are cachectic or have a serious underlying medical illness; such patients may also be at particular risk with clozapine, although this has not been definitely demonstrated.
- Table 1 provides a summary of the frequency of monitoring that should occur based on various stages of therapy (e.g., initiation of therapy) or results from WBC count and ANC monitoring tests (e.g., moderate leukopenia). The text that follows should be consulted for additional details regarding the treatment of patients under the various conditions (e.g., severe leukopenia).
- Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat or any other signs of infection which may be indicative of neutropenia occurring at any time during clozapine therapy. Such patients should have a WBC count and ANC performed promptly.
- Consult Table 1 above to determine how to monitor patients who experience decrements in WBC count and ANC at any point during treatment. Additionally, patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.
- If the total WBC count falls below 2000/mm3 or the ANC falls below 1000/mm3, bone marrow aspiration should be considered to ascertain granulopoietic status and patients should not be rechallenged with clozapine. Protective isolation with close observation may be indicated if granulopoiesis is determined to be deficient. Should evidence of infection develop, the patient should have appropriate cultures performed and an appropriate antibiotic regimen instituted.
- Patients discontinued from clozapine therapy due to significant granulopoietic suppression have been found to develop agranulocytosis upon rechallenge, often with a shorter latency on reexposure. To reduce the chances of rechallenge occurring in patients who have experienced significant bone marrow suppression during clozapine therapy, a single, national master file (i.e., Non-rechallengeable Database) is maintained confidentially.
- Patients may be rechallenged with clozapine if their WBC count does not fall below 2000/mm3 and the ANC does not fall below 1000/mm3. However, analysis of data from the Clozapine National Registry suggests that patients who have an initial episode of moderate leukopenia (3000/mm3 > WBC ≥ 2000/mm3) have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged compared to the full cohort of patients treated with clozapine. Although clozapine therapy may be resumed if no symptoms of infection develop, and when the WBC count rises above 3500/mm3 and the ANC rises above 2000/mm3, prescribers are strongly advised to consider whether the benefit of continuing clozapine treatment outweighs the increased risk of agranulocytosis.
- Analyses of the Clozapine National Registry have shown an increased risk of having a subsequent episode of granulopoietic suppression up to a year after recovery from the initial episode. Therefore, as noted in Table 1 above, patients must undergo weekly WBC count and ANC monitoring for one year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia regardless of when the episode develops. If acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥2000/mm3) have been maintained during the year of weekly monitoring, WBC counts can be monitored every 2 weeks for the next 6 months. If acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) continue to be maintained during the 6 months of every 2 week monitoring, WBC counts can be monitored every 4 weeks thereafter, ad infinitum.
- Figure 2 provides instructions regarding reinitiating therapy and subsequently the frequency of WBC count and ANC monitoring after a period of interruption.
- Figure 2. Resuming Monitoring Frequency after Interruption in Therapy.
- Transitions to reduce frequency of monitoring only permitted if all WBC ≥ 3500 and ANC ≥ 2000.
- In clinical trials, 1% of patients developed eosinophilia, which, in rare cases, can be substantial. If a differential count reveals a total eosinophil count above 4000/mm3, clozapine therapy should be interrupted until the eosinophil count falls below 3000/mm3.
- Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizure in 61 of 1,743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). Dose appears to be an important predictor of seizure, with a greater likelihood of seizure at the higher clozapine doses used.
- Caution should be used in administering clozapine to patients having a history of seizure or other predisposing factors. Because of the substantial risk of seizure associated with clozapine use, patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others, e.g., the operation of complex machinery, driving an automobile, swimming, climbing, etc.
- Post-marketing surveillance data from four countries that employ hematological monitoring of clozapine-treated patients revealed: 30 reports of myocarditis with 17 fatalities in 205,493 U.S. patients (August 2001); seven reports of myocarditis with one fatality in 15,600 Canadian patients (April 2001); 30 reports of myocarditis with eight fatalities in 24,108 U.K. patients (August 2001); 15 reports of myocarditis with five fatalities in 8,000 Australian patients (March 1999). These reports represent an incidence of 5, 16.3, 43.2, and 96.6 cases/100,000 patient years, respectively. The number of fatalities represent an incidence of 2.8, 2.3, 11.5, and 32.2 cases/100,000 patient years, respectively.
- The overall incidence rate of myocarditis in patients with schizophrenia treated with antipsychotic agents is unknown. However, for the established market economies (WHO), the incidence of myocarditis is 0.3 cases/100,000 patient years and the fatality rate is 0.2 cases/100,000 patient years. Therefore, the rate of myocarditis in clozapine-treated patients appears to be 17 to 322 times greater than the general population and is associated with an increased risk of fatal myocarditis that is 14 to 161 times greater than the general population.
- The total reports of myocarditis for these four countries was 82 of which 51 (62%) occurred within the first month of clozapine treatment, 25 (31%) occurred after the first month of therapy and six (7%) were unknown. The median duration of treatment was 3 weeks. Of 5 patients rechallenged with clozapine, three had a recurrence of myocarditis. Of the 82 reports, 31 (38%) were fatal and 25 patients who died had evidence of myocarditis at autopsy. These data also suggest that the incidence of fatal myocarditis may be highest during the first month of therapy.
- Therefore, the possibility of myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic findings such as abnormalities or arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. Tachycardia, which has been associated with clozapine treatment, has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis.
- Prompt discontinuation of clozapine treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged with clozapine.
- QT prolongation is associated with an increased risk for life threatening ventricular arrhythmias including Torsades de pointes. Treatment with clozapine, has been associated with QT prolongation as well as ventricular arrthymia, Torsades de pointes, cardiac arrest, and sudden death.
- Caution should be exercised when clozapine is prescribed in patients with a history of long QT syndrome or QT prolongation, or other conditions that may increase their risk for QT prolongation or sudden death, including recent acute myocardial infarction, uncompensated heart failure, or clinically significant cardiac arrhythmia. Caution is also indicated when treating patients with cardiovascular disease or family history of long QT syndrome.
- Caution should be exercised when clozapine is used in combination with other medications known to prolong the QTc interval. These include antipsychotic medication (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), certain antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), antiarrhythmic medication in Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol), and other medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).
- Hypokalemia, (which can result from diuretic therapy, diarrhea, and other causes), and/or hypomagnesemia can also increase the risk of QT prolongation. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Baseline measurements of serum potassium and magnesium levels, as well as periodic monitoring of electrolytes, should be performed. Electrolyte abnormalities should be corrected before initiating treatment with clozapine.
- Persistent QT prolongation predisposes patients to further QTc prolongation and potentially to significant and life threatening cardiac arrhythmias. Routine ECG assessment may detect QTc prolongation but is not always effective in preventing arrhythmias. Clozapine treatment should be discontinued if the QTc interval exceeds 500 msec. Patients taking clozapine who experience symptoms that could indicate the occurrence of Torsades de pointes, (e.g., syncope, dizziness and palpitations) should have further evaluation, including cardiac monitoring.
- Use caution when prescribing clozapine concomitantly with drugs that inhibit the metabolism of clozapine. Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing clozapine in patients with reduced activity of 1A2, 2D6, and 3A4.
- Orthostatic hypotension with or without syncope can occur with clozapine treatment and may represent a continuing risk in some patients. Rarely (approximately one case per 3,000 patients), collapse can be profound and be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation and may even occur on first dose. In one report, initial doses as low as 12.5 mg were associated with collapse and respiratory arrest. When restarting patients who have had even a brief interval off clozapine, i.e., 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily.
- Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even clozapine by itself. Although it has not been established that there is an interaction between clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepineor any other psychotropic drug.
- Tachycardia, which may be sustained, has also been observed in approximately 25% of patients taking clozapine, with patients having an average increase in pulse rate of 10 to 15 bpm. The sustained tachycardia is not simply a reflex response to hypotension, and is present in all positions monitored. Either tachycardia or hypotension may pose a serious risk for an individual with compromised cardiovascular function.
- A minority of clozapine treated patients experience ECG repolarization changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves, which all normalize after discontinuation of clozapine. The clinical significance of these changes is unclear. However, in clinical trials with clozapine, several patients experienced significant cardiac events, including ischemic changes, myocardial infarction, arrhythmias and sudden death. In addition, there have been post-marketing reports of congestive heart failure, pericarditis, pericardial effusions and myocardial infarction which may be fatal. Causality assessment was difficult in many of these cases because of serious preexisting cardiac disease and plausible alternative causes. Rare instances of sudden death have been reported in psychiatric patients, with or without associated antipsychotic drug treatment, and the relationship of these events to antipsychotic drug use is unknown.
- Clozapine should be used with caution in patients with known cardiovascular and/or pulmonary disease, and the recommendation for gradual titration of dose should be carefully observed.
- Atypical antipsychotic drugs, including clozapine have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycemia, dyslipidemia and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
- In a pooled data analysis of eight studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were + 11 mg/dL and + 4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 3). The clozapine doses were 100 to 900 mg/day (mean modal dose: 512 mg/day). The maximum chlorpromazine dose was 1800 mg/day (mean modal dose: 1029 mg/day). The median duration of exposure was 42 days for clozapine and chlorpromazine.
- Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of two studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 4). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 5.The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.
- Weight gain has occurred with the use of antipsychotics, including clozapine. Monitor weight during treatment with clozapine. Table 6 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728 and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.
- Table 6 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥ 7% of body weight relative to baseline. The median duration of exposure was 609, 728 and 42 days, in the clozapine, olanzapine and chlorpromazine group, respectively.
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- There have been several reported cases of NMS in patients receiving clozapine alone or in combination with lithium or other CNS-active agents.
- A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of treatment, which patients are likely to develop the syndrome.
- There are several reasons for predicting that clozapine may be different from other antipsychotic drugs in its potential for inducing tardive dyskinesia, including the preclinical finding that it has a relatively weak dopamine blocking effect and the clinical finding of a low incidence of certain acute extrapyramidal symptoms, e.g., dystonia. A few cases of tardive dyskinesia have been reported in patients on clozapine who had been previously treated with other antipsychotic agents, so that a causal relationship cannot be established. There have been no reports of tardive dyskinesia directly attributable to clozapine alone. Nevertheless, it cannot be concluded, without more extended experience, that clozapine is incapable of inducing this syndrome.
- Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptom suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, clozapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. As with any antipsychotic drug, chronic clozapine use should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on clozapine, drug discontinuation should be considered. However, some patients may require treatment with clozapine despite the presence of the syndrome.
# Adverse Reactions
## Clinical Trials Experience
- Sixteen percent of 1,080 patients who received clozapine in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to clozapine treatment and those that might more appropriately be considered intercurrent illness. The more common events considered to be causes of discontinuation included: CNS, primarily drowsiness/sedation, seizures, dizziness/syncope; cardiovascular, primarily tachycardia, hypotension and ECG changes; gastrointestinal, primarily nausea/vomiting; hematologic, primarily leukopenia/granulocytopenia/agranulocytosis; and fever. None of the events enumerated accounts for more than 1.7% of all discontinuations attributed to adverse clinical events.
- Class Effect:
- Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia.
- Commonly Observed:
- Adverse events observed in association with the use of clozapine in clinical trials at an incidence of greater than 5% were: central nervous system complaints, including drowsiness/sedation, dizziness/vertigo, headache and tremor; autonomic nervous system complaints, including salivation, sweating, dry mouth and visual disturbances; cardiovascular findings, including tachycardia, hypotension and syncope; and gastrointestinal complaints, including constipation and nausea; and fever. Complaints of drowsiness/sedation tend to subside with continued therapy or dose reduction. Salivation may be profuse, especially during sleep, but may be diminished with dose reduction.
- Incidence in Clinical Trials:
- The following table enumerates adverse events that occurred at a frequency of 1% or greater among clozapine patients who participated in clinical trials. These rates are not adjusted for duration of exposure.
- The following table enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least one dose of study medication during their participation in InterSePT, which was an adequate and well controlled 2-year study evaluating the efficacy of clozapine relative to Zyprexa in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.
- Other Events Observed During the Premarketing Evaluation of Clozapine:
- This section reports additional, less frequent adverse events which occurred among the patients taking clozapine in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to clozapine treatment cannot be determined in the absence of appropriate controls in some of the studies. The table above enumerates adverse events that occurred at a frequency of at least 1% of patients treated with clozapine. The list below includes all additional adverse experiences reported as being temporally associated with the use of the drug which occurred at a frequency less than 1%, enumerated by organ system.
- Loss of speech, amentia, tics, poor coordination, delusions/hallucinations, involuntary movement, stuttering, dysarthria, amnesia/memory loss, histrionic movements, libido increase or decrease, paranoia, shakiness, Parkinsonism, and irritability.
- Edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nosebleed.
- Abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, and eructation.
- Dysmenorrhea, impotence, breast pain/discomfort, and vaginal itch/infection.
- Numbness, polydipsia, hot flashes, dry throat, and mydriasis.
- Pruritus, pallor, eczema, erythema, bruise, dermatitis, petechiae, and urticaria.
- Twitching and joint pain
- Coughing, pneumonia/pneumonia-like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, and sneezing.
- Anemia and leukocytosis
- Chills/chills with fever, malaise, appetite increase, ear disorder, hypothermia, eyelid disorder, bloodshot eyes, and nystagmus.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Delirium, cholinergic syndrome, EEG abnormal; exacerbation of psychosis, myoclonus, overdose, paresthesia, possible mild cataplexy, status epilepticus and obsessive compulsive symptoms.
- Atrial or ventricular fibrillation, myocardial infarction, ventricular tachycardia, cardiac arrest, QT interval prolongation, Torsades de Pointes, and periorbital edema.
- Acute pancreatitis, dysphagia, fecal impaction, intestinal obstruction/paralytic ileus and salivary gland swelling.
- Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.
- Acute interstitial nephritis, priapism and renal failure.
- Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.
- Hypercholesterolemia, hypertriglyceridemia and new onset diabetes.
- Myasthenic syndrome and rhabdomyolysis.
- Aspiration, pleural effusion, pneumonia and lower respiratory tract infection which may be fatal.
- Deep vein thrombosis; elevated hemoglobin/hematocrit; ESR increased; pulmonary embolism; sepsis; thrombocytosis; and thrombocytopenia.
- Narrow angle glaucoma.
- CPK elevation; hyperglycemia; hyperuricemia; hyponatremia; and weight loss.
# Drug Interactions
- The risks of using clozapine in combination with other drugs have not been systematically evaluated.
- The mechanism of clozapine induced agranulocytosis is unknown; nonetheless, the possibility that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression warrants consideration. Therefore, clozapine should not be used with other agents having a well-known potential to suppress bone marrow function.
- Given the primary CNS effects of clozapine, caution is advised in using it concomitantly with other CNS-active drugs or alcohol.
- Orthostatic hypotension in patients taking clozapine can, in rare cases (approximately one case per 3,000 patients), be accompanied by profound collapse and respiratory and/or cardiac arrest. Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even clozapine by itself. Although it has not been established that there is an interaction between clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.
- Clozapine may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine-type drugs. The administration of epinephrine should be avoided in the treatment of drug induced hypotension because of a possible reverse epinephrine effect.
- QT Prolongation
- Treatment with clozapine, has been associated with QT interval prolongation and fatal arrhythmia. Clozapine should be used with caution when coadministered with medications known to prolong the QTc interval. Such medications include: Class 1A (e.g., quinidine, procainamide), Class III (e.g., amiodarone, sotalol) antiarrrythmic medications, certain antipsychotic medications (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), certain antibiotics (e.g. gatifloxacin, moxifloxacin, sparfloxacin), and other medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol and tacrolimus). Use caution when coadministering clozapine with medications that can cause electrolyte imbalance (e.g., diuretics).
- Clozapine is a substrate for many CYP450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes.
- Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine. Phenytoin, tobacco smoke, and rifampin may decrease clozapine plasma levels, resulting in a decrease in effectiveness of a previously effective clozapine dose.
- QT Prolongation:
- Use caution when prescribing clozapine concomitantly with drugs that inhibit clozapine metabolism. Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing clozapine in patients with reduced activity 1A2, 2D6, and 3A4.
- Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine, citalopram, ciprofloxacin and erythromycin may increase plasma levels of clozapine, potentially resulting in adverse effects. Although concomitant use of clozapine and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in clozapine plasma levels.
- In a study of schizophrenic patients who received clozapine under steady-state conditions, fluvoxamine or paroxetine was added in 16 and 14 patients, respectively. After 14 days of coadministration, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated with fluvoxamine by about 3-fold compared to baseline concentrations. Paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than 2-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Therefore, such combined treatment should be approached with caution and patients should be monitored closely when clozapine is combined with these drugs, particularly with fluvoxamine. A reduced clozapine dose should be considered.
- A subset (3% to 10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450 2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, the tricyclic antidepressants, and clozapine. These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interaction.
- Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug. Therefore, coadministration of clozapine with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats and rabbits at doses of approximately 2 to 4 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to clozapine. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and in view of the desirability of keeping the administration of all drugs to a minimum during pregnancy, this drug should be used only if clearly needed.
- Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- antipsychotic drugs, including clozapine, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clozapine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Clozapine during labor and delivery.
### Nursing Mothers
- Animal studies suggest that clozapine may be excreted in breast milk and have an effect on the nursing infant. Therefore, women receiving clozapine should not breast-feed.
### Pediatric Use
There is no FDA guidance on the use of Clozapine with respect to pediatric patients.
### Geriatic Use
- Clinical studies of clozapine did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.
- Orthostatic hypotension can occur with clozapine treatment and tachycardia, which may be sustained, has been observed in about 25% of patients taking clozapine. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.
- Also, elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation.
- Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Other reported clinical experience does suggest that the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women.
### Gender
There is no FDA guidance on the use of Clozapine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Clozapine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Clozapine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Clozapine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses approximately 7 times the typical human dose on a mg/kg basis. Fertility in male and female rats was not adversely affected by clozapine. Clozapine did not produce genotoxic or mutagenic effects when assayed in appropriate bacterial and mammalian tests.
### Immunocompromised Patients
There is no FDA guidance one the use of Clozapine in patients who are immunocompromised.
### Others
(Description)
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Because of the significant risk of agranulocytosis, a potentially life threatening adverse event (see following), Clozapine should be reserved for use in the following indications: 1) For treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard drug treatment for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with Clozapine; it is strongly recommended that a patient be given at least two trials, each with a different standard drug product for schizophrenia, at an adequate dose, and for an adequate duration. 2) For reducing the risk for recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of re-experiencing suicidal behavior.
- Clozapine is available only through a distribution system that ensures monitoring of white blood cell (WBC) count and absolute neutrophil count (ANC) according to the schedule described below prior to delivery of the next supply of medication.
- As described in table 1, patients who are being treated with Clozapine must have a baseline WBC count and ANC before initiation of treatment, and a WBC count and ANC every week for the first 6 months. Thereafter, if acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) have been maintained during the first 6 months of continuous therapy, WBC counts and ANC can be monitored every 2 weeks for the next 6 months. Thereafter, if acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.
- When treatment with Clozapine is discontinued (regardless of the reason), WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3.
- Background:
- agranulocytosis, defined as an ANC of less than 500/mm3, has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 1.3%, based on the occurrence of 15 U.S. cases out of 1,743 patients exposed to clozapine during its clinical testing prior to domestic marketing. All of these cases occurred at a time when the need for close monitoring of WBC counts was already recognized. agranulocytosis could prove fatal if not detected early and therapy interrupted. Of the 149 cases of agranulocytosis reported worldwide in association with clozapine use as of December 31, 1989, 32% were fatal. However, few of these deaths occurred since 1977, at which time the knowledge of clozapine-induced agranulocytosis became more widespread, and close monitoring of WBC counts more widely practiced. In the U.S., under a weekly WBC count monitoring system with clozapine, there have been 585 cases of agranulocytosis as of August 21, 1997; 19 were fatal (3%). During this period 150,409 patients received clozapine. A hematologic risk analysis was conducted based upon the available information in the Clozapine National Registry (CNR) for U.S. patients. Based upon a cut-off date of April 30, 1995, the incidence rates of agranulocytosis based upon a weekly monitoring schedule, rose steeply during the first 2 months of therapy, peaking in the third month. Among clozapine patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell to a substantial degree. After 6 months, the weekly incidence of agranulocytosis declines still further, however, it never reaches zero. It should be noted that any type of reduction in the frequency of monitoring WBC counts may result in an increased incidence of agranulocytosis.
- Risk Factors:
- Experience from clinical development, as well as from examples in the medical literature, suggest that patients who have developed agranulocytosis during clozapine therapy are at increased risk of subsequent episodes of agranulocytosis. Analysis of WBC count data from the Clozapine National Registry also suggests that patients who have an initial episode of moderate leukopenia (3000/mm3 > WBC ≥ 2000/mm3) are at an increased risk of subsequent episodes of agranulocytosis. Except for bone marrow suppression during initial clozapine therapy, there are no other established risk factors, based on worldwide experience, for the development of agranulocytosis in association with clozapine use. However, a disproportionate number of the U.S. cases of agranulocytosis occurred in patients of Jewish background compared to the overall proportion of such patients exposed during domestic development of clozapine. Most of the U.S. cases of agranulocytosis occurred within 4 to 10 weeks of exposure but neither dose nor duration is a reliable predictor of this problem. agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in women, the elderly and in patients who are cachectic or have a serious underlying medical illness; such patients may also be at particular risk with clozapine, although this has not been definitely demonstrated.
- Table 1 provides a summary of the frequency of monitoring that should occur based on various stages of therapy (e.g., initiation of therapy) or results from WBC count and ANC monitoring tests (e.g., moderate leukopenia). The text that follows should be consulted for additional details regarding the treatment of patients under the various conditions (e.g., severe leukopenia).
- Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat or any other signs of infection which may be indicative of neutropenia occurring at any time during clozapine therapy. Such patients should have a WBC count and ANC performed promptly.
- Consult Table 1 above to determine how to monitor patients who experience decrements in WBC count and ANC at any point during treatment. Additionally, patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.
- If the total WBC count falls below 2000/mm3 or the ANC falls below 1000/mm3, bone marrow aspiration should be considered to ascertain granulopoietic status and patients should not be rechallenged with clozapine. Protective isolation with close observation may be indicated if granulopoiesis is determined to be deficient. Should evidence of infection develop, the patient should have appropriate cultures performed and an appropriate antibiotic regimen instituted.
- Patients discontinued from clozapine therapy due to significant granulopoietic suppression have been found to develop agranulocytosis upon rechallenge, often with a shorter latency on reexposure. To reduce the chances of rechallenge occurring in patients who have experienced significant bone marrow suppression during clozapine therapy, a single, national master file (i.e., Non-rechallengeable Database) is maintained confidentially.
- Patients may be rechallenged with clozapine if their WBC count does not fall below 2000/mm3 and the ANC does not fall below 1000/mm3. However, analysis of data from the Clozapine National Registry suggests that patients who have an initial episode of moderate leukopenia (3000/mm3 > WBC ≥ 2000/mm3) have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged compared to the full cohort of patients treated with clozapine. Although clozapine therapy may be resumed if no symptoms of infection develop, and when the WBC count rises above 3500/mm3 and the ANC rises above 2000/mm3, prescribers are strongly advised to consider whether the benefit of continuing clozapine treatment outweighs the increased risk of agranulocytosis.
- Analyses of the Clozapine National Registry have shown an increased risk of having a subsequent episode of granulopoietic suppression up to a year after recovery from the initial episode. Therefore, as noted in Table 1 above, patients must undergo weekly WBC count and ANC monitoring for one year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia regardless of when the episode develops. If acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥2000/mm3) have been maintained during the year of weekly monitoring, WBC counts can be monitored every 2 weeks for the next 6 months. If acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) continue to be maintained during the 6 months of every 2 week monitoring, WBC counts can be monitored every 4 weeks thereafter, ad infinitum.
- Figure 2 provides instructions regarding reinitiating therapy and subsequently the frequency of WBC count and ANC monitoring after a period of interruption.
- Figure 2. Resuming Monitoring Frequency after Interruption in Therapy.
- Transitions to reduce frequency of monitoring only permitted if all WBC ≥ 3500 and ANC ≥ 2000.
- Post-marketing surveillance data from four countries that employ hematological monitoring of clozapine-treated patients revealed: 30 reports of myocarditis with 17 fatalities in 205,493 U.S. patients (August 2001); seven reports of myocarditis with one fatality in 15,600 Canadian patients (April 2001); 30 reports of myocarditis with eight fatalities in 24,108 U.K. patients (August 2001); 15 reports of myocarditis with five fatalities in 8,000 Australian patients (March 1999). These reports represent an incidence of 5, 16.3, 43.2, and 96.6 cases/100,000 patient years, respectively. The number of fatalities represent an incidence of 2.8, 2.3, 11.5, and 32.2 cases/100,000 patient years, respectively.
- The overall incidence rate of myocarditis in patients with schizophrenia treated with antipsychotic agents is unknown. However, for the established market economies (WHO), the incidence of myocarditis is 0.3 cases/100,000 patient years and the fatality rate is 0.2 cases/100,000 patient years. Therefore, the rate of myocarditis in clozapine-treated patients appears to be 17 to 322 times greater than the general population and is associated with an increased risk of fatal myocarditis that is 14 to 161 times greater than the general population.
- The total reports of myocarditis for these four countries was 82 of which 51 (62%) occurred within the first month of clozapine treatment, 25 (31%) occurred after the first month of therapy and six (7%) were unknown. The median duration of treatment was 3 weeks. Of 5 patients rechallenged with clozapine, three had a recurrence of myocarditis. Of the 82 reports, 31 (38%) were fatal and 25 patients who died had evidence of myocarditis at autopsy. These data also suggest that the incidence of fatal myocarditis may be highest during the first month of therapy.
- Therefore, the possibility of myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic findings such as ST-T wave abnormalities or arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. Tachycardia, which has been associated with clozapine treatment, has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis.
- Prompt discontinuation of clozapine treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged with clozapine.
- QT prolongation is associated with an increased risk for life threatening ventricular arrhythmias including Torsades de pointes. Treatment with clozapine, has been associated with QT prolongation as well as ventricular arrthymia, Torsades de pointes, cardiac arrest, and sudden death.
- Caution should be exercised when clozapine is prescribed in patients with a history of long QT syndrome or QT prolongation, or other conditions that may increase their risk for QT prolongation or sudden death, including recent acute myocardial infarction, uncompensated heart failure, or clinically significant cardiac arrhythmia. Caution is also indicated when treating patients with cardiovascular disease or family history of long QT syndrome.
- Caution should be exercised when clozapine is used in combination with other medications known to prolong the QTc interval. These include antipsychotic medication (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), certain antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), antiarrhythmic medication in Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol), and other medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).
- Hypokalemia, (which can result from diuretic therapy, diarrhea, and other causes), and/or hypomagnesemia can also increase the risk of QT prolongation. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Baseline measurements of serum potassium and magnesium levels, as well as periodic monitoring of electrolytes, should be performed. Electrolyte abnormalities should be corrected before initiating treatment with clozapine.
- Persistent QT prolongation predisposes patients to further QTc prolongation and potentially to significant and life threatening cardiac arrhythmias. Routine ECG assessment may detect QTc prolongation but is not always effective in preventing arrhythmias. Clozapine treatment should be discontinued if the QTc interval exceeds 500 msec. Patients taking clozapine who experience symptoms that could indicate the occurrence of Torsades de pointes, (e.g., syncope, dizziness and palpitations) should have further evaluation, including cardiac monitoring.
- Use caution when prescribing clozapine concomitantly with drugs that inhibit the metabolism of clozapine. Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing clozapine in patients with reduced activity of 1A2, 2D6, and 3A4.
- Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of two studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 4). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 5.The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- There have been several reported cases of NMS in patients receiving clozapine alone or in combination with lithium or other CNS-active agents.
# IV Compatibility
There is limited information regarding IV Compatibility of Clozapine in the drug label.
# Overdosage
- The most commonly reported signs and symptoms associated with clozapine overdose are: altered states of consciousness, including drowsiness, delirium and coma; tachycardia; hypotension; respiratory depression or failure; hypersalivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. seizure have occurred in a minority of reported cases. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.
- Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia.
- There are no specific antidotes for clozapine. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
- In managing overdosage, the physician should consider the possibility of multiple drug involvement.
- Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center.
# Pharmacology
## Mechanism of Action
- Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.
- Clozapine is a partial antagonist at the 5-HT1A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.
- A direct interaction of clozapine with the GABAB receptor has also been shown. GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.
- Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons.
- Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.
## Structure
- Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepinederivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo diazepine. Clozapine’s structural formula, molecular formula, and molecular weight are as follows:
## Pharmacodynamics
- Clozapine is classified as an ‘atypical’ antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine mediated behaviors differ from those exhibited by more typical antipsychotic drug products. In particular, although clozapine does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that clozapine is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of clozapine from extrapyramidal side effects.
- Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.
- In contrast to more typical antipsychotic drugs, clozapine therapy produces little or no prolactin elevation.
- As is true of more typical antipsychotic drugs, clinical EEG studies have shown that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave activity and spike and wave complexes may also develop. Patients, on rare occasions, may report an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.
## Pharmacokinetics
- In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following a dosage of 100 mg b.i.d., the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady-state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, clozapine may be administered with or without food.
- Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein bound drugs has not been fully evaluated but may be important. (See PRECAUTIONS.)
- Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive.
- The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life, after achieving steady-state with 100 mg b.i.d. dosing, of 12 hours (range: 4 to 66 hours). A comparison of single-dose and multiple-dose administration of clozapine showed that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration dependent pharmacokinetics. However, at steady-state, linearly dose proportional changes with respect to AUC (area under the curve), peak and minimum clozapine plasma concentrations were observed after administration of 37.5 mg, 75 mg, and 150 mg b.i.d.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Clozapine in the drug label.
# Clinical Studies
- The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™), which was a prospective, randomized, international, parallel-group comparison of clozapine vs. Zyprexa®- (olanzapine) in patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for reexperiencing suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment, and the remainder were not. Patients met one of the following criteria:
- They had attempted suicide within the 3 years prior to their baseline evaluation.
- They had been hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation.
- They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation.
- They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation.
- Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200 to 900 mg/day for clozapine and 5 to 20 mg/day for Zyprexa. For the 956 patients who received clozapine or Zyprexa in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics; 65% with anxiolytics; 53% with antidepressants, and 28% with mood stabilizers.
- There was significantly greater use of concomitant psychotropic medications among the patients in the Zyprexa group.
- The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide, (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized), or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB, a group of experts blinded to patient data).
- A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years (range 18 to 69). Most patients were Caucasian (71%), 15% were Black, 1% were Oriental, and 13% were classified as being of “other” races.
- Data from this study indicate that clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with Zyprexa. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior, and not a demonstration of the superior efficacy of clozapine over Zyprexa.
- The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized) was lower for clozapine patients than for Zyprexa patients at Week 104: clozapine 24% vs. Zyprexa 32%; 95% C.I. of the difference: 2%, 14% (Figure 1).
# How Supplied
- Clozapine Tablets USP, 25 mg, 100 mg and 200 mg are available as follows:
- The 25 mg tablets are round, peach, scored tablets debossed with C to the left of the score and 7 to the right of the score on one side of the tablet and M on the other side. They are available as follows:
- NDC 51079-921-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- The 100 mg tablets are round, green, scored tablets debossed with C11 above the score and blank below the score on one side of the tablet and M on the other side. They are available as follows:
- NDC 51079-922-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- The 200 mg tablets are round, green, scored tablets debossed with C73 above the score and blank below the score on one side of the tablet and M on the other side. They are available as follows:
- NDC 51079-749-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for White Blood Cell (WBC) count and Absolute Neutrophil Count (ANC) testing every 2 weeks, then a 2-week supply of clozapine tablets can be dispensed. If a patient is eligible for WBC count and ANC testing every 4 weeks, then a 4-week supply of clozapine tablets can be dispensed. Dispensing should be contingent upon the WBC count and ANC test results.
- The brands listed are trademarks of their respective owners.
- Manufactured by:
- Mylan Pharmaceuticals Inc.
- Morgantown, WV 26505 U.S.A.
- Distributed by:
- Mylan Institutional Inc.
- Rockford, IL 61103 U.S.A.
- S-12077
## Storage
- Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Physicians are advised to discuss the following issues with patients for whom they prescribe clozapine:
- Patients who are to receive clozapine should be warned about the significant risk of developing agranulocytosis. Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.
- Patients should be informed that clozapine tablets will be made available only through a special program designed to ensure the required blood monitoring in order to reduce the risk of developing agranulocytosis.
- Patients should be informed that their WBC count and ANC will be monitored as follows:
- Weekly blood tests are required for the first 6 months.
- If acceptable WBC counts and ANCs (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm 3) have been maintained during the first 6 months of continuous therapy, then WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.
- Thereafter, if acceptable WBC counts and ANCs have been maintained during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.
- Patients should be informed of the significant risk of seizure during clozapine treatment, and they should be advised to avoid driving and any other potentially hazardous activity while taking clozapine.
- Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration.
- Patients should be informed that if they miss taking clozapine for more than 2 days, they should not restart their medication at the same dosage, but should contact their physician for dosing instructions.
- Patients should notify their physician if they are taking, or plan to take, any prescription or over-the-counter drugs or alcohol.
- Patients should notify their physician if they become pregnant or intend to become pregnant during therapy.
- Patients should not breast-feed an infant if they are taking clozapine.
# Precautions with Alcohol
- Patients should notify their physician if they are taking, or plan to take, any prescription or over-the-counter drugs or alcohol.
- Given the primary CNS effects of clozapine, caution is advised in using it concomitantly with other CNS-active drugs or alcohol.
# Brand Names
- Clozaril®
- FazaClo®
- Versacloz®
# Look-Alike Drug Names
- Clozaril® - Clinoril®
- cloZAPine® - clonazePAM®
- cloZAPine® - cloNIDine®
- Clozaril® - Colazal®
# Drug Shortage Status
Drug Shortage
# Price | Clozapine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
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# Black Box Warning
# Overview
Clozapine is a antipsychotic, dibenzodiazepine, central nervous system agent that is FDA approved for the treatment of treatment-resistant schizophrenia, reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders. There is a Black Box Warning for this drug as shown here. Common adverse reactions include drowsiness/sedation, dizziness/vertigo, headache, tremor; excessive salivation, sweating, Xerostomia, tachycardia, hypotension, syncope, constipation, nausea, weight increased, fever and visual disturbance..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Clozapine tablets are indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, Clozapine tablets should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs.
- The effectiveness of Clozapine in a treatment-resistant schizophrenic population was demonstrated in a 6-week study comparing Clozapine and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean BPRS total score of 61 were demonstrated to be treatment-resistant by history and by open, prospective treatment with haloperidol before entering into the double-blind phase of the study. The superiority of clozapine tablets to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect.
- Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically reevaluated.
- Clozapine tablets are indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that puts him/herself at risk for death.
- The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a 2-year treatment period in the InterSePT Trial . Therefore, clozapine tablet treatment to reduce the risk of suicidal behavior should be continued for at least 2 years.
- The prescriber should be aware that a majority of patients in both treatment groups in InterSePT received other treatments as well to reduce suicide risk, such as antidepressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.
- It is generally recommended that clozapine tablets should not be used in combination with other antipsychotics. When clozapine tablet therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the dosage of other antipsychotics be reduced or discontinued by gradually tapering it downwards. Based on the clinical circumstances, the prescribing physician should judge whether or not to discontinue the other antipsychotic therapy before initiating treatment with clozapine tablets.
- Upon initiation of clozapine tablet therapy, up to a one week supply of additional clozapine tablets may be provided to the patient to be held for emergencies (e.g., weather, holidays).
- Initial Treatment
- It is recommended that treatment with clozapine tablets begin with one-half of a 25 mg tablet (12.5 mg) once or twice daily and then be continued with daily dosage increments of 25 to 50 mg/day, if well tolerated, to achieve a target dose of 300 to 450 mg/day by the end of 2 weeks. Subsequent dosage increments should be made no more than once or twice weekly, in increments not to exceed 100 mg. Cautious titration and a divided dosage schedule are necessary to minimize the risks of hypotension, seizure, and sedation.
- In the multicenter study that provides primary support for the effectiveness of clozapine in patients resistant to standard drug treatment for schizophrenia, patients were titrated during the first 2 weeks up to a maximum dose of 500 mg/day, on a t.i.d. basis, and were then dosed in a total daily dose range of 100 to 900 mg/day, on a t.i.d. basis thereafter, with clinical response and adverse effects as guides to correct dosing.
- Therapeutic Dose Adjustment
- Daily dosing should continue on a divided basis as an effective and tolerable dose level is sought. While many patients may respond adequately at doses between 300 to 600 mg/day, it may be necessary to raise the dose to the 600 to 900 mg/day range to obtain an acceptable response. (Note: In the multicenter study providing the primary support for the superiority of clozapine tablets in treatment-resistant patients, the mean and median clozapine tablet doses were both approximately 600 mg/day.)
- Because of the possibility of increased adverse reactions at higher doses, particularly seizure, patients should ordinarily be given adequate time to respond to a given dose level before escalation to a higher dose is contemplated. Clozapine tablets can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalized seizures. These symptoms may be likely to occur with rapid dose increase and in patients with preexisting epilepsy. In this case, the dose should be reduced and, if necessary, anticonvulsant treatment initiated.
- Dosing should not exceed 900 mg/day.
- Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided.
- Maintenance Treatment
- While the maintenance effectiveness of clozapine in schizophrenia is still under study, the effectiveness of maintenance treatment is well established for many other drugs used to treat schizophrenia. It is recommended that responding patients be continued on clozapine tablets, but at the lowest level needed to maintain remission. Because of the significant risk associated with the use of clozapine tablets, patients should be periodically reassessed to determine the need for maintenance treatment.
- Discontinuation of Treatment
- In the event of planned termination of clozapine tablet therapy, gradual reduction in dose is recommended over a 1 to 2 week period. However, should a patient’s medical condition require abrupt discontinuation (e.g., leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as headache, nausea, vomiting, and diarrhea.
- Reinitiation of Treatment in Patients Previously Discontinued
- When restarting patients who have had even a brief interval off clozapine tablets, i.e., 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily. If that dose is well tolerated, it may be feasible to titrate patients back to a therapeutic dose more quickly than is recommended for initial treatment. However, any patient who has previously experienced respiratory or cardiac arrest with initial dosing, but was then able to be successfully titrated to a therapeutic dose, should be retitrated with extreme caution after even 24 hours of discontinuation.
- Certain additional precautions seem prudent when reinitiating treatment. The mechanisms underlying clozapine induced adverse reactions are unknown. It is conceivable, however, that reexposure of a patient might enhance the risk of an untoward event’s occurrence and increase its severity. Such phenomena, for example, occur when immune mediated mechanisms are responsible. Consequently, during the reinitiation of treatment, additional caution is advised. Patients discontinued for WBC counts below 2000/mm3 or an ANC below 1000/mm3 must not be restarted on clozapine tablets.
- Reducing the Risk of Recurrent Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder
- The dosage and administration recommendations outlined above regarding the use of clozapine tablets in patients with treatment-resistant schizophrenia should also be followed when treating patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior.
- The InterSePT study demonstrated the efficacy of clozapine in treatment of patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior where the mean daily dose was about 300 mg (range 12.5 mg to 900 mg).
- Patients previously treated with other antipsychotics were cross-titrated to clozapine tablets over a one-month interval; the dose of the previous antipsychotic was gradually decreased simultaneous with a gradual increase in clozapine tablet dose over the first month of the study. Patients on depot antipsychotic medication began clozapine tablets after one full dosing interval since the last injection.
- Recommendations to Reduce the Risk of Recurrent suicidal Behavior in Patients Who Otherwise Previously Responded to Treatment of Schizophrenia or Schizoaffective Disorder with Another Antipsychotic Medication
- The results of the InterSePT study demonstrated that, for a 2-year treatment period, the probability of a suicide attempt or a hospitalization due to imminent suicide risk is stable at approximately 24% after one year of treatment with clozapine tablets (Figure 1 Clinical Trial Data Section). A course of treatment with clozapine tablets of at least 2 years is therefore recommended in order to maintain the reduction of risk for suicidal behavior. After 2 years, it is recommended that the patient’s risk of suicidal behavior be assessed. If the physician’s assessment indicates that a significant risk for suicidal behavior is still present, treatment with clozapine tablets should be continued. Thereafter, the decision to continue treatment with clozapine tablets should be revisited at regular intervals, based on thorough assessments of the patient’s risk for suicidal behavior during treatment. If the physician determines that the patient is no longer at risk for suicidal behavior, treatment with clozapine tablets may be discontinued (see recommendations above regarding discontinuation of treatment) and treatment of the underlying disorder with an antipsychotic medication to which the patient has previously responded may be resumed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Parkinson's disease - Psychotic disorder
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clozapine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Clozapine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clozapine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clozapine in pediatric patients.
# Contraindications
- Clozapine tablets are contraindicated in patients with a previous hypersensitivity to clozapine or any other component of this drug, in patients with myeloproliferative disorders, uncontrolled epilepsy, paralytic ileus, or a history of clozapine induced agranulocytosis or severe granulocytopenia. As with more typical antipsychotic drugs, clozapine is contraindicated in severe central nervous system depression or comatose states from any cause.
- Clozapine should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function. The mechanism of Clozapine induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.
# Warnings
- Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozapine is not approved for the treatment of patients with dementia-related psychosis.
- Because of the significant risk of agranulocytosis, a potentially life threatening adverse event (see following), Clozapine should be reserved for use in the following indications: 1) For treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard drug treatment for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with Clozapine; it is strongly recommended that a patient be given at least two trials, each with a different standard drug product for schizophrenia, at an adequate dose, and for an adequate duration. 2) For reducing the risk for recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of re-experiencing suicidal behavior.
- Clozapine is available only through a distribution system that ensures monitoring of white blood cell count (WBC) and absolute neutrophil count (ANC) according to the schedule described below prior to delivery of the next supply of medication.
- As described in table 1, patients who are being treated with Clozapine must have a baseline WBC count and ANC before initiation of treatment, and a WBC count and ANC every week for the first 6 months. Thereafter, if acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) have been maintained during the first 6 months of continuous therapy, WBC counts and ANC can be monitored every 2 weeks for the next 6 months. Thereafter, if acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.
- When treatment with Clozapine is discontinued (regardless of the reason), WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3.
- Background:
- Agranulocytosis, defined as an ANC of less than 500/mm3, has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 1.3%, based on the occurrence of 15 U.S. cases out of 1,743 patients exposed to clozapine during its clinical testing prior to domestic marketing. All of these cases occurred at a time when the need for close monitoring of WBC counts was already recognized. agranulocytosis could prove fatal if not detected early and therapy interrupted. Of the 149 cases of agranulocytosis reported worldwide in association with clozapine use as of December 31, 1989, 32% were fatal. However, few of these deaths occurred since 1977, at which time the knowledge of clozapine-induced agranulocytosis became more widespread, and close monitoring of WBC counts more widely practiced. In the U.S., under a weekly WBC count monitoring system with clozapine, there have been 585 cases of agranulocytosis as of August 21, 1997; 19 were fatal (3%). During this period 150,409 patients received clozapine. A hematologic risk analysis was conducted based upon the available information in the Clozapine National Registry (CNR) for U.S. patients. Based upon a cut-off date of April 30, 1995, the incidence rates of agranulocytosis based upon a weekly monitoring schedule, rose steeply during the first 2 months of therapy, peaking in the third month. Among clozapine patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell to a substantial degree. After 6 months, the weekly incidence of agranulocytosis declines still further, however, it never reaches zero. It should be noted that any type of reduction in the frequency of monitoring WBC counts may result in an increased incidence of agranulocytosis.
- Risk Factors:
- Experience from clinical development, as well as from examples in the medical literature, suggest that patients who have developed agranulocytosis during clozapine therapy are at increased risk of subsequent episodes of agranulocytosis. Analysis of WBC count data from the Clozapine National Registry also suggests that patients who have an initial episode of moderate leukopenia (3000/mm3 > WBC ≥ 2000/mm3) are at an increased risk of subsequent episodes of agranulocytosis. Except for bone marrow suppression during initial clozapine therapy, there are no other established risk factors, based on worldwide experience, for the development of agranulocytosis in association with clozapine use. However, a disproportionate number of the U.S. cases of agranulocytosis occurred in patients of Jewish background compared to the overall proportion of such patients exposed during domestic development of clozapine. Most of the U.S. cases of agranulocytosis occurred within 4 to 10 weeks of exposure but neither dose nor duration is a reliable predictor of this problem. agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in women, the elderly and in patients who are cachectic or have a serious underlying medical illness; such patients may also be at particular risk with clozapine, although this has not been definitely demonstrated.
- Table 1 provides a summary of the frequency of monitoring that should occur based on various stages of therapy (e.g., initiation of therapy) or results from WBC count and ANC monitoring tests (e.g., moderate leukopenia). The text that follows should be consulted for additional details regarding the treatment of patients under the various conditions (e.g., severe leukopenia).
- Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat or any other signs of infection which may be indicative of neutropenia occurring at any time during clozapine therapy. Such patients should have a WBC count and ANC performed promptly.
- Consult Table 1 above to determine how to monitor patients who experience decrements in WBC count and ANC at any point during treatment. Additionally, patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.
- If the total WBC count falls below 2000/mm3 or the ANC falls below 1000/mm3, bone marrow aspiration should be considered to ascertain granulopoietic status and patients should not be rechallenged with clozapine. Protective isolation with close observation may be indicated if granulopoiesis is determined to be deficient. Should evidence of infection develop, the patient should have appropriate cultures performed and an appropriate antibiotic regimen instituted.
- Patients discontinued from clozapine therapy due to significant granulopoietic suppression have been found to develop agranulocytosis upon rechallenge, often with a shorter latency on reexposure. To reduce the chances of rechallenge occurring in patients who have experienced significant bone marrow suppression during clozapine therapy, a single, national master file (i.e., Non-rechallengeable Database) is maintained confidentially.
- Patients may be rechallenged with clozapine if their WBC count does not fall below 2000/mm3 and the ANC does not fall below 1000/mm3. However, analysis of data from the Clozapine National Registry suggests that patients who have an initial episode of moderate leukopenia (3000/mm3 > WBC ≥ 2000/mm3) have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged compared to the full cohort of patients treated with clozapine. Although clozapine therapy may be resumed if no symptoms of infection develop, and when the WBC count rises above 3500/mm3 and the ANC rises above 2000/mm3, prescribers are strongly advised to consider whether the benefit of continuing clozapine treatment outweighs the increased risk of agranulocytosis.
- Analyses of the Clozapine National Registry have shown an increased risk of having a subsequent episode of granulopoietic suppression up to a year after recovery from the initial episode. Therefore, as noted in Table 1 above, patients must undergo weekly WBC count and ANC monitoring for one year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia regardless of when the episode develops. If acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥2000/mm3) have been maintained during the year of weekly monitoring, WBC counts can be monitored every 2 weeks for the next 6 months. If acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) continue to be maintained during the 6 months of every 2 week monitoring, WBC counts can be monitored every 4 weeks thereafter, ad infinitum.
- Figure 2 provides instructions regarding reinitiating therapy and subsequently the frequency of WBC count and ANC monitoring after a period of interruption.
- Figure 2. Resuming Monitoring Frequency after Interruption in Therapy.
- Transitions to reduce frequency of monitoring only permitted if all WBC ≥ 3500 and ANC ≥ 2000.
- In clinical trials, 1% of patients developed eosinophilia, which, in rare cases, can be substantial. If a differential count reveals a total eosinophil count above 4000/mm3, clozapine therapy should be interrupted until the eosinophil count falls below 3000/mm3.
- Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizure in 61 of 1,743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). Dose appears to be an important predictor of seizure, with a greater likelihood of seizure at the higher clozapine doses used.
- Caution should be used in administering clozapine to patients having a history of seizure or other predisposing factors. Because of the substantial risk of seizure associated with clozapine use, patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others, e.g., the operation of complex machinery, driving an automobile, swimming, climbing, etc.
- Post-marketing surveillance data from four countries that employ hematological monitoring of clozapine-treated patients revealed: 30 reports of myocarditis with 17 fatalities in 205,493 U.S. patients (August 2001); seven reports of myocarditis with one fatality in 15,600 Canadian patients (April 2001); 30 reports of myocarditis with eight fatalities in 24,108 U.K. patients (August 2001); 15 reports of myocarditis with five fatalities in 8,000 Australian patients (March 1999). These reports represent an incidence of 5, 16.3, 43.2, and 96.6 cases/100,000 patient years, respectively. The number of fatalities represent an incidence of 2.8, 2.3, 11.5, and 32.2 cases/100,000 patient years, respectively.
- The overall incidence rate of myocarditis in patients with schizophrenia treated with antipsychotic agents is unknown. However, for the established market economies (WHO), the incidence of myocarditis is 0.3 cases/100,000 patient years and the fatality rate is 0.2 cases/100,000 patient years. Therefore, the rate of myocarditis in clozapine-treated patients appears to be 17 to 322 times greater than the general population and is associated with an increased risk of fatal myocarditis that is 14 to 161 times greater than the general population.
- The total reports of myocarditis for these four countries was 82 of which 51 (62%) occurred within the first month of clozapine treatment, 25 (31%) occurred after the first month of therapy and six (7%) were unknown. The median duration of treatment was 3 weeks. Of 5 patients rechallenged with clozapine, three had a recurrence of myocarditis. Of the 82 reports, 31 (38%) were fatal and 25 patients who died had evidence of myocarditis at autopsy. These data also suggest that the incidence of fatal myocarditis may be highest during the first month of therapy.
- Therefore, the possibility of myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic findings such as abnormalities or arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. Tachycardia, which has been associated with clozapine treatment, has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis.
- Prompt discontinuation of clozapine treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged with clozapine.
- QT prolongation is associated with an increased risk for life threatening ventricular arrhythmias including Torsades de pointes. Treatment with clozapine, has been associated with QT prolongation as well as ventricular arrthymia, Torsades de pointes, cardiac arrest, and sudden death.
- Caution should be exercised when clozapine is prescribed in patients with a history of long QT syndrome or QT prolongation, or other conditions that may increase their risk for QT prolongation or sudden death, including recent acute myocardial infarction, uncompensated heart failure, or clinically significant cardiac arrhythmia. Caution is also indicated when treating patients with cardiovascular disease or family history of long QT syndrome.
- Caution should be exercised when clozapine is used in combination with other medications known to prolong the QTc interval. These include antipsychotic medication (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), certain antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), antiarrhythmic medication in Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol), and other medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).
- Hypokalemia, (which can result from diuretic therapy, diarrhea, and other causes), and/or hypomagnesemia can also increase the risk of QT prolongation. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Baseline measurements of serum potassium and magnesium levels, as well as periodic monitoring of electrolytes, should be performed. Electrolyte abnormalities should be corrected before initiating treatment with clozapine.
- Persistent QT prolongation predisposes patients to further QTc prolongation and potentially to significant and life threatening cardiac arrhythmias. Routine ECG assessment may detect QTc prolongation but is not always effective in preventing arrhythmias. Clozapine treatment should be discontinued if the QTc interval exceeds 500 msec. Patients taking clozapine who experience symptoms that could indicate the occurrence of Torsades de pointes, (e.g., syncope, dizziness and palpitations) should have further evaluation, including cardiac monitoring.
- Use caution when prescribing clozapine concomitantly with drugs that inhibit the metabolism of clozapine. Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing clozapine in patients with reduced activity of 1A2, 2D6, and 3A4.
- Orthostatic hypotension with or without syncope can occur with clozapine treatment and may represent a continuing risk in some patients. Rarely (approximately one case per 3,000 patients), collapse can be profound and be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation and may even occur on first dose. In one report, initial doses as low as 12.5 mg were associated with collapse and respiratory arrest. When restarting patients who have had even a brief interval off clozapine, i.e., 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily.
- Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even clozapine by itself. Although it has not been established that there is an interaction between clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepineor any other psychotropic drug.
- Tachycardia, which may be sustained, has also been observed in approximately 25% of patients taking clozapine, with patients having an average increase in pulse rate of 10 to 15 bpm. The sustained tachycardia is not simply a reflex response to hypotension, and is present in all positions monitored. Either tachycardia or hypotension may pose a serious risk for an individual with compromised cardiovascular function.
- A minority of clozapine treated patients experience ECG repolarization changes similar to those seen with other antipsychotic drugs, including S-T segment depression and flattening or inversion of T waves, which all normalize after discontinuation of clozapine. The clinical significance of these changes is unclear. However, in clinical trials with clozapine, several patients experienced significant cardiac events, including ischemic changes, myocardial infarction, arrhythmias and sudden death. In addition, there have been post-marketing reports of congestive heart failure, pericarditis, pericardial effusions and myocardial infarction which may be fatal. Causality assessment was difficult in many of these cases because of serious preexisting cardiac disease and plausible alternative causes. Rare instances of sudden death have been reported in psychiatric patients, with or without associated antipsychotic drug treatment, and the relationship of these events to antipsychotic drug use is unknown.
- Clozapine should be used with caution in patients with known cardiovascular and/or pulmonary disease, and the recommendation for gradual titration of dose should be carefully observed.
- Atypical antipsychotic drugs, including clozapine have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes may include hyperglycemia, dyslipidemia and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.
- Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
- Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
- In a pooled data analysis of eight studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were + 11 mg/dL and + 4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 3). The clozapine doses were 100 to 900 mg/day (mean modal dose: 512 mg/day). The maximum chlorpromazine dose was 1800 mg/day (mean modal dose: 1029 mg/day). The median duration of exposure was 42 days for clozapine and chlorpromazine.
- Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of two studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 4). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 5.The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.
- Weight gain has occurred with the use of antipsychotics, including clozapine. Monitor weight during treatment with clozapine. Table 6 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728 and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.
- Table 6 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥ 7% of body weight relative to baseline. The median duration of exposure was 609, 728 and 42 days, in the clozapine, olanzapine and chlorpromazine group, respectively.
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- There have been several reported cases of NMS in patients receiving clozapine alone or in combination with lithium or other CNS-active agents.
- A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of treatment, which patients are likely to develop the syndrome.
- There are several reasons for predicting that clozapine may be different from other antipsychotic drugs in its potential for inducing tardive dyskinesia, including the preclinical finding that it has a relatively weak dopamine blocking effect and the clinical finding of a low incidence of certain acute extrapyramidal symptoms, e.g., dystonia. A few cases of tardive dyskinesia have been reported in patients on clozapine who had been previously treated with other antipsychotic agents, so that a causal relationship cannot be established. There have been no reports of tardive dyskinesia directly attributable to clozapine alone. Nevertheless, it cannot be concluded, without more extended experience, that clozapine is incapable of inducing this syndrome.
- Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptom suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, clozapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. As with any antipsychotic drug, chronic clozapine use should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on clozapine, drug discontinuation should be considered. However, some patients may require treatment with clozapine despite the presence of the syndrome.
# Adverse Reactions
## Clinical Trials Experience
- Sixteen percent of 1,080 patients who received clozapine in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to clozapine treatment and those that might more appropriately be considered intercurrent illness. The more common events considered to be causes of discontinuation included: CNS, primarily drowsiness/sedation, seizures, dizziness/syncope; cardiovascular, primarily tachycardia, hypotension and ECG changes; gastrointestinal, primarily nausea/vomiting; hematologic, primarily leukopenia/granulocytopenia/agranulocytosis; and fever. None of the events enumerated accounts for more than 1.7% of all discontinuations attributed to adverse clinical events.
- Class Effect:
- Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia.
- Commonly Observed:
- Adverse events observed in association with the use of clozapine in clinical trials at an incidence of greater than 5% were: central nervous system complaints, including drowsiness/sedation, dizziness/vertigo, headache and tremor; autonomic nervous system complaints, including salivation, sweating, dry mouth and visual disturbances; cardiovascular findings, including tachycardia, hypotension and syncope; and gastrointestinal complaints, including constipation and nausea; and fever. Complaints of drowsiness/sedation tend to subside with continued therapy or dose reduction. Salivation may be profuse, especially during sleep, but may be diminished with dose reduction.
- Incidence in Clinical Trials:
- The following table enumerates adverse events that occurred at a frequency of 1% or greater among clozapine patients who participated in clinical trials. These rates are not adjusted for duration of exposure.
- The following table enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least one dose of study medication during their participation in InterSePT, which was an adequate and well controlled 2-year study evaluating the efficacy of clozapine relative to Zyprexa in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.
- Other Events Observed During the Premarketing Evaluation of Clozapine:
- This section reports additional, less frequent adverse events which occurred among the patients taking clozapine in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to clozapine treatment cannot be determined in the absence of appropriate controls in some of the studies. The table above enumerates adverse events that occurred at a frequency of at least 1% of patients treated with clozapine. The list below includes all additional adverse experiences reported as being temporally associated with the use of the drug which occurred at a frequency less than 1%, enumerated by organ system.
- Loss of speech, amentia, tics, poor coordination, delusions/hallucinations, involuntary movement, stuttering, dysarthria, amnesia/memory loss, histrionic movements, libido increase or decrease, paranoia, shakiness, Parkinsonism, and irritability.
- Edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nosebleed.
- Abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, and eructation.
- Dysmenorrhea, impotence, breast pain/discomfort, and vaginal itch/infection.
- Numbness, polydipsia, hot flashes, dry throat, and mydriasis.
- Pruritus, pallor, eczema, erythema, bruise, dermatitis, petechiae, and urticaria.
- Twitching and joint pain
- Coughing, pneumonia/pneumonia-like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, and sneezing.
- Anemia and leukocytosis
- Chills/chills with fever, malaise, appetite increase, ear disorder, hypothermia, eyelid disorder, bloodshot eyes, and nystagmus.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Delirium, cholinergic syndrome, EEG abnormal; exacerbation of psychosis, myoclonus, overdose, paresthesia, possible mild cataplexy, status epilepticus and obsessive compulsive symptoms.
- Atrial or ventricular fibrillation, myocardial infarction, ventricular tachycardia, cardiac arrest, QT interval prolongation, Torsades de Pointes, and periorbital edema.
- Acute pancreatitis, dysphagia, fecal impaction, intestinal obstruction/paralytic ileus and salivary gland swelling.
- Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.
- Acute interstitial nephritis, priapism and renal failure.
- Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.
- Hypercholesterolemia, hypertriglyceridemia and new onset diabetes.
- Myasthenic syndrome and rhabdomyolysis.
- Aspiration, pleural effusion, pneumonia and lower respiratory tract infection which may be fatal.
- Deep vein thrombosis; elevated hemoglobin/hematocrit; ESR increased; pulmonary embolism; sepsis; thrombocytosis; and thrombocytopenia.
- Narrow angle glaucoma.
- CPK elevation; hyperglycemia; hyperuricemia; hyponatremia; and weight loss.
# Drug Interactions
- The risks of using clozapine in combination with other drugs have not been systematically evaluated.
- The mechanism of clozapine induced agranulocytosis is unknown; nonetheless, the possibility that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression warrants consideration. Therefore, clozapine should not be used with other agents having a well-known potential to suppress bone marrow function.
- Given the primary CNS effects of clozapine, caution is advised in using it concomitantly with other CNS-active drugs or alcohol.
- Orthostatic hypotension in patients taking clozapine can, in rare cases (approximately one case per 3,000 patients), be accompanied by profound collapse and respiratory and/or cardiac arrest. Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even clozapine by itself. Although it has not been established that there is an interaction between clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.
- Clozapine may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine-type drugs. The administration of epinephrine should be avoided in the treatment of drug induced hypotension because of a possible reverse epinephrine effect.
- QT Prolongation
- Treatment with clozapine, has been associated with QT interval prolongation and fatal arrhythmia. Clozapine should be used with caution when coadministered with medications known to prolong the QTc interval. Such medications include: Class 1A (e.g., quinidine, procainamide), Class III (e.g., amiodarone, sotalol) antiarrrythmic medications, certain antipsychotic medications (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), certain antibiotics (e.g. gatifloxacin, moxifloxacin, sparfloxacin), and other medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol and tacrolimus). Use caution when coadministering clozapine with medications that can cause electrolyte imbalance (e.g., diuretics).
- Clozapine is a substrate for many CYP450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes.
- Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine. Phenytoin, tobacco smoke, and rifampin may decrease clozapine plasma levels, resulting in a decrease in effectiveness of a previously effective clozapine dose.
- QT Prolongation:
- Use caution when prescribing clozapine concomitantly with drugs that inhibit clozapine metabolism. Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing clozapine in patients with reduced activity 1A2, 2D6, and 3A4.
- Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine, citalopram, ciprofloxacin and erythromycin may increase plasma levels of clozapine, potentially resulting in adverse effects. Although concomitant use of clozapine and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in clozapine plasma levels.
- In a study of schizophrenic patients who received clozapine under steady-state conditions, fluvoxamine or paroxetine was added in 16 and 14 patients, respectively. After 14 days of coadministration, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated with fluvoxamine by about 3-fold compared to baseline concentrations. Paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than 2-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Therefore, such combined treatment should be approached with caution and patients should be monitored closely when clozapine is combined with these drugs, particularly with fluvoxamine. A reduced clozapine dose should be considered.
- A subset (3% to 10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450 2D6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, the tricyclic antidepressants, and clozapine. These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interaction.
- Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug. Therefore, coadministration of clozapine with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in rats and rabbits at doses of approximately 2 to 4 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to clozapine. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and in view of the desirability of keeping the administration of all drugs to a minimum during pregnancy, this drug should be used only if clearly needed.
- Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.
- antipsychotic drugs, including clozapine, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clozapine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Clozapine during labor and delivery.
### Nursing Mothers
- Animal studies suggest that clozapine may be excreted in breast milk and have an effect on the nursing infant. Therefore, women receiving clozapine should not breast-feed.
### Pediatric Use
There is no FDA guidance on the use of Clozapine with respect to pediatric patients.
### Geriatic Use
- Clinical studies of clozapine did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.
- Orthostatic hypotension can occur with clozapine treatment and tachycardia, which may be sustained, has been observed in about 25% of patients taking clozapine. Elderly patients, particularly those with compromised cardiovascular functioning, may be more susceptible to these effects.
- Also, elderly patients may be particularly susceptible to the anticholinergic effects of clozapine, such as urinary retention and constipation.
- Dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Other reported clinical experience does suggest that the prevalence of tardive dyskinesia appears to be highest among the elderly, especially elderly women.
### Gender
There is no FDA guidance on the use of Clozapine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Clozapine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Clozapine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Clozapine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses approximately 7 times the typical human dose on a mg/kg basis. Fertility in male and female rats was not adversely affected by clozapine. Clozapine did not produce genotoxic or mutagenic effects when assayed in appropriate bacterial and mammalian tests.
### Immunocompromised Patients
There is no FDA guidance one the use of Clozapine in patients who are immunocompromised.
### Others
(Description)
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Because of the significant risk of agranulocytosis, a potentially life threatening adverse event (see following), Clozapine should be reserved for use in the following indications: 1) For treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard drug treatment for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with Clozapine; it is strongly recommended that a patient be given at least two trials, each with a different standard drug product for schizophrenia, at an adequate dose, and for an adequate duration. 2) For reducing the risk for recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of re-experiencing suicidal behavior.
- Clozapine is available only through a distribution system that ensures monitoring of white blood cell (WBC) count and absolute neutrophil count (ANC) according to the schedule described below prior to delivery of the next supply of medication.
- As described in table 1, patients who are being treated with Clozapine must have a baseline WBC count and ANC before initiation of treatment, and a WBC count and ANC every week for the first 6 months. Thereafter, if acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) have been maintained during the first 6 months of continuous therapy, WBC counts and ANC can be monitored every 2 weeks for the next 6 months. Thereafter, if acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) have been maintained during the second 6 months of continuous therapy, WBC count and ANC can be monitored every 4 weeks.
- When treatment with Clozapine is discontinued (regardless of the reason), WBC count and ANC must be monitored weekly for at least 4 weeks from the day of discontinuation or until WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3.
- Background:
- agranulocytosis, defined as an ANC of less than 500/mm3, has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 1.3%, based on the occurrence of 15 U.S. cases out of 1,743 patients exposed to clozapine during its clinical testing prior to domestic marketing. All of these cases occurred at a time when the need for close monitoring of WBC counts was already recognized. agranulocytosis could prove fatal if not detected early and therapy interrupted. Of the 149 cases of agranulocytosis reported worldwide in association with clozapine use as of December 31, 1989, 32% were fatal. However, few of these deaths occurred since 1977, at which time the knowledge of clozapine-induced agranulocytosis became more widespread, and close monitoring of WBC counts more widely practiced. In the U.S., under a weekly WBC count monitoring system with clozapine, there have been 585 cases of agranulocytosis as of August 21, 1997; 19 were fatal (3%). During this period 150,409 patients received clozapine. A hematologic risk analysis was conducted based upon the available information in the Clozapine National Registry (CNR) for U.S. patients. Based upon a cut-off date of April 30, 1995, the incidence rates of agranulocytosis based upon a weekly monitoring schedule, rose steeply during the first 2 months of therapy, peaking in the third month. Among clozapine patients who continued the drug beyond the third month, the weekly incidence of agranulocytosis fell to a substantial degree. After 6 months, the weekly incidence of agranulocytosis declines still further, however, it never reaches zero. It should be noted that any type of reduction in the frequency of monitoring WBC counts may result in an increased incidence of agranulocytosis.
- Risk Factors:
- Experience from clinical development, as well as from examples in the medical literature, suggest that patients who have developed agranulocytosis during clozapine therapy are at increased risk of subsequent episodes of agranulocytosis. Analysis of WBC count data from the Clozapine National Registry also suggests that patients who have an initial episode of moderate leukopenia (3000/mm3 > WBC ≥ 2000/mm3) are at an increased risk of subsequent episodes of agranulocytosis. Except for bone marrow suppression during initial clozapine therapy, there are no other established risk factors, based on worldwide experience, for the development of agranulocytosis in association with clozapine use. However, a disproportionate number of the U.S. cases of agranulocytosis occurred in patients of Jewish background compared to the overall proportion of such patients exposed during domestic development of clozapine. Most of the U.S. cases of agranulocytosis occurred within 4 to 10 weeks of exposure but neither dose nor duration is a reliable predictor of this problem. agranulocytosis associated with other antipsychotic drugs has been reported to occur with a greater frequency in women, the elderly and in patients who are cachectic or have a serious underlying medical illness; such patients may also be at particular risk with clozapine, although this has not been definitely demonstrated.
- Table 1 provides a summary of the frequency of monitoring that should occur based on various stages of therapy (e.g., initiation of therapy) or results from WBC count and ANC monitoring tests (e.g., moderate leukopenia). The text that follows should be consulted for additional details regarding the treatment of patients under the various conditions (e.g., severe leukopenia).
- Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat or any other signs of infection which may be indicative of neutropenia occurring at any time during clozapine therapy. Such patients should have a WBC count and ANC performed promptly.
- Consult Table 1 above to determine how to monitor patients who experience decrements in WBC count and ANC at any point during treatment. Additionally, patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.
- If the total WBC count falls below 2000/mm3 or the ANC falls below 1000/mm3, bone marrow aspiration should be considered to ascertain granulopoietic status and patients should not be rechallenged with clozapine. Protective isolation with close observation may be indicated if granulopoiesis is determined to be deficient. Should evidence of infection develop, the patient should have appropriate cultures performed and an appropriate antibiotic regimen instituted.
- Patients discontinued from clozapine therapy due to significant granulopoietic suppression have been found to develop agranulocytosis upon rechallenge, often with a shorter latency on reexposure. To reduce the chances of rechallenge occurring in patients who have experienced significant bone marrow suppression during clozapine therapy, a single, national master file (i.e., Non-rechallengeable Database) is maintained confidentially.
- Patients may be rechallenged with clozapine if their WBC count does not fall below 2000/mm3 and the ANC does not fall below 1000/mm3. However, analysis of data from the Clozapine National Registry suggests that patients who have an initial episode of moderate leukopenia (3000/mm3 > WBC ≥ 2000/mm3) have up to a 12-fold increased risk of having a subsequent episode of agranulocytosis when rechallenged compared to the full cohort of patients treated with clozapine. Although clozapine therapy may be resumed if no symptoms of infection develop, and when the WBC count rises above 3500/mm3 and the ANC rises above 2000/mm3, prescribers are strongly advised to consider whether the benefit of continuing clozapine treatment outweighs the increased risk of agranulocytosis.
- Analyses of the Clozapine National Registry have shown an increased risk of having a subsequent episode of granulopoietic suppression up to a year after recovery from the initial episode. Therefore, as noted in Table 1 above, patients must undergo weekly WBC count and ANC monitoring for one year following recovery from an episode of moderate leukopenia and/or moderate granulocytopenia regardless of when the episode develops. If acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥2000/mm3) have been maintained during the year of weekly monitoring, WBC counts can be monitored every 2 weeks for the next 6 months. If acceptable WBC counts and ANC (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) continue to be maintained during the 6 months of every 2 week monitoring, WBC counts can be monitored every 4 weeks thereafter, ad infinitum.
- Figure 2 provides instructions regarding reinitiating therapy and subsequently the frequency of WBC count and ANC monitoring after a period of interruption.
- Figure 2. Resuming Monitoring Frequency after Interruption in Therapy.
- Transitions to reduce frequency of monitoring only permitted if all WBC ≥ 3500 and ANC ≥ 2000.
- Post-marketing surveillance data from four countries that employ hematological monitoring of clozapine-treated patients revealed: 30 reports of myocarditis with 17 fatalities in 205,493 U.S. patients (August 2001); seven reports of myocarditis with one fatality in 15,600 Canadian patients (April 2001); 30 reports of myocarditis with eight fatalities in 24,108 U.K. patients (August 2001); 15 reports of myocarditis with five fatalities in 8,000 Australian patients (March 1999). These reports represent an incidence of 5, 16.3, 43.2, and 96.6 cases/100,000 patient years, respectively. The number of fatalities represent an incidence of 2.8, 2.3, 11.5, and 32.2 cases/100,000 patient years, respectively.
- The overall incidence rate of myocarditis in patients with schizophrenia treated with antipsychotic agents is unknown. However, for the established market economies (WHO), the incidence of myocarditis is 0.3 cases/100,000 patient years and the fatality rate is 0.2 cases/100,000 patient years. Therefore, the rate of myocarditis in clozapine-treated patients appears to be 17 to 322 times greater than the general population and is associated with an increased risk of fatal myocarditis that is 14 to 161 times greater than the general population.
- The total reports of myocarditis for these four countries was 82 of which 51 (62%) occurred within the first month of clozapine treatment, 25 (31%) occurred after the first month of therapy and six (7%) were unknown. The median duration of treatment was 3 weeks. Of 5 patients rechallenged with clozapine, three had a recurrence of myocarditis. Of the 82 reports, 31 (38%) were fatal and 25 patients who died had evidence of myocarditis at autopsy. These data also suggest that the incidence of fatal myocarditis may be highest during the first month of therapy.
- Therefore, the possibility of myocarditis should be considered in patients receiving clozapine who present with unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs or symptoms of heart failure, or electrocardiographic findings such as ST-T wave abnormalities or arrhythmias. It is not known whether eosinophilia is a reliable predictor of myocarditis. Tachycardia, which has been associated with clozapine treatment, has also been noted as a presenting sign in patients with myocarditis. Therefore, tachycardia during the first month of therapy warrants close monitoring for other signs of myocarditis.
- Prompt discontinuation of clozapine treatment is warranted upon suspicion of myocarditis. Patients with clozapine-related myocarditis should not be rechallenged with clozapine.
- QT prolongation is associated with an increased risk for life threatening ventricular arrhythmias including Torsades de pointes. Treatment with clozapine, has been associated with QT prolongation as well as ventricular arrthymia, Torsades de pointes, cardiac arrest, and sudden death.
- Caution should be exercised when clozapine is prescribed in patients with a history of long QT syndrome or QT prolongation, or other conditions that may increase their risk for QT prolongation or sudden death, including recent acute myocardial infarction, uncompensated heart failure, or clinically significant cardiac arrhythmia. Caution is also indicated when treating patients with cardiovascular disease or family history of long QT syndrome.
- Caution should be exercised when clozapine is used in combination with other medications known to prolong the QTc interval. These include antipsychotic medication (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), certain antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), antiarrhythmic medication in Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol), and other medications known to prolong the QT interval (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).
- Hypokalemia, (which can result from diuretic therapy, diarrhea, and other causes), and/or hypomagnesemia can also increase the risk of QT prolongation. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Baseline measurements of serum potassium and magnesium levels, as well as periodic monitoring of electrolytes, should be performed. Electrolyte abnormalities should be corrected before initiating treatment with clozapine.
- Persistent QT prolongation predisposes patients to further QTc prolongation and potentially to significant and life threatening cardiac arrhythmias. Routine ECG assessment may detect QTc prolongation but is not always effective in preventing arrhythmias. Clozapine treatment should be discontinued if the QTc interval exceeds 500 msec. Patients taking clozapine who experience symptoms that could indicate the occurrence of Torsades de pointes, (e.g., syncope, dizziness and palpitations) should have further evaluation, including cardiac monitoring.
- Use caution when prescribing clozapine concomitantly with drugs that inhibit the metabolism of clozapine. Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Use caution when prescribing clozapine in patients with reduced activity of 1A2, 2D6, and 3A4.
- Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using clozapine is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of two studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 4). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 5.The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- There have been several reported cases of NMS in patients receiving clozapine alone or in combination with lithium or other CNS-active agents.
# IV Compatibility
There is limited information regarding IV Compatibility of Clozapine in the drug label.
# Overdosage
- The most commonly reported signs and symptoms associated with clozapine overdose are: altered states of consciousness, including drowsiness, delirium and coma; tachycardia; hypotension; respiratory depression or failure; hypersalivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. seizure have occurred in a minority of reported cases. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.
- Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia.
- There are no specific antidotes for clozapine. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
- In managing overdosage, the physician should consider the possibility of multiple drug involvement.
- Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center.
# Pharmacology
## Mechanism of Action
- Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.
- Clozapine is a partial antagonist at the 5-HT1A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.
- A direct interaction of clozapine with the GABAB receptor has also been shown. GABAB receptor-deficient mice exhibit increased extracellular dopamine levels and altered locomotor behaviour equivalent to that in schizophrenia animal models. GABAB receptor agonists and positive allosteric modulators reduce the locomotor changes in these models.
- Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes, and reduces the expression of astrocytic glutamate transporters. These are direct effects that are also present in astrocyte cell cultures not containing neurons.
- Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.
## Structure
- Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepinederivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine. Clozapine’s structural formula, molecular formula, and molecular weight are as follows:
## Pharmacodynamics
- Clozapine is classified as an ‘atypical’ antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine mediated behaviors differ from those exhibited by more typical antipsychotic drug products. In particular, although clozapine does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that clozapine is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of clozapine from extrapyramidal side effects.
- Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.
- In contrast to more typical antipsychotic drugs, clozapine therapy produces little or no prolactin elevation.
- As is true of more typical antipsychotic drugs, clinical EEG studies have shown that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave activity and spike and wave complexes may also develop. Patients, on rare occasions, may report an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.
## Pharmacokinetics
- In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following a dosage of 100 mg b.i.d., the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady-state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, clozapine may be administered with or without food.
- Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein bound drugs has not been fully evaluated but may be important. (See PRECAUTIONS.)
- Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive.
- The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life, after achieving steady-state with 100 mg b.i.d. dosing, of 12 hours (range: 4 to 66 hours). A comparison of single-dose and multiple-dose administration of clozapine showed that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration dependent pharmacokinetics. However, at steady-state, linearly dose proportional changes with respect to AUC (area under the curve), peak and minimum clozapine plasma concentrations were observed after administration of 37.5 mg, 75 mg, and 150 mg b.i.d.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Clozapine in the drug label.
# Clinical Studies
- The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™), which was a prospective, randomized, international, parallel-group comparison of clozapine vs. Zyprexa®* (olanzapine) in patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for reexperiencing suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment, and the remainder were not. Patients met one of the following criteria:
- They had attempted suicide within the 3 years prior to their baseline evaluation.
- They had been hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation.
- They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation.
- They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one week prior to their baseline evaluation.
- Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200 to 900 mg/day for clozapine and 5 to 20 mg/day for Zyprexa. For the 956 patients who received clozapine or Zyprexa in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics; 65% with anxiolytics; 53% with antidepressants, and 28% with mood stabilizers.
- There was significantly greater use of concomitant psychotropic medications among the patients in the Zyprexa group.
- The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide, (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized), or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB, a group of experts blinded to patient data).
- A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment-resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years (range 18 to 69). Most patients were Caucasian (71%), 15% were Black, 1% were Oriental, and 13% were classified as being of “other” races.
- Data from this study indicate that clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with Zyprexa. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior, and not a demonstration of the superior efficacy of clozapine over Zyprexa.
- The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized) was lower for clozapine patients than for Zyprexa patients at Week 104: clozapine 24% vs. Zyprexa 32%; 95% C.I. of the difference: 2%, 14% (Figure 1).
# How Supplied
- Clozapine Tablets USP, 25 mg, 100 mg and 200 mg are available as follows:
- The 25 mg tablets are round, peach, scored tablets debossed with C to the left of the score and 7 to the right of the score on one side of the tablet and M on the other side. They are available as follows:
- NDC 51079-921-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- The 100 mg tablets are round, green, scored tablets debossed with C11 above the score and blank below the score on one side of the tablet and M on the other side. They are available as follows:
- NDC 51079-922-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- The 200 mg tablets are round, green, scored tablets debossed with C73 above the score and blank below the score on one side of the tablet and M on the other side. They are available as follows:
- NDC 51079-749-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
- Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for White Blood Cell (WBC) count and Absolute Neutrophil Count (ANC) testing every 2 weeks, then a 2-week supply of clozapine tablets can be dispensed. If a patient is eligible for WBC count and ANC testing every 4 weeks, then a 4-week supply of clozapine tablets can be dispensed. Dispensing should be contingent upon the WBC count and ANC test results.
- The brands listed are trademarks of their respective owners.
- Manufactured by:
- Mylan Pharmaceuticals Inc.
- Morgantown, WV 26505 U.S.A.
- Distributed by:
- Mylan Institutional Inc.
- Rockford, IL 61103 U.S.A.
- S-12077
- 1/14
## Storage
- Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Physicians are advised to discuss the following issues with patients for whom they prescribe clozapine:
- Patients who are to receive clozapine should be warned about the significant risk of developing agranulocytosis. Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.
- Patients should be informed that clozapine tablets will be made available only through a special program designed to ensure the required blood monitoring in order to reduce the risk of developing agranulocytosis.
- Patients should be informed that their WBC count and ANC will be monitored as follows:
- Weekly blood tests are required for the first 6 months.
- If acceptable WBC counts and ANCs (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm 3) have been maintained during the first 6 months of continuous therapy, then WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.
- Thereafter, if acceptable WBC counts and ANCs have been maintained during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.
- Patients should be informed of the significant risk of seizure during clozapine treatment, and they should be advised to avoid driving and any other potentially hazardous activity while taking clozapine.
- Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration.
- Patients should be informed that if they miss taking clozapine for more than 2 days, they should not restart their medication at the same dosage, but should contact their physician for dosing instructions.
- Patients should notify their physician if they are taking, or plan to take, any prescription or over-the-counter drugs or alcohol.
- Patients should notify their physician if they become pregnant or intend to become pregnant during therapy.
- Patients should not breast-feed an infant if they are taking clozapine.
# Precautions with Alcohol
- Patients should notify their physician if they are taking, or plan to take, any prescription or over-the-counter drugs or alcohol.
- Given the primary CNS effects of clozapine, caution is advised in using it concomitantly with other CNS-active drugs or alcohol.
# Brand Names
- Clozaril®
- FazaClo®
- Versacloz®
# Look-Alike Drug Names
- Clozaril® - Clinoril®
- cloZAPine® - clonazePAM®
- cloZAPine® - cloNIDine®
- Clozaril® - Colazal®
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Clopine | |
fe1f25f67a52502131a4d34edf6c3798c2a8bfba | wikidoc | Sensorium | Sensorium
# Overview
The term sensorium (plural: sensoria) refers to the sum of an organism's perception, the "seat of sensation" where it experiences and interprets the environments within which it lives. The term originally enters English from the Late Latin in the mid-17th century, from the stem sens- (see: sense). In earlier use it referred, in a broader sense, to the brain as the mind's organ (Oxford English Dictionary 1989). In medical, psychological, and physiological discourse it has come to refer to the total character of the unique and changing sensory environments perceived by individuals. These include the sensation, perception, and interpretation of information about the world by senses, perceptual systems and minds (MedTerms 2001).
# Ratios of sensation
In the 20th-century the concept behind the sensorium became a key part of the cultural theories of Marshall McLuhan, Edmund Carpenter and Walter J. Ong (Carpenter and McLuhan 1960; Ong 1991).
McLuhan, like his mentor Harold Innis, believed that media were biased according to time and space. He paid particular attention to what he called the sensorium, or the effects of media on our senses, positing that media affect us by manipulating the ratio of our senses. For example, the alphabet stresses the sense of sight, which in turn causes us to think in linear, objective terms: the medium of the alphabet thus has the effect of reshaping the way in which we, collectively and individually, perceive and understand our environment.
Focusing on variations in the sensorium across social contexts, these theorists collectively suggest that the world is explained and experienced differently depending on the specific "ratios of sense" that members of a culture share in the sensoria they learn to inhabit (Howes 1991, p. 8). More recent work has demonstrated that individuals may include in their unique sensoria perceptual proclivities that exceed their cultural norms; even when, as in the history of smell in the West, the sense in question is suppressed or mostly ignored (Classen, Howes and Synnott 1994).
This interplay of various ways of conceiving the world could be compared to the experience of synesthesia, where stimulus of one sense causes a perception by another, seemingly unrelated sense, as in musicians who can taste the intervals between notes they hear (Beeli et al., 2005), or artists who can smell colours. Many individuals who have one or more senses restricted or lost develop a sensorium with a ratio of sense which favours those they possess more fully. Frequently the blind or deaf speak of a compensating effect, whereby their touch or smell become more acute, changing the ways they perceive and reason about the world; especially telling examples are found in the cases of 'wild children,' whose early childhoods were spent in abusive, neglected or non-human environments, both intensifying and minimizing perceptual abilities (Classen 1991).
# Development of unique sensoria in cultures and individuals
Although some consider these modalities abnormal, it is more likely that these examples demonstrate the contextual and socially learned nature of sensation. A 'normal' sensorium and a 'synesthetic' one differ based on the division, connection, and interplay of the body's manifold sensory apparatus. A synesthete has simply developed a different set of relationships, including cognitive or interpretive skills which deliver unique abilities and understanding of the world (Beeli et al., 2005). The sensorium is a creation of the physical, biological, social and cultural environments of the individual organism and its relationships while being in the world.
What is considered a strange blurring of sensation from one perspective, is a normal and 'natural' way of perception of the world in another, and indeed many individuals and their cultures develop sensoria fundamentally different from the vision-centric modality of most Western science and culture. One revealing contrast is the thought of a former Russian on the matter:
As David Howes explains:
# Sensory ecology and anthropology
These sorts of insights were the impetus for the development of the burgeoning field of sensory anthropology, which seeks to understand other cultures from within their own unique sensoria. Anthropologists such as Paul Stoller (1989) and Michael Jackson (1983, 1989) have focused on a critique of the hegemony of vision and textuality in the social sciences. They argue persuasively for an understanding and analysis that is embodied, one sensitive to the unique context of sensation of those one wishes to understand. They believe that a thorough awareness and adoption of other sensoria is a key requirement if ethnography is to approach true understanding.
A related area of study is sensory (or perceptual) ecology. This field aims at understanding the unique sensory and interpretive systems all organisms develop, based on the specific ecological environments they live in, experience and adapt to. A key researcher in this field has been psychologist James J. Gibson, who has written numerous seminal volumes considering the senses in terms of holistic, self-contained perceptual systems. These exhibit their own mindful, interpretive behaviour, rather than acting simply as conduits delivering information for cognitive processing, as in more representational philosophies of perception or theories of psychology (1966, 1979). Perceptual systems detect affordances in objects in the world, directing attention towards information about an object in terms of the possible uses it affords an organism.
The individual sensory systems of the body are only parts of these broader perceptual ecologies, which include the physical apparatus of sensation, the environment being sensed, as well as both learned and innate systems for directing attention and interpreting the results. These systems represent and enact the information (as an influence which leads to a transformation) required to perceive, identify or reason about the world, and are distributed across the very design and structures of the body, in relation to the physical environment, as well as in the concepts and interpretations of the mind. This information varies according to species, physical environment, and the context of information in the social and cultural systems of perception, which also change over time and space, and as an individual learns through living. Any single perceptual modality may include or overlap multiple sensory structures, as well as other modes of perception, and the sum of their relations and the ratio of mixture and importance comprise a sensorium. The perception, understanding, and reasoning of an organism is dependent on the particular experience of the world delivered by changing ratios of sense.
# Clouded Sensorium
A "clouded sensorium" is a medical term used to describe an inability to think clearly or concentrate. It is associated with a huge variety of underlying causes from drug induced states to pathogenic states induced by disease or mineral deficiency.
# Footnotes
- ↑ Old Messengers, New Media: The Legacy of Innis and McLuhan, a virtual museum exhibition at Library and Archives Canada
# Further reading
- "Sensorium." 1989. Oxford English Dictionary. J.A. Simpson and E.S.C. Weiner, eds. 2nd ed. Oxford: Clarendon Press. OED Online. Oxford University Press. Accessed 15 April 2005.
- Anonymous. 1953. "Russian Sensory Images." In The Study of Culture at a Distance, Margaret Mead and Rhoda Métraux, eds. Chicago: University of Chigago Press. Pp. 162-69.
- Beeli, Gian, Michaela Esslen and Lutz Jäncke. 2005. "Synaesthesia: When Coloured Sounds Taste Sweet." Nature 434 (38). . Accessed 15 April 2005.
- Carpenter, Edmund and Marshall McLuhan, eds. 1960. Explorations in Communication. Boston: Beacon Press.
- Classen, Constance. 1991. The Sensory Orders of 'Wild Children.' In The Varieties of Sensory Experience. David Howes, ed. Toronto: University of Toronto Press. Pp. 47-60.
- Classen, Constance, David Howes and Anthony Synott. 1994. Aroma: The Cultural History of Smell. London and New York: Routledge.
- Gibson, James J. 1966. The Senses Considered as Perceptual Systems. Boston: Houghton Mifflin.
- Gibson, James J. 1979. The Ecological Approach to Visual Perception. Boston: Houghton Mifflin.
- Howes, David, ed. 1991. The Varieties of Sensory Experience. Toronto: University of Toronto Press.
- Howes, David. 2003. Sensual Relations: Engaging the Senses in Culture and Social Theory. Ann Arbor, MI: University of Michigan Press.
- Jackson, Michael. 1983. "Thinking through the Body: An Essay on Understanding Metaphor." Social Analysis 14:127-48.
- Jackson, Michael. 1989. Paths toward a Clearing: Radical Empiricism and Ethnographic Inquiry. Bloomington: Indiana University Press.
- MedTerms. 3 January 2001. "Sensorium - Medical Dictionary." Accessed 15 April 2004.
- Ong, Walter J. 1991. The Shifting Sensorium. In The Varieties of Sensory Experience. David Howes, ed. Toronto: University of Toronto Press. Pp. 47-60.
- Simon, B., ed. 1957. Psychology in the Soviet Union. Stanford: Stanford University Press.
- Stoller, Paul. 1989. The Taste of Ethnographic Things: The Senses in Anthropology. Philadelphia: University of Pennsylvania Press.
- Trippy, Dr. 2006 "Dr Trippy's Sensorium." This is a website dedicated to the study of the human sensorium and social organisation. | Sensorium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The term sensorium (plural: sensoria) refers to the sum of an organism's perception, the "seat of sensation" where it experiences and interprets the environments within which it lives. The term originally enters English from the Late Latin in the mid-17th century, from the stem sens- (see: sense). In earlier use it referred, in a broader sense, to the brain as the mind's organ (Oxford English Dictionary 1989). In medical, psychological, and physiological discourse it has come to refer to the total character of the unique and changing sensory environments perceived by individuals. These include the sensation, perception, and interpretation of information about the world by senses, perceptual systems and minds (MedTerms 2001).
# Ratios of sensation
In the 20th-century the concept behind the sensorium became a key part of the cultural theories of Marshall McLuhan, Edmund Carpenter and Walter J. Ong (Carpenter and McLuhan 1960; Ong 1991).
McLuhan, like his mentor Harold Innis, believed that media were biased according to time and space. He paid particular attention to what he called the sensorium, or the effects of media on our senses, positing that media affect us by manipulating the ratio of our senses. For example, the alphabet stresses the sense of sight, which in turn causes us to think in linear, objective terms: the medium of the alphabet thus has the effect of reshaping the way in which we, collectively and individually, perceive and understand our environment. [1]
Focusing on variations in the sensorium across social contexts, these theorists collectively suggest that the world is explained and experienced differently depending on the specific "ratios of sense" that members of a culture share in the sensoria they learn to inhabit (Howes 1991, p. 8). More recent work has demonstrated that individuals may include in their unique sensoria perceptual proclivities that exceed their cultural norms; even when, as in the history of smell in the West, the sense in question is suppressed or mostly ignored (Classen, Howes and Synnott 1994).
This interplay of various ways of conceiving the world could be compared to the experience of synesthesia, where stimulus of one sense causes a perception by another, seemingly unrelated sense, as in musicians who can taste the intervals between notes they hear (Beeli et al., 2005), or artists who can smell colours. Many individuals who have one or more senses restricted or lost develop a sensorium with a ratio of sense which favours those they possess more fully. Frequently the blind or deaf speak of a compensating effect, whereby their touch or smell become more acute, changing the ways they perceive and reason about the world; especially telling examples are found in the cases of 'wild children,' whose early childhoods were spent in abusive, neglected or non-human environments, both intensifying and minimizing perceptual abilities (Classen 1991).
# Development of unique sensoria in cultures and individuals
Although some consider these modalities abnormal, it is more likely that these examples demonstrate the contextual and socially learned nature of sensation. A 'normal' sensorium and a 'synesthetic' one differ based on the division, connection, and interplay of the body's manifold sensory apparatus. A synesthete has simply developed a different set of relationships, including cognitive or interpretive skills which deliver unique abilities and understanding of the world (Beeli et al., 2005). The sensorium is a creation of the physical, biological, social and cultural environments of the individual organism and its relationships while being in the world.
What is considered a strange blurring of sensation from one perspective, is a normal and 'natural' way of perception of the world in another, and indeed many individuals and their cultures develop sensoria fundamentally different from the vision-centric modality of most Western science and culture. One revealing contrast is the thought of a former Russian on the matter:
As David Howes explains:
# Sensory ecology and anthropology
These sorts of insights were the impetus for the development of the burgeoning field of sensory anthropology, which seeks to understand other cultures from within their own unique sensoria. Anthropologists such as Paul Stoller (1989) and Michael Jackson (1983, 1989) have focused on a critique of the hegemony of vision and textuality in the social sciences. They argue persuasively for an understanding and analysis that is embodied, one sensitive to the unique context of sensation of those one wishes to understand. They believe that a thorough awareness and adoption of other sensoria is a key requirement if ethnography is to approach true understanding.
A related area of study is sensory (or perceptual) ecology. This field aims at understanding the unique sensory and interpretive systems all organisms develop, based on the specific ecological environments they live in, experience and adapt to. A key researcher in this field has been psychologist James J. Gibson, who has written numerous seminal volumes considering the senses in terms of holistic, self-contained perceptual systems. These exhibit their own mindful, interpretive behaviour, rather than acting simply as conduits delivering information for cognitive processing, as in more representational philosophies of perception or theories of psychology (1966, 1979). Perceptual systems detect affordances in objects in the world, directing attention towards information about an object in terms of the possible uses it affords an organism.
The individual sensory systems of the body are only parts of these broader perceptual ecologies, which include the physical apparatus of sensation, the environment being sensed, as well as both learned and innate systems for directing attention and interpreting the results. These systems represent and enact the information (as an influence which leads to a transformation) required to perceive, identify or reason about the world, and are distributed across the very design and structures of the body, in relation to the physical environment, as well as in the concepts and interpretations of the mind. This information varies according to species, physical environment, and the context of information in the social and cultural systems of perception, which also change over time and space, and as an individual learns through living. Any single perceptual modality may include or overlap multiple sensory structures, as well as other modes of perception, and the sum of their relations and the ratio of mixture and importance comprise a sensorium. The perception, understanding, and reasoning of an organism is dependent on the particular experience of the world delivered by changing ratios of sense.
# Clouded Sensorium
A "clouded sensorium" is a medical term used to describe an inability to think clearly or concentrate. It is associated with a huge variety of underlying causes from drug induced states to pathogenic states induced by disease or mineral deficiency.
# Footnotes
- ↑ Old Messengers, New Media: The Legacy of Innis and McLuhan, a virtual museum exhibition at Library and Archives Canada
# Further reading
- "Sensorium." 1989. Oxford English Dictionary. J.A. Simpson and E.S.C. Weiner, eds. 2nd ed. Oxford: Clarendon Press. OED Online. Oxford University Press. Accessed 15 April 2005. http://oed.com/cgi/entry/50219915 <subscription required>
- Anonymous. 1953. "Russian Sensory Images." In The Study of Culture at a Distance, Margaret Mead and Rhoda Métraux, eds. Chicago: University of Chigago Press. Pp. 162-69.
- Beeli, Gian, Michaela Esslen and Lutz Jäncke. 2005. "Synaesthesia: When Coloured Sounds Taste Sweet." Nature 434 (38). <http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v434/n7029/full/434038a_fs.html>. Accessed 15 April 2005.
- Carpenter, Edmund and Marshall McLuhan, eds. 1960. Explorations in Communication. Boston: Beacon Press.
- Classen, Constance. 1991. The Sensory Orders of 'Wild Children.' In The Varieties of Sensory Experience. David Howes, ed. Toronto: University of Toronto Press. Pp. 47-60.
- Classen, Constance, David Howes and Anthony Synott. 1994. Aroma: The Cultural History of Smell. London and New York: Routledge.
- Gibson, James J. 1966. The Senses Considered as Perceptual Systems. Boston: Houghton Mifflin.
- Gibson, James J. 1979. The Ecological Approach to Visual Perception. Boston: Houghton Mifflin.
- Howes, David, ed. 1991. The Varieties of Sensory Experience. Toronto: University of Toronto Press.
- Howes, David. 2003. Sensual Relations: Engaging the Senses in Culture and Social Theory. Ann Arbor, MI: University of Michigan Press.
- Jackson, Michael. 1983. "Thinking through the Body: An Essay on Understanding Metaphor." Social Analysis 14:127-48.
- Jackson, Michael. 1989. Paths toward a Clearing: Radical Empiricism and Ethnographic Inquiry. Bloomington: Indiana University Press.
- MedTerms. 3 January 2001. "Sensorium - Medical Dictionary." Accessed 15 April 2004.
- Ong, Walter J. 1991. The Shifting Sensorium. In The Varieties of Sensory Experience. David Howes, ed. Toronto: University of Toronto Press. Pp. 47-60.
- Simon, B., ed. 1957. Psychology in the Soviet Union. Stanford: Stanford University Press.
- Stoller, Paul. 1989. The Taste of Ethnographic Things: The Senses in Anthropology. Philadelphia: University of Pennsylvania Press.
- Trippy, Dr. 2006 "Dr Trippy's Sensorium." This is a website dedicated to the study of the human sensorium and social organisation.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Clouded_sensorium | |
1b336d8e4559e9280b322551005add46458ac4a5 | wikidoc | Clusterin | Clusterin
Clusterin (apolipoprotein J) is a 75 - 80 kDa disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis. In humans, clusterin is encoded by the CLU gene on chromosome 8. CLU is a molecular chaperone responsible for aiding protein folding of secreted proteins, and its three isoforms have been differentially implicated in pro- or antiapoptotic processes. Through this function, CLU is involved in many diseases related to oxidative stress, including neurodegenerative diseases, cancers, inflammatory diseases, and aging.
# Structure
The CLU gene contains nine exons and expresses three isoforms alternatively-spliced at the first exon. The encoded protein isoforms all localize to different subcellular compartments: one isoform localizes to the nucleus; a second isoform localizes to the cytoplasm; and the third is secreted from the cell. They also perform opposing functions: the nuclear CLU binds Ku70 to release BAX and induce apoptosis, whereas the cytosolic and secretory isoforms inhibit apoptosis. The nuclear isoform encodes a 49 kDa protein, while the secretory isoform, which is the main gene transcript, encodes a 75–80 kDa protein after maturation (glycosylation, secretion, and dimerization). The mature protein is a 449-residue, heterodimeric, disulfide-linked glycoprotein composed of two subunits of 40 kDa α- and β-chains.
# Function
Clusterin was first identified in ram rete testis fluid where it showed signs of clustering with rat sertoli cells and erythrocytes, hence its name.
CLU is a member of the small heat shock protein family and, thus, a molecular chaperone. Unlike most other chaperone proteins, which aid intracellular proteins, CLU is a Golgi chaperone that facilitates the folding of secreted proteins in an ATP-independent way. The gene is highly conserved in species, and the protein is widely distributed in many tissues and organs, where it participates in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement-mediated cell lysis. Overexpression of the secretory CLU isoform protects the cell from apoptosis induced by cellular stress, such as chemotherapy, radiotherapy, or androgen/estrogen depletion. CLU promotes cell survival by a number of means, including inhibition of BAX on the mitochondrial membrane, activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, modulation of extracellularular signal-regulated kinase (ERK) 1/2 signaling and matrix metallopeptidase-9 expression, promotion of angiogenesis, and mediation of the nuclear factor kappa B (NF-κB) pathway. Meanwhile, its downregulation allows for p53 activation, which then skews the proapoptotic:antiapoptotic ratio of present Bcl-2 family members, resulting in mitochondrial dysfunction and cell death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade.
# Clinical associations
Two independent genome-wide association studies found a statistical association between a SNP within the clusterin gene and the risk of having Alzheimer's disease. Further studies have suggested that people who already have Alzheimer's disease have more clusterin in their blood, and that clusterin levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease, but have not found that clusterin levels predicted the onset of Alzheimer's disease. In addition to Alzheimer’s disease, CLU is involved in other neurodegenerative diseases such as Huntington disease.
CLU may promote tumorigenesis by facilitating BAX-KLU70 binding and, consequently, preventing BAX from localizing to the outer mitochondrial membrane to stimulate cell death. In clear cell renal cell carcinoma, CLU functions to regulate ERK 1/2 signaling and matrix metallopeptidase-9 expression to promote tumor cell migration, invasion, and metastasis. In epithelial ovarian cancer, CLU has been observed to promote angiogenesis and chemoresistance. Other pathways CLU participates in to downplay apoptosis in tumor cells include the PI3K/AKT/mTOR pathway and NF-κB pathway. Unlike most other cancers, which feature upregulated CLU levels to enhance tumor cell survival, testicular seminoma features downregulated CLU levels, allowing for increased sensitivity to chemotherapy treatments. Other cancers CLU has been implicated in include breast cancer, pancreatic cancer, hepatocellular carcinoma, and melanoma.
As evident by its key roles in cancer development, CLU can serve as a therapeutic target for fighting tumor growth and chemoresistance. Studies revealed that inhibition of CLU resulted in increased effectiveness of chemotherapeutic agents to kill tumor cells. In particular, custirsen, an antisense oligonucleotide that blocks the CLU mRNA transcript, enhanced heat-shock protein 90 (HSP90) inhibitor activity by suppressing the heat-shock response in castrate-resistant prostate cancer, and is currently in phase III trials.
CLU activity is also involved in infectious diseases, such as hepatitis C. CLU is induced by the stress of hepatitis C viral infection, which disrupts glucose regulation. The chaperone protein then aids hepatitis C viral assembly by stabilizing its core and NS5A units. CLU expression in the kidney also plays a role in renal diseases, such as nephropathic cystinosis, which is a major cause of Fanconi syndrome. In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction.
# Interactions
CLU has been shown to interact with Ku70. | Clusterin
Clusterin (apolipoprotein J) is a 75 - 80 kDa disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis.[1] In humans, clusterin is encoded by the CLU gene on chromosome 8.[2] CLU is a molecular chaperone responsible for aiding protein folding of secreted proteins, and its three isoforms have been differentially implicated in pro- or antiapoptotic processes. Through this function, CLU is involved in many diseases related to oxidative stress, including neurodegenerative diseases, cancers, inflammatory diseases, and aging.[3][4][5]
# Structure
The CLU gene contains nine exons and expresses three isoforms alternatively-spliced at the first exon.[3] The encoded protein isoforms all localize to different subcellular compartments: one isoform localizes to the nucleus; a second isoform localizes to the cytoplasm; and the third is secreted from the cell.[3][5] They also perform opposing functions: the nuclear CLU binds Ku70 to release BAX and induce apoptosis, whereas the cytosolic and secretory isoforms inhibit apoptosis.[3][4] The nuclear isoform encodes a 49 kDa protein, while the secretory isoform, which is the main gene transcript, encodes a 75–80 kDa protein after maturation (glycosylation, secretion, and dimerization).[3][4] The mature protein is a 449-residue, heterodimeric, disulfide-linked glycoprotein composed of two subunits of 40 kDa α- and β-chains.[3][4][5]
# Function
Clusterin was first identified in ram rete testis fluid where it showed signs of clustering with rat sertoli cells and erythrocytes, hence its name.[6]
CLU is a member of the small heat shock protein family and, thus, a molecular chaperone. Unlike most other chaperone proteins, which aid intracellular proteins, CLU is a Golgi chaperone that facilitates the folding of secreted proteins in an ATP-independent way.[5] The gene is highly conserved in species, and the protein is widely distributed in many tissues and organs, where it participates in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement-mediated cell lysis.[3][4][5] Overexpression of the secretory CLU isoform protects the cell from apoptosis induced by cellular stress, such as chemotherapy, radiotherapy, or androgen/estrogen depletion. CLU promotes cell survival by a number of means, including inhibition of BAX on the mitochondrial membrane, activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, modulation of extracellularular signal-regulated kinase (ERK) 1/2 signaling and matrix metallopeptidase-9 expression, promotion of angiogenesis, and mediation of the nuclear factor kappa B (NF-κB) pathway. Meanwhile, its downregulation allows for p53 activation, which then skews the proapoptotic:antiapoptotic ratio of present Bcl-2 family members, resulting in mitochondrial dysfunction and cell death. p53 may also transcriptionally repress secretory CLU to further promote the proapoptotic cascade.[3]
# Clinical associations
Two independent genome-wide association studies found a statistical association between a SNP within the clusterin gene and the risk of having Alzheimer's disease. Further studies have suggested that people who already have Alzheimer's disease have more clusterin in their blood, and that clusterin levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease, but have not found that clusterin levels predicted the onset of Alzheimer's disease.[7][8][9][10] In addition to Alzheimer’s disease, CLU is involved in other neurodegenerative diseases such as Huntington disease.[4]
CLU may promote tumorigenesis by facilitating BAX-KLU70 binding and, consequently, preventing BAX from localizing to the outer mitochondrial membrane to stimulate cell death. In clear cell renal cell carcinoma, CLU functions to regulate ERK 1/2 signaling and matrix metallopeptidase-9 expression to promote tumor cell migration, invasion, and metastasis. In epithelial ovarian cancer, CLU has been observed to promote angiogenesis and chemoresistance. Other pathways CLU participates in to downplay apoptosis in tumor cells include the PI3K/AKT/mTOR pathway and NF-κB pathway. Unlike most other cancers, which feature upregulated CLU levels to enhance tumor cell survival, testicular seminoma features downregulated CLU levels, allowing for increased sensitivity to chemotherapy treatments. Other cancers CLU has been implicated in include breast cancer, pancreatic cancer, hepatocellular carcinoma, and melanoma.
As evident by its key roles in cancer development, CLU can serve as a therapeutic target for fighting tumor growth and chemoresistance. Studies revealed that inhibition of CLU resulted in increased effectiveness of chemotherapeutic agents to kill tumor cells.[3] In particular, custirsen, an antisense oligonucleotide that blocks the CLU mRNA transcript, enhanced heat-shock protein 90 (HSP90) inhibitor activity by suppressing the heat-shock response in castrate-resistant prostate cancer, and is currently in phase III trials.[3][5]
CLU activity is also involved in infectious diseases, such as hepatitis C. CLU is induced by the stress of hepatitis C viral infection, which disrupts glucose regulation. The chaperone protein then aids hepatitis C viral assembly by stabilizing its core and NS5A units.[5] CLU expression in the kidney also plays a role in renal diseases, such as nephropathic cystinosis, which is a major cause of Fanconi syndrome.[4] In addition to the above diseases, CLU has been linked to other conditions resulting from oxidative damage, including aging, glomerulonephritis, atherosclerosis, and myocardial infarction.[4][5]
# Interactions
CLU has been shown to interact with Ku70.[3] | https://www.wikidoc.org/index.php/Clusterin | |
a068641f859eeac71db36df3f3251f71df4242fe | wikidoc | Cobalt-60 | Cobalt-60
Cobalt-60 (60Co) is a radioactive isotope of cobalt, with a half life of 5.27 years. 60Co decays by negative beta decay to the stable isotope nickel-60 (60Ni). In the process of decay, 60Co emits one electron with an energy of up to 315 keV and then two gamma rays with energies of 1.17 and 1.33 MeV, respectively.
One gram of 60Co contains approximately 50 curies (1.85 terabecquerels) of radioactivity. With a point source at a range of 1 m, this amount of 60Co would give a person a radiation dose of 0.5 sievert (50 rem) per hour.
60Co has seven main beneficial uses:
- As a tracer for cobalt in chemical reactions,
- Sterilization of medical equipment,
- Radiation source for medical radiotherapy,
- Radiation source for industrial radiography,
- Radioactive source for leveling devices and thickness gauges,
- As a radioactive source for food irradiation and blood irradiation, and
- As a radioactive source for laboratory use.
The creation of 60Co is an important step in nucleosynthesis. Without the 60Co step, no elements from number 27 through 83 would be created in supernovas. Artificial 60Co is created by bombarding a 59Co target with a slow neutron source, usually 252Cf moderated through water to slow the neutrons down, or in a nuclear reactor such as CANDU, where adjuster rods usually made of steel are instead made of Co-59. 60Co is also the active isotope in a so-called cobalt bomb, a form of nuclear weapon.
# Excretion
After entering a living mammal (such as a human), most of the 60Co gets excreted in feces. A small amount is absorbed by liver, kidneys, and bones, where the prolonged exposure to gamma radiation can cause cancer.
# Incidents
Accidental mixing of radioactive sources containing cobalt with metal scrap can result in production of radioactive steel. An example was the radiation accident from December 6 1983 in Mexico, where a discarded radiation therapy source caused contamination of 5,000 metric tons of steel. Another example of Co-60 contamination is the March 1, 2008 incident at the Italian port of La Spezia, where a cargo ship from China was found to contain 30 tons of steel contaminated by 60Co. | Cobalt-60
Template:This
Cobalt-60 (60Co) is a radioactive isotope of cobalt, with a half life of 5.27 years. 60Co decays by negative beta decay to the stable isotope nickel-60 (60Ni). In the process of decay, 60Co emits one electron with an energy of up to 315 keV and then two gamma rays with energies of 1.17 and 1.33 MeV, respectively.
One gram of 60Co contains approximately 50 curies (1.85 terabecquerels) of radioactivity. With a point source at a range of 1 m, this amount of 60Co would give a person a radiation dose of 0.5 sievert (50 rem) per hour.
60Co has seven main beneficial uses:
- As a tracer for cobalt in chemical reactions,
- Sterilization of medical equipment,
- Radiation source for medical radiotherapy,
- Radiation source for industrial radiography,
- Radioactive source for leveling devices and thickness gauges,
- As a radioactive source for food irradiation and blood irradiation, and
- As a radioactive source for laboratory use.
The creation of 60Co is an important step in nucleosynthesis. Without the 60Co step, no elements from number 27 through 83 would be created in supernovas. [1] Artificial 60Co is created by bombarding a 59Co target with a slow neutron source, usually 252Cf moderated through water to slow the neutrons down, or in a nuclear reactor such as CANDU, where adjuster rods usually made of steel are instead made of Co-59.[2] 60Co is also the active isotope in a so-called cobalt bomb, a form of nuclear weapon.
## Excretion
After entering a living mammal (such as a human), most of the 60Co gets excreted in feces. A small amount is absorbed by liver, kidneys, and bones, where the prolonged exposure to gamma radiation can cause cancer.
## Incidents
Accidental mixing of radioactive sources containing cobalt with metal scrap can result in production of radioactive steel. An example was the radiation accident from December 6 1983 in Mexico, where a discarded radiation therapy source caused contamination of 5,000 metric tons of steel. Another example of Co-60 contamination is the March 1, 2008 incident at the Italian port of La Spezia, where a cargo ship from China was found to contain 30 tons of steel contaminated by 60Co[3][4].
# External links
- Cobalt-60, Environmental Protection Agency.
- National Pollutant Inventory - Cobalt fact sheet
- Cobalt-60, Oak Ridge National Laboratory.
- Cobalt-60, Centers for Disease Control and Prevention.
- NLM Hazardous Substances Databank – Cobalt, Radioactive
- Beta decay of Cobalt-60, HyperPhysics, Georgia State University.
- Dr. Henry Kelly. Cobalt-60 as a Dirty Bomb, Federation of American Scientists, March 6 2002.
- Sequestrato acciaio radioattivo contaminato da cobalto, ItalyGlobalNation
- Italians seize 30 tons of radioactive steel, USA Today
mk:Кобалт-60
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cobalt-60 | |
8ba37f88705e18a7e15cb154d395979745ad3298 | wikidoc | Cochineal | Cochineal
Cochineal is the name of both crimson or carmine dye and the cochineal insect (Dactylopius coccus), a scale insect in the suborder Sternorrhyncha, from which the dye is derived. There are other species in the genus Dactylopius which can be used to produce cochineal extract, but they are extremely difficult to distinguish from D. coccus, even for expert taxonomists, and the latter scientific name (and the use of the term "cochineal insect") is therefore commonly used when one is actually referring to other biological species; suffice it to say that the reader should be aware that there is more than one cochineal insect. The primary biological distinctions between species are minor differences in host plant preferences, in addition to very different geographic distributions. D. coccus itself is native to tropical and subtropical South America and Mexico.
This type of insect, a primarily sessile parasite, lives on cacti from the genus Opuntia, feeding on moisture and nutrients in the cacti. The insect produces carminic acid which deters predation by other insects. Carminic acid can be extracted from the insect's body and eggs to make the dye. Cochineal is primarily used as a food colouring and for cosmetics.
After synthetic pigments and dyes such as alizarin were invented in the late 19th century, natural-dye production gradually diminished. However, current health concerns over artificial food additives have renewed the popularity of cochineal dyes, and the increased demand has made cultivation of the insect profitable again.
# History
The cochineal dye was used by the Aztec and Maya peoples of Central and North America. Eleven cities conquered by Montezuma in the 15th century paid a yearly tribute of 2000 decorated cotton blankets and 40 bags of cochineal dye each. During the colonial period the production of cochineal (grana fina) grew rapidly. Produced almost exclusively in Oaxaca, Mexico by indigenous producers, cochineal became Mexico's second most valued export after silver. The dyestuff was consumed throughout Europe and was so highly prized that its price was regularly quoted on the London and Amsterdam Commodity Exchanges.
After the Mexican War of Independence in 1810–1821, the Mexican monopoly on cochineal came to an end. Large scale production of cochineal emerged especially in Guatemala and the Canary Islands. The demand for cochineal fell sharply with the appearance on the market of alizarin crimson and many other artificial dyes discovered in Europe in the middle of the 19th century, causing a significant financial shock in Spain as a major industry almost ceased to exist. The delicate manual labor required for the breeding of the insect could not compete with the modern methods of the new industry and even less so with the lowering of production costs. The "tuna blood" dye (from the Mexican name for the Opuntia fruit) stopped being used and trade in cochineal almost totally disappeared in the course of the 20th century. The breeding of the cochineal insect has been done mainly for the purposes of maintaining the tradition rather than to satisfy any sort of demand.
In recent years it has become commercially valuable again, though most consumers are unaware that the phrases "cochineal extract", "carmine", "crimson lake", "natural red 4", "C.I. 75470", "E120", or even "natural colouring" refer to a dye that is derived from an insect. One reason for its popularity is that, unlike many commercial synthetic red dyes, it is not toxic or carcinogenic. However, the dye can induce an anaphylactic shock reaction in a small number of people.
# Biology
Cochineal insects are soft-bodied, flat, oval-shaped scale insects. The females, wingless and about 5 mm (0.2 in) long, cluster on cactus pads. They penetrate the cactus with their beak-like mouthparts and feed on its juices, remaining immobile. After mating, the fertilized female increases in size and gives birth to tiny nymphs. The nymphs secrete a waxy white substance over their bodies for protection from water and excessive sun. This substance makes the cochineal insect appear white or grey from the outside, though the body of the insect and its nymphs produces the red pigment, which makes the insides of the insect look dark purple. Adult males can be distinguished from females by their diminutive size and their wings.
It is in the nymph stage (also called the crawler stage) that the cochineal disperses. The juveniles move to a feeding spot and produce long wax filaments. Later they move to the edge of the cactus pad where the wind catches the wax filaments and carries the cochineals to a new host. These individuals establish feeding sites on the new host and produce a new generation of cochineals. Male nymphs feed on the cactus until they reach sexual maturity; when they mature they cannot feed at all and live only long enough to fertilize the eggs. They are therefore seldom observed.
## Host cacti
Dactylopius coccus is native to tropical and subtropical South America and Mexico, where their host cacti grow natively. They have been introduced to Spain, the Canary Islands, Algiers and Australia along with their host cacti; and Eritrea, where their host cacti were already abundant. There are 150 species of Opuntia cacti, and while it is possible to cultivate cochineal on almost all of them, the best to use is Opuntia ficus-indica. All of the host plants of cochineal colonies were identified as species of Opuntia including Opuntia amyclaea, O. atropes, O. cantabrigiensis, O. brasilienis, O. ficus-indica, O. fuliginosa, O. jaliscana, O. leucotricha, O. lindheimeri, O. microdasys, O. megacantha, O. pilifera, O. robusta, O. sarca, O. schikendantzii, O. stricta, O. streptacantha, and O. tomentosa. Feeding cochineals can damage the cacti, sometimes killing their host. Cochineals other than D. coccus will feed on many of the same Opuntia species, and it is likely that the wide range of hosts reported for the former species is because of the difficulty in distinguishing it from these other, less common species.
# Farming
There are two methods of farming cochineal: traditional and controlled. Cochineals are farmed in the traditional method by planting infected cactus pads or infecting existing cacti with cochineals and harvesting the insects by hand. The controlled method uses small baskets called Zapotec nests placed on host cacti. The baskets contain clean, fertile females which leave the nests and settle on the cactus to await insemination by the males. In both cases the cochineals have to be protected from predators, cold and rain. The complete cycle lasts 3 months during which the cacti are kept at a constant temperature of 27 °C. Once the cochineals have finished the cycle, the new cochineals are ready to begin the cycle again or to be dried for dye production.
To produce dye from cochineals, the insects are collected when they are approximately ninety days old. Harvesting the insects is labor-intensive as they must be individually knocked, brushed or picked from the cacti and placed into bags. The insects are gathered by small groups of collectors who sell them to local processors or exporters.
Several natural enemies can reduce the population of the insect on its cacti hosts. Of all the predators, insects seem to be the most important group. Insects and their larvae such as pyralid moths (order Lepidoptera), which destroy the cactus, and predators such as lady bugs (Coleoptera), various Diptera (such as Syrphidae and Chamaemyiidae), lacewings (Neuroptera) and ants (Hymenoptera) have been identified, as well as numerous parasitic wasps. Many birds; human-commensal rodents, especially rats; and reptiles also prey on cochineal insects. In regions dependent on cochineal production, pest control measures have to be taken seriously. For small-scale cultivation manual methods of control have proved to be the most effective and safe. For large-scale cultivation advanced pest control methods have to be developed, including alternative bioinsecticides or traps with pheromones.
## Farming in Australia
Prickly pear was first taken to Australia to start a cochineal dye industry in 1788, when Captain Arthur Phillip collected a number of cochineal-infested plants from Brazil on his way to establish the first European settlement at Botany Bay (part of which is now Sydney, New South Wales). At that time, Spain and Portugal had a world-wide monopoly (via their New World colonial sources) on the cochineal dye industry, and the British desired a source under their own control, as the dye was important to their clothing and garment industries (it was used to colour the British soldiers' red coats, for example).
# Dye
A deep crimson dye is extracted from the female cochineal insects. Cochineal is used to produce scarlet, orange and other red tints. The colouring comes from carminic acid. Cochineal extract's natural carminic-acid content is usually 19–22%. The insects are killed by immersion in hot water (after which they are dried) or by exposure to sunlight, steam, or the heat of an oven. Each method produces a different colour which results in the varied appearance of commercial cochineal. The insects must be dried to about 30 percent of their original body weight before they can be stored without decaying. It takes about 155,000 insects to make one kilogram of cochineal.
There are two principal forms of cochineal dye: cochineal extract is a colouring made from the raw dried and pulverised bodies of insects, and carmine is a more purified colouring made from the cochineal. To prepare carmine, the powdered insect bodies are boiled in ammonia or a sodium carbonate solution, the insoluble matter is removed by filtering, and alum is added to the clear salt solution of carminic acid to precipitate the red aluminium salt. Purity of colour is ensured by the absence of iron. Stannous chloride, citric acid, borax, or gelatin may be added to regulate the formation of the precipitate. For shades of purple, lime is added to the alum.
As of 2005, Peru produced 200 tonnes of cochineal dye per year and the Canary Islands produced 20 tonnes per year. Chile and Mexico have also recently begun to export cochineal. France is believed to be the world's largest importer of cochineal; Japan and Italy also import the insect. Much of these imports are processed and reexported to other developed economies. As of 2005, the market price of cochineal was between 50 and 80 USD per kilogram, while synthetic raw food dyes are available at prices as low as 10–20 USD per kilogram.
## Usage
Traditionally cochineal was used for colouring fabrics. During the colonial period, with the introduction of sheep to Latin America, the use of cochineal increased, as it provided the most intense colour and it set more firmly on woolen garments than on clothes made of materials of pre-Hispanic origin such as cotton, agave fibers and yucca fibers. Once the European market had discovered the qualities of this product, their demand for it increased dramatically. Carmine became strong competition for other colourants such as madder root, kermes, Polish cochineal, brazilwood, and Tyrian purple, as they were used for dyeing the clothes of kings, nobles and the clergy. It was also used for painting, handicrafts and tapestries. Cochineal-coloured wool and cotton are still important materials for Mexican folk art and crafts.
Now it is used as a fabric and cosmetics dye and as a natural food colouring, as well as for oil paints, pigments and watercolours. When used as a food additive, the dye must be labelled on packaging labels. Sometimes carmine is labelled as E120. An unknown percentage of people have been found to have allergies to carmine, ranging from mild cases of hives to atrial fibrillation and anaphylactic shock. Carmine has been found to cause asthma in some people. Cochineal is one of the colours that the Hyperactive Children's Support Group recommends be eliminated from the diet of hyperactive children. Natural carmine dye used in food and cosmetics can render it unacceptable to strict vegetarian consumers, and many Muslims and Jews consider carmine-containing food forbidden (haraam and treif) because the dye is extracted from insects.
Cochineal is one of the few water-soluble colourants that resist degradation with time. It is one of the most light- and heat-stable and oxidation-resistant of all the natural colourants and is even more stable than many synthetic food colours. The water-soluble form is used in alcoholic drinks with calcium carmine; the insoluble form is used in a wider variety of products. Together with ammonium carmine they can be found in meat, sausages, processed poultry products (meat products cannot be coloured in the United States unless they are labeled as such), surimi, marinades, alcoholic drinks, bakery products and toppings, cookies, desserts, icings, pie fillings, jams, preserves, gelatin desserts, juice beverages, varieties of cheddar cheese and other dairy products, sauces and sweets. The average human consumes one to two drops of carminic acid each year with food.
Carmine is one of the very few pigments considered safe enough for use in eye cosmetics. A significant proportion of the insoluble carmine pigment produced is used in the cosmetics industry for hair- and skin-care products, lipsticks, face powders, rouges, and blushes. A bright red dye and the stain carmine used in microbiology is often made from the carmine extract, too. The pharmaceutical industry uses cochineal to colour pills and ointments. | Cochineal
Cochineal is the name of both crimson or carmine dye and the cochineal insect (Dactylopius coccus), a scale insect in the suborder Sternorrhyncha, from which the dye is derived. There are other species in the genus Dactylopius which can be used to produce cochineal extract, but they are extremely difficult to distinguish from D. coccus, even for expert taxonomists, and the latter scientific name (and the use of the term "cochineal insect") is therefore commonly used when one is actually referring to other biological species; suffice it to say that the reader should be aware that there is more than one cochineal insect. The primary biological distinctions between species are minor differences in host plant preferences, in addition to very different geographic distributions. D. coccus itself is native to tropical and subtropical South America and Mexico.
This type of insect, a primarily sessile parasite, lives on cacti from the genus Opuntia, feeding on moisture and nutrients in the cacti. The insect produces carminic acid which deters predation by other insects. Carminic acid can be extracted from the insect's body and eggs to make the dye. Cochineal is primarily used as a food colouring and for cosmetics.
After synthetic pigments and dyes such as alizarin were invented in the late 19th century, natural-dye production gradually diminished. However, current health concerns over artificial food additives have renewed the popularity of cochineal dyes, and the increased demand has made cultivation of the insect profitable again.[1]
# History
The cochineal dye was used by the Aztec and Maya peoples of Central and North America. Eleven cities conquered by Montezuma in the 15th century paid a yearly tribute of 2000 decorated cotton blankets and 40 bags of cochineal dye each.[2] During the colonial period the production of cochineal (grana fina) grew rapidly. Produced almost exclusively in Oaxaca, Mexico by indigenous producers, cochineal became Mexico's second most valued export after silver.[3] The dyestuff was consumed throughout Europe and was so highly prized that its price was regularly quoted on the London and Amsterdam Commodity Exchanges.
After the Mexican War of Independence in 1810–1821, the Mexican monopoly on cochineal came to an end. Large scale production of cochineal emerged especially in Guatemala and the Canary Islands. The demand for cochineal fell sharply with the appearance on the market of alizarin crimson and many other artificial dyes discovered in Europe in the middle of the 19th century, causing a significant financial shock in Spain as a major industry almost ceased to exist.[3] The delicate manual labor required for the breeding of the insect could not compete with the modern methods of the new industry and even less so with the lowering of production costs. The "tuna blood" dye (from the Mexican name for the Opuntia fruit) stopped being used and trade in cochineal almost totally disappeared in the course of the 20th century. The breeding of the cochineal insect has been done mainly for the purposes of maintaining the tradition rather than to satisfy any sort of demand.[4]
In recent years it has become commercially valuable again,[5] though most consumers are unaware that the phrases "cochineal extract", "carmine", "crimson lake", "natural red 4", "C.I. 75470", "E120", or even "natural colouring" refer to a dye that is derived from an insect. One reason for its popularity is that, unlike many commercial synthetic red dyes, it is not toxic or carcinogenic. However, the dye can induce an anaphylactic shock reaction in a small number of people.[6]
# Biology
Cochineal insects are soft-bodied, flat, oval-shaped scale insects. The females, wingless and about 5 mm (0.2 in) long, cluster on cactus pads. They penetrate the cactus with their beak-like mouthparts and feed on its juices, remaining immobile. After mating, the fertilized female increases in size and gives birth to tiny nymphs. The nymphs secrete a waxy white substance over their bodies for protection from water and excessive sun. This substance makes the cochineal insect appear white or grey from the outside, though the body of the insect and its nymphs produces the red pigment, which makes the insides of the insect look dark purple. Adult males can be distinguished from females by their diminutive size and their wings.
It is in the nymph stage (also called the crawler stage) that the cochineal disperses. The juveniles move to a feeding spot and produce long wax filaments. Later they move to the edge of the cactus pad where the wind catches the wax filaments and carries the cochineals to a new host. These individuals establish feeding sites on the new host and produce a new generation of cochineals.[7] Male nymphs feed on the cactus until they reach sexual maturity; when they mature they cannot feed at all and live only long enough to fertilize the eggs.[8] They are therefore seldom observed.[7]
## Host cacti
Dactylopius coccus is native to tropical and subtropical South America and Mexico, where their host cacti grow natively. They have been introduced to Spain, the Canary Islands, Algiers and Australia along with their host cacti; and Eritrea, where their host cacti were already abundant. There are 150 species of Opuntia cacti, and while it is possible to cultivate cochineal on almost all of them, the best to use is Opuntia ficus-indica.[9] All of the host plants of cochineal colonies were identified as species of Opuntia including Opuntia amyclaea, O. atropes, O. cantabrigiensis, O. brasilienis, O. ficus-indica, O. fuliginosa, O. jaliscana, O. leucotricha, O. lindheimeri, O. microdasys, O. megacantha, O. pilifera, O. robusta, O. sarca, O. schikendantzii, O. stricta, O. streptacantha, and O. tomentosa.[1] Feeding cochineals can damage the cacti, sometimes killing their host. Cochineals other than D. coccus will feed on many of the same Opuntia species, and it is likely that the wide range of hosts reported for the former species is because of the difficulty in distinguishing it from these other, less common species.
# Farming
There are two methods of farming cochineal: traditional and controlled. Cochineals are farmed in the traditional method by planting infected cactus pads or infecting existing cacti with cochineals and harvesting the insects by hand. The controlled method uses small baskets called Zapotec nests placed on host cacti. The baskets contain clean, fertile females which leave the nests and settle on the cactus to await insemination by the males. In both cases the cochineals have to be protected from predators, cold and rain. The complete cycle lasts 3 months during which the cacti are kept at a constant temperature of 27 °C. Once the cochineals have finished the cycle, the new cochineals are ready to begin the cycle again or to be dried for dye production.[9]
To produce dye from cochineals, the insects are collected when they are approximately ninety days old. Harvesting the insects is labor-intensive as they must be individually knocked, brushed or picked from the cacti and placed into bags. The insects are gathered by small groups of collectors who sell them to local processors or exporters.[10]
Several natural enemies can reduce the population of the insect on its cacti hosts. Of all the predators, insects seem to be the most important group. Insects and their larvae such as pyralid moths (order Lepidoptera), which destroy the cactus, and predators such as lady bugs (Coleoptera), various Diptera (such as Syrphidae and Chamaemyiidae), lacewings (Neuroptera) and ants (Hymenoptera) have been identified, as well as numerous parasitic wasps. Many birds; human-commensal rodents, especially rats; and reptiles also prey on cochineal insects. In regions dependent on cochineal production, pest control measures have to be taken seriously. For small-scale cultivation manual methods of control have proved to be the most effective and safe. For large-scale cultivation advanced pest control methods have to be developed, including alternative bioinsecticides or traps with pheromones.[1]
## Farming in Australia
Prickly pear was first taken to Australia to start a cochineal dye industry in 1788, when Captain Arthur Phillip collected a number of cochineal-infested plants from Brazil on his way to establish the first European settlement at Botany Bay (part of which is now Sydney, New South Wales). At that time, Spain and Portugal had a world-wide monopoly (via their New World colonial sources) on the cochineal dye industry, and the British desired a source under their own control, as the dye was important to their clothing and garment industries (it was used to colour the British soldiers' red coats, for example).[11]
# Dye
A deep crimson dye is extracted from the female cochineal insects. Cochineal is used to produce scarlet, orange and other red tints. The colouring comes from carminic acid. Cochineal extract's natural carminic-acid content is usually 19–22%.[5] The insects are killed by immersion in hot water (after which they are dried) or by exposure to sunlight, steam, or the heat of an oven. Each method produces a different colour which results in the varied appearance of commercial cochineal. The insects must be dried to about 30 percent of their original body weight before they can be stored without decaying.[10] It takes about 155,000 insects to make one kilogram of cochineal.
There are two principal forms of cochineal dye: cochineal extract is a colouring made from the raw dried and pulverised bodies of insects, and carmine is a more purified colouring made from the cochineal. To prepare carmine, the powdered insect bodies are boiled in ammonia or a sodium carbonate solution, the insoluble matter is removed by filtering, and alum is added to the clear salt solution of carminic acid to precipitate the red aluminium salt. Purity of colour is ensured by the absence of iron. Stannous chloride, citric acid, borax, or gelatin may be added to regulate the formation of the precipitate. For shades of purple, lime is added to the alum.[2]
As of 2005, Peru produced 200 tonnes of cochineal dye per year and the Canary Islands produced 20 tonnes per year.[10][5] Chile and Mexico have also recently begun to export cochineal.[1] France is believed to be the world's largest importer of cochineal; Japan and Italy also import the insect. Much of these imports are processed and reexported to other developed economies.[10] As of 2005, the market price of cochineal was between 50 and 80 USD per kilogram,[9] while synthetic raw food dyes are available at prices as low as 10–20 USD per kilogram.[12]
## Usage
Traditionally cochineal was used for colouring fabrics. During the colonial period, with the introduction of sheep to Latin America, the use of cochineal increased, as it provided the most intense colour and it set more firmly on woolen garments than on clothes made of materials of pre-Hispanic origin such as cotton, agave fibers and yucca fibers. Once the European market had discovered the qualities of this product, their demand for it increased dramatically. Carmine became strong competition for other colourants such as madder root, kermes, Polish cochineal, brazilwood, and Tyrian purple,[13] as they were used for dyeing the clothes of kings, nobles and the clergy. It was also used for painting, handicrafts and tapestries.[4] Cochineal-coloured wool and cotton are still important materials for Mexican folk art and crafts.
Now it is used as a fabric and cosmetics dye and as a natural food colouring, as well as for oil paints, pigments and watercolours. When used as a food additive, the dye must be labelled on packaging labels.[14] Sometimes carmine is labelled as E120. An unknown percentage of people have been found to have allergies to carmine, ranging from mild cases of hives to atrial fibrillation and anaphylactic shock. Carmine has been found to cause asthma in some people.[14] Cochineal is one of the colours that the Hyperactive Children's Support Group recommends be eliminated from the diet of hyperactive children. Natural carmine dye used in food and cosmetics can render it unacceptable to strict vegetarian consumers, and many Muslims and Jews consider carmine-containing food forbidden (haraam and treif) because the dye is extracted from insects.
Cochineal is one of the few water-soluble colourants that resist degradation with time. It is one of the most light- and heat-stable and oxidation-resistant of all the natural colourants and is even more stable than many synthetic food colours.[15] The water-soluble form is used in alcoholic drinks with calcium carmine; the insoluble form is used in a wider variety of products. Together with ammonium carmine they can be found in meat, sausages, processed poultry products (meat products cannot be coloured in the United States unless they are labeled as such), surimi, marinades, alcoholic drinks, bakery products and toppings, cookies, desserts, icings, pie fillings, jams, preserves, gelatin desserts, juice beverages, varieties of cheddar cheese and other dairy products, sauces and sweets. The average human consumes one to two drops of carminic acid each year with food.[15]
Carmine is one of the very few pigments considered safe enough for use in eye cosmetics.[16] A significant proportion of the insoluble carmine pigment produced is used in the cosmetics industry for hair- and skin-care products, lipsticks, face powders, rouges, and blushes.[15] A bright red dye and the stain carmine used in microbiology is often made from the carmine extract, too.[8] The pharmaceutical industry uses cochineal to colour pills and ointments.[10] | https://www.wikidoc.org/index.php/Cochineal | |
dc00cb4d4e9f21193ea6ad255509d9e5d9009e15 | wikidoc | Cofilin-2 | Cofilin-2
Cofilin 2 (muscle) also known as CFL2 is a protein which in humans is encoded by the CFL2 gene.
# Function
Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner. Cofilin-2 is a member of the AC group of proteins that also includes cofilin-1 (CFL1) and destrin (DSTN), all of which regulate actin-filament dynamics. The CFL2 gene encodes a skeletal muscle-specific isoform localized to the thin filaments, where it exerts its effect on actin, in part through interactions with tropomyosins.
# Clinical significance
Mutations in the CFL2 gene are associated with nemaline myopathy. Deficiency of cofilin-2 may result in reduced depolymerization of actin filaments, causing their accumulation in nemaline bodies, minicores, and, possibly concentric laminated bodies. | Cofilin-2
Cofilin 2 (muscle) also known as CFL2 is a protein which in humans is encoded by the CFL2 gene.[1][2]
# Function
Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner.[2] Cofilin-2 is a member of the AC group of proteins that also includes cofilin-1 (CFL1) and destrin (DSTN), all of which regulate actin-filament dynamics.[3][4] The CFL2 gene encodes a skeletal muscle-specific isoform[5] localized to the thin filaments, where it exerts its effect on actin, in part through interactions with tropomyosins.[6]
# Clinical significance
Mutations in the CFL2 gene are associated with nemaline myopathy. Deficiency of cofilin-2 may result in reduced depolymerization of actin filaments, causing their accumulation in nemaline bodies, minicores, and, possibly concentric laminated bodies.[7] | https://www.wikidoc.org/index.php/Cofilin-2 | |
349a68a7c14d4517f8e7b8fedc18e6f12d97e574 | wikidoc | Cofilin 1 | Cofilin 1
Cofilin 1 (non-muscle; n-cofilin), also known as CFL1, is a human gene, part of the ADF/cofilin family.
Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner. It is involved in the translocation of actin-cofilin complex from cytoplasm to nucleus.
One group reports that reelin signaling leads to serine3-phosphorylation of cofilin-1, and this interaction may play a role in the reelin-related regulation of neuronal migration.
# Interactions
Cofilin 1 has been shown to interact with HSPH1 and LIMK1. | Cofilin 1
Cofilin 1 (non-muscle; n-cofilin), also known as CFL1, is a human gene, part of the ADF/cofilin family.
Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner. It is involved in the translocation of actin-cofilin complex from cytoplasm to nucleus.[1]
One group reports that reelin signaling leads to serine3-phosphorylation of cofilin-1, and this interaction may play a role in the reelin-related regulation of neuronal migration.[2][3]
# Interactions
Cofilin 1 has been shown to interact with HSPH1[4] and LIMK1.[5][6] | https://www.wikidoc.org/index.php/Cofilin_1 | |
f706ca0511e3fd448b25d5aaf661ed4410aec36a | wikidoc | Cognition | Cognition
The term cognition is used in different ways by different disciplines. In psychology, it refers to an information processing view of an individual's psychological functions. Other interpretations of the meaning of cognition link it to the development of concepts; individual minds, groups, organizations, and even larger coalitions of entities, can be modelled as societies which cooperate to form concepts. The autonomous elements of each 'society' would have the opportunity to demonstrate emergent behavior in the face of some crisis or opportunity. Cognition can also be interpreted as "understanding and trying to make sense of the world".
# Introduction
The term cognition (Latin: cognoscere, "to know") is used in several loosely related ways to refer to a faculty for the human-like processing of information, applying knowledge and changing preferences. Cognition or cognitive processes can be natural and artificial, conscious and not conscious; therefore, they are analyzed from different perspectives and in different contexts, in anesthesia, neurology, psychology, philosophy, systemics and computer science. The concept of cognition is closely related to such abstract concepts as mind, reasoning, perception, intelligence, learning, and many others that describe numerous capabilities of the human mind and expected properties of artificial or synthetic intelligence. Cognition is an abstract property of advanced living organisms; therefore, it is studied as a direct property of a brain or of an abstract mind on sub-symbolic and symbolic levels.OR
In psychology and in artificial intelligence, it is used to refer to the mental functions, mental processes and states of intelligent entities (humans, human organizations, highly autonomous robots), with a particular focus toward the study of such mental processes as comprehension, inferencing, decision-making, planning and learning (see also cognitive science and cognitivism). Recently, advanced cognitive researchers have been especially focused on the capacities of abstraction, generalization, concretization/specialization and meta-reasoning which descriptions involve such concepts as beliefs, knowledge, desires, preferences and intentions of intelligent individuals/objects/agents/systems.
The term "cognition" is also used in a wider sense to mean the act of knowing or knowledge, and may be interpreted in a social or cultural sense to describe the emergent development of knowledge and concepts within a group that culminates in both thought and action.
# Cognition in mainstream psychology
The sort of mental processes described as cognitive or cognitive processes are largely influenced by research which has successfully used this paradigm in the past. Consequently, this description tends to apply to processes such as memory, attention, perception, action, problem solving and mental imagery. Traditionally, emotion was not thought of as a cognitive process. This division is now regarded as largely artificial, and much research is currently being undertaken to examine the cognitive psychology of emotion; research also includes one's awareness of strategies and methods of cognition, known as metacognition.
Empirical research into cognition is usually scientific and quantitative, or involves creating models to describe or explain certain behaviors.
While few people would deny that cognitive processes are a function of the brain, a cognitive theory will not necessarily make any reference to the brain or any other biological process (compare neurocognitive). It may purely describe behaviour in terms of information flow or function. Relatively recent fields of study such as cognitive science and neuropsychology aim to bridge this gap, using cognitive paradigms to understand how the brain implements these information-processing functions (see also cognitive neuroscience), or how pure information-processing systems (e.g., computers) can simulate cognition (see also artificial intelligence). The branch of psychology that studies brain injury to infer normal cognitive function is called cognitive neuropsychology. The links of cognition to evolutionary demands are studied through the investigation of animal cognition. And conversely, evolutionary-based perspectives can inform hypotheses about cognitive functional systems evolutionary psychology.
The theoretical school of thought derived from the cognitive approach is often called cognitivism.
The phenomenal success of the cognitive approach can be seen by its current dominance as the core model in contemporary psychology (usurping behaviorism in the late 1950s).
## Influence and influences
This success has led to its application within a wide range of areas:
- Psychology (particularly cognitive psychology), cognitive science and psychophysics
- Cognitive neuroscience, neurology and neuropsychology
- Behavioral economics and behavioral finance
- Artificial intelligence and cybernetics
- Ergonomics and user interface design
- Philosophy of mind
- Linguistics, especially psycholinguistics and cognitive linguistics
- Economics, especially experimental economics
- Learning styles and learning
In its widest sense, the field is quite eclectic and draws from a number of areas, such as:
- Computer science and information theory, where attempts at artificial intelligence, collective intelligence and robotics focus on mimicking living beings' capacities for cognition, or applying the experience gathered in one place by one being to actions by another being elsewhere.
- Philosophy, epistemology and ontology
- Moral philosophy, where it deals with the problem of ignorance, often seen as the opposite of cognition.
- Biology and neuroscience
- Mathematics and probability
- Physics, where observer effects are studied in depth mathematically.
# Cognitive ontology
On an individual being level, these questions are studied by the separate fields above, but are also more integrated into cognitive ontology of various kinds. This challenges the older linguistically dependent views of ontology, wherein one could debate being, perceiving, and doing, with no cognizance of innate human limits, varying human lifeways, and loyalties that may let a being "know" something (see qualia) that for others remains very much in doubt.
On the level of an individual mind, an emergent behavior might be the formation of a new concept, 'bubbling up' from below the conscious level of the mind. A simple way of stating this is that beings preserve their own attention and are at every level concerned with avoiding interruption and distraction. Such cognitive specialization can be observed in particular in language, with adults markedly less able to hear or say distinctions made in languages to which they were not exposed in youth.
# Cognition as compression
By the 1980s, researchers in the Engineering departments of the University of Leeds, UK hypothesized that 'Cognition is a form of compression', i.e., cognition was an economic, not just a philosophical or a psychological, process; in other words, skill in the process of cognition confers a competitive advantage. An implication of this view is that choices about what to cognize are being made at all levels from the neurological expression up to species-wide priority setting; in other words, the compression process is a form of optimization. This is a force for self-organizing behavior; thus we have the opportunity to see samples of emergent behavior at each successive level, from individual, to groups of individuals, to formal organizations.
# Cognition as and in a social process
It has been observed since antiquity that language acquisition in human children fails to emerge unless the children are exposed to language. Thus, language acquisition is an example of an emergent behavior, which in fact requires a narrow, yet evolutionarily reliably occurring, set of inputs. In this case, the individual is made up of a set of mechanisms 'expecting' such input from the social world.
In education, for instance, which has the explicit task in society of developing child cognition, choices are made regarding the environment and permitted action that lead to a formed experience. In social cognition, face perception in human babies emerges by the age of two months. This is in turn affected by the risk or cost of providing these, for instance, those associated with a playground or swimming pool or field trip. On the other hand, the macro-choices made by the teachers are extremely influential on the micro-choices made by children.
In a large systemic perspective, cognition is considered closely related to the social and human organization functioning and constrains. Managerial decision making processes can be erroneous in politics, economy and industry for the reason of different reciprocally dependent socio-cognitive factors. This domain became the field of interest of emergent socio-cognitive engineering (Google search).
# Cognition in a cultural context
One famous image, Earthrise, taken during Apollo 8, the first Apollo mission to the Moon, shows planet Earth in a single photograph. Earthrise is now the icon for Earth Day, which did not arise until after the image became widespread. At this level, an example of an 'emergent behavior' might be concern for Spaceship Earth, as encouraged by the development of orbiting space observatories etc.
Other concepts which seem to have arisen only recently (in the last century) include increased expectations for human rights. In this case, an example of an 'emergent behavior' might perhaps be the use of the mass media to publicize inequities in the human condition, perhaps using highly portable cameras and telephones.
# Example of emergent organization
It is possible to find other examples of critical mass necessary to develop a concept. For example, a nascent coalition of individuals might fail in the implementation of some agreement among them; but in the words of Ward Cunningham, the inventor of the Wiki-wiki Web:
In other words, when the organization adapted, the concept adapted and survived the incipient failure mode. | Cognition
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The term cognition is used in different ways by different disciplines. In psychology, it refers to an information processing view of an individual's psychological functions. Other interpretations of the meaning of cognition link it to the development of concepts; individual minds, groups, organizations, and even larger coalitions of entities, can be modelled as societies which cooperate to form concepts. The autonomous elements of each 'society' would have the opportunity to demonstrate emergent behavior in the face of some crisis or opportunity. Cognition can also be interpreted as "understanding and trying to make sense of the world".[citation needed]
Template:Psychology (sidebar)
# Introduction
The term cognition (Latin: cognoscere, "to know") is used in several loosely related ways to refer to a faculty for the human-like processing of information, applying knowledge and changing preferences. Cognition or cognitive processes can be natural and artificial, conscious and not conscious; therefore, they are analyzed from different perspectives and in different contexts, in anesthesia, neurology, psychology, philosophy, systemics and computer science. The concept of cognition is closely related to such abstract concepts as mind, reasoning, perception, intelligence, learning, and many others that describe numerous capabilities of the human mind and expected properties of artificial or synthetic intelligence. Cognition is an abstract property of advanced living organisms; therefore, it is studied as a direct property of a brain or of an abstract mind on sub-symbolic and symbolic levels.OR
In psychology and in artificial intelligence, it is used to refer to the mental functions, mental processes and states of intelligent entities (humans, human organizations, highly autonomous robots), with a particular focus toward the study of such mental processes as comprehension, inferencing, decision-making, planning and learning (see also cognitive science and cognitivism). Recently, advanced cognitive researchers have been especially focused on the capacities of abstraction, generalization, concretization/specialization and meta-reasoning which descriptions involve such concepts as beliefs, knowledge, desires, preferences and intentions of intelligent individuals/objects/agents/systems.
The term "cognition" is also used in a wider sense to mean the act of knowing or knowledge, and may be interpreted in a social or cultural sense to describe the emergent development of knowledge and concepts within a group that culminates in both thought and action.
# Cognition in mainstream psychology
The sort of mental processes described as cognitive or cognitive processes are largely influenced by research which has successfully used this paradigm in the past. Consequently, this description tends to apply to processes such as memory, attention, perception, action, problem solving and mental imagery. Traditionally, emotion was not thought of as a cognitive process. This division is now regarded as largely artificial, and much research is currently being undertaken to examine the cognitive psychology of emotion; research also includes one's awareness of strategies and methods of cognition, known as metacognition.
Empirical research into cognition is usually scientific and quantitative, or involves creating models to describe or explain certain behaviors.
While few people would deny that cognitive processes are a function of the brain, a cognitive theory will not necessarily make any reference to the brain or any other biological process (compare neurocognitive). It may purely describe behaviour in terms of information flow or function. Relatively recent fields of study such as cognitive science and neuropsychology aim to bridge this gap, using cognitive paradigms to understand how the brain implements these information-processing functions (see also cognitive neuroscience), or how pure information-processing systems (e.g., computers) can simulate cognition (see also artificial intelligence). The branch of psychology that studies brain injury to infer normal cognitive function is called cognitive neuropsychology. The links of cognition to evolutionary demands are studied through the investigation of animal cognition. And conversely, evolutionary-based perspectives can inform hypotheses about cognitive functional systems evolutionary psychology.
The theoretical school of thought derived from the cognitive approach is often called cognitivism.
The phenomenal success of the cognitive approach can be seen by its current dominance as the core model in contemporary psychology (usurping behaviorism in the late 1950s).
## Influence and influences
This success has led to its application within a wide range of areas:
- Psychology (particularly cognitive psychology), cognitive science and psychophysics
- Cognitive neuroscience, neurology and neuropsychology
- Behavioral economics and behavioral finance
- Artificial intelligence and cybernetics
- Ergonomics and user interface design
- Philosophy of mind
- Linguistics, especially psycholinguistics and cognitive linguistics
- Economics, especially experimental economics
- Learning styles and learning
In its widest sense, the field is quite eclectic and draws from a number of areas, such as:
- Computer science and information theory, where attempts at artificial intelligence, collective intelligence and robotics focus on mimicking living beings' capacities for cognition, or applying the experience gathered in one place by one being to actions by another being elsewhere.
- Philosophy, epistemology and ontology
- Moral philosophy, where it deals with the problem of ignorance, often seen as the opposite of cognition.
- Biology and neuroscience
- Mathematics and probability
- Physics, where observer effects are studied in depth mathematically.
# Cognitive ontology
On an individual being level, these questions are studied by the separate fields above, but are also more integrated into cognitive ontology of various kinds. This challenges the older linguistically dependent views of ontology, wherein one could debate being, perceiving, and doing, with no cognizance of innate human limits, varying human lifeways, and loyalties that may let a being "know" something (see qualia) that for others remains very much in doubt.
On the level of an individual mind, an emergent behavior might be the formation of a new concept, 'bubbling up' from below the conscious level of the mind. A simple way of stating this is that beings preserve their own attention and are at every level concerned with avoiding interruption and distraction. Such cognitive specialization can be observed in particular in language, with adults markedly less able to hear or say distinctions made in languages to which they were not exposed in youth.
# Cognition as compression
By the 1980s, researchers in the Engineering departments of the University of Leeds, UK hypothesized that 'Cognition is a form of compression', i.e., cognition was an economic, not just a philosophical or a psychological, process; in other words, skill in the process of cognition confers a competitive advantage. An implication of this view is that choices about what to cognize are being made at all levels from the neurological expression up to species-wide priority setting; in other words, the compression process is a form of optimization. This is a force for self-organizing behavior; thus we have the opportunity to see samples of emergent behavior at each successive level, from individual, to groups of individuals, to formal organizations.
# Cognition as and in a social process
It has been observed since antiquity that language acquisition in human children fails to emerge unless the children are exposed to language. Thus, language acquisition is an example of an emergent behavior, which in fact requires a narrow, yet evolutionarily reliably occurring, set of inputs. In this case, the individual is made up of a set of mechanisms 'expecting' such input from the social world.
In education, for instance, which has the explicit task in society of developing child cognition, choices are made regarding the environment and permitted action that lead to a formed experience. In social cognition, face perception in human babies emerges by the age of two months. This is in turn affected by the risk or cost of providing these, for instance, those associated with a playground or swimming pool or field trip. On the other hand, the macro-choices made by the teachers are extremely influential on the micro-choices made by children.
In a large systemic perspective, cognition is considered closely related to the social and human organization functioning and constrains. Managerial decision making processes can be erroneous in politics, economy and industry for the reason of different reciprocally dependent socio-cognitive factors. This domain became the field of interest of emergent socio-cognitive engineering (Google search).
# Cognition in a cultural context
One famous image, Earthrise, taken during Apollo 8, the first Apollo mission to the Moon, shows planet Earth in a single photograph. Earthrise is now the icon for Earth Day, which did not arise until after the image became widespread. At this level, an example of an 'emergent behavior' might be concern for Spaceship Earth, as encouraged by the development of orbiting space observatories etc.
Other concepts which seem to have arisen only recently (in the last century) include increased expectations for human rights. In this case, an example of an 'emergent behavior' might perhaps be the use of the mass media to publicize inequities in the human condition, perhaps using highly portable cameras and telephones.
# Example of emergent organization
It is possible to find other examples of critical mass necessary to develop a concept. For example, a nascent coalition of individuals might fail in the implementation of some agreement among them; but in the words of Ward Cunningham, the inventor of the Wiki-wiki Web:
In other words, when the organization adapted, the concept adapted and survived the incipient failure mode. | https://www.wikidoc.org/index.php/Cognition | |
3737073129c393bdc8da5ce3ec46d7a0b3ccf51b | wikidoc | Colectomy | Colectomy
# Overview
Colectomy consists of the surgical resection of any extent of the large bowel (colon).
# Indications
Some of the most common indications for colectomy are:
- Colon cancer.
- Diverticulitis and diverticular disease of the large bowel.
- Trauma.
- Inflammatory bowel disease such as Ulcerative Colitis or Crohn's disease.
- Prophylactic colectomy can be indicated in some forms of polyposis, Lynch syndrome and certain cases of inflammatory bowel disease because of high risk for development of colorectal cancer.
- bowel infarction
# Basic principles
Traditionally, colectomy is performed via an abdominal incision (laparotomy), though minimally invasive colectomy, by means of laparoscopy, is growing both in scope of indications and popularity, and is a well-established procedure as of 2006 in many medical centers.
Resection of any part of the colon entails mobilization and ligation of the corresponding blood vessels. Lymphadenectomy is usually performed through excision of the fatty tissue adjacent to these vessels (mesocolon), in operations for colon cancer.
When the resection is complete, the surgeon has the option of immediately restoring the bowel, by stitching together both the cut ends (primary anastomosis), or creating a colostomy. Several factors are taken into account, including:
- Circumstances of the operation (elective vs emergency);
- Disease being treated;
- Acute physiological state of the patient;
- Impact of living with a colostomy, albeit temporarily;
- Use of a specific preoperative regimen of low-residue diet and laxatives (so-called "bowel prep").
An anastomosis carries the risk of dehiscence (breakdown of the stitches), which can lead to contamination of the peritoneal cavity, peritonitis, sepsis and death. Colostomy is always safer, but places a societal, psychological and physical burden on the patient. The choice is by no means an easy one and is rife with controversy, being a frequent topic of heated debate among surgeons all over the world.
# Types
- Right hemicolectomy and left hemicolectomy refer to the resection of the ascending (right) colon and the descending (left) colon, respectively. When part of the transverse colon is also resected, it may be referred to as an extended hemicolectomy
- Transverse colectomy is also possible, though uncommon.
- Sigmoidectomy is a resection of the sigmoid colon, sometimes including part or all of the rectum (proctosigmoidectomy). When a sigmoidectomy is followed by terminal colostomy and closure of the rectal stump, it is called a Hartmann operation; this is usually done out of impossibility to perform a "double-barrel" or Mikulicz colostomy, which is preferred because it makes "takedown" (reoperation to restore normal intestinal continuity by means of an anastomosis) considerably easier.
- When the entire colon is removed, this is called a total colectomy. If the rectum is also removed, it is a total proctocolectomy.
- Subtotal colectomy is resection of part of colon or a resection of all of the colon without complete resection of the rectum.
- Anterior resection is resection of the lower part of the left colon and adjacent rectum. The operation is often combined with removal of the tissue behind the rectum (mesorectum}. This extra procedure is commonly called a total mesorectal excision or TME. A TME procedure removes the rectal lymph glands. | Colectomy
Template:Interventions infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Colectomy consists of the surgical resection of any extent of the large bowel (colon).
# Indications
Some of the most common indications for colectomy are:
- Colon cancer.
- Diverticulitis and diverticular disease of the large bowel.
- Trauma.
- Inflammatory bowel disease such as Ulcerative Colitis or Crohn's disease.
- Prophylactic colectomy can be indicated in some forms of polyposis, Lynch syndrome and certain cases of inflammatory bowel disease because of high risk for development of colorectal cancer.
- bowel infarction
# Basic principles
Traditionally, colectomy is performed via an abdominal incision (laparotomy), though minimally invasive colectomy, by means of laparoscopy, is growing both in scope of indications and popularity, and is a well-established procedure as of 2006 in many medical centers.
Resection of any part of the colon entails mobilization and ligation of the corresponding blood vessels. Lymphadenectomy is usually performed through excision of the fatty tissue adjacent to these vessels (mesocolon), in operations for colon cancer.
When the resection is complete, the surgeon has the option of immediately restoring the bowel, by stitching together both the cut ends (primary anastomosis), or creating a colostomy. Several factors are taken into account, including:
- Circumstances of the operation (elective vs emergency);
- Disease being treated;
- Acute physiological state of the patient;
- Impact of living with a colostomy, albeit temporarily;
- Use of a specific preoperative regimen of low-residue diet and laxatives (so-called "bowel prep").
An anastomosis carries the risk of dehiscence (breakdown of the stitches), which can lead to contamination of the peritoneal cavity, peritonitis, sepsis and death. Colostomy is always safer, but places a societal, psychological and physical burden on the patient. The choice is by no means an easy one and is rife with controversy, being a frequent topic of heated debate among surgeons all over the world.
# Types
- Right hemicolectomy and left hemicolectomy refer to the resection of the ascending (right) colon and the descending (left) colon, respectively. When part of the transverse colon is also resected, it may be referred to as an extended hemicolectomy
- Transverse colectomy is also possible, though uncommon.
- Sigmoidectomy is a resection of the sigmoid colon, sometimes including part or all of the rectum (proctosigmoidectomy). When a sigmoidectomy is followed by terminal colostomy and closure of the rectal stump, it is called a Hartmann operation; this is usually done out of impossibility to perform a "double-barrel" or Mikulicz colostomy, which is preferred because it makes "takedown" (reoperation to restore normal intestinal continuity by means of an anastomosis) considerably easier.
- When the entire colon is removed, this is called a total colectomy. If the rectum is also removed, it is a total proctocolectomy.
- Subtotal colectomy is resection of part of colon or a resection of all of the colon without complete resection of the rectum.[1]
- Anterior resection is resection of the lower part of the left colon and adjacent rectum. The operation is often combined with removal of the tissue behind the rectum (mesorectum}. This extra procedure is commonly called a total mesorectal excision or TME. A TME procedure removes the rectal lymph glands. | https://www.wikidoc.org/index.php/Colectomy | |
8f104e8a615c20a3783616a35c82bf70c7bc0700 | wikidoc | Collectin | Collectin
# Overview
Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids which are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and also danger-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation, complement activation, opsonization, activation of phagocytosis or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.
# Structure
Functionally collectins are trimers. Monomeric subunit consists of four parts:
- A cysteine-rich domain at the N-terminus
- A collagen-like domain
- A coiled-coil neck domain
- A C-type lectin domain that is also called a carbohydrate recognition domain (CRD)
Recognition of specific parts of microorganism is mediated by CRD in presence of calcium. Affinity of interaction between microbes and collectins depends on the degree of collectin oligomerization and also on the density of ligands on the surface of the microbe.
# Types of Collectins
9 types of collectins have been defined to date:
- MBL = mannan-binding lectin (mannose-binding lectin)
- SP-A = surfactant protein A
- SP-D = surfactant protein D
- CL-L1 = collectin liver 1
- CL-P1 = collectin placenta 1
- CL-43 = conglutinin collectin of 43 kDa
- CL-46 = collectin of 46 kDa
- CL-K1 = collectin kidney 1
- Conglutinin
CL-43, CL-46 and conglutinin are found in bovine.
# Function
## Aggregation
Collectins can bind on the surface of the microorganism and between carbohydrate ligands can be made a bond. Due to those properties the interaction can result into aggregation.
## Opsonization and Activation of Phagocytosis
Collectins can act as opsonins. There is a specific interaction between collectins and receptors on phagocytic cells which can lead to increased clearance of microorganisms. MBL can bind to microorganisms and this interaction can lead to opsonization through complement activation, or it can opsonize the microorganism directly. SP-A and SP-D can also interact with microorganisms and phagocytic cells to enhance phagocytosis of the microorganism.
## Inhibition of Microbial Growth
Collectins have effect on microorganism survival. SP-A and SP-D can bind to LPS (lipopolysaccharide) of both Gram-negative and Gram-positive bacteria. SP-A and SP-D can increase permeability of Gram-negative bacterial cell membrane.
## Modulation of Inflammatory Responses
SP-A and SP-D can damp induction of inflammation by LPS or endotoxin. It can be caused by removing the LPS or by binding the LPS to CD14 receptor on macrophages which can block the inflammatory response. SP-A can also bind to TLR2 (Toll-like receptor 2). This interaction causes decrease of TNF-α (Tumor necrosis factor-α) production by alveolar macrophages stimulated with peptidoglycan. SP-A and SP-D can modulate cytokine production. They modulate the production of oxygen and nitrogen reactive species which are very important for phagocytic cells. SP-A and SP-D has s function as chemoattractants for alveolar neutrophils and monocytes. MBL can recognize peptidoglykan via N-acetylglukosamine. This interaction leads to inhibition of ligand-induced inflammatory by macrophage chemokine production.
## Modulation of the Adaptive Immune System
SP-A and SP-D can suppress activated T-lymphocytes and IL-2 (interleukin-2) production. SP-D increases bacterial antigen presentation by dendritic cells whereas SP-A blocs differentation of the immature dendritic cells.
## Modulation of Allergic Response
Collectins SP-A and SP-D have anti-allergic effect. They inhibit IgE binding to allergen, decrease histamin release from basophils and inhibit T-lymfocyte production in the late phase of the inflammation.
## Apoptosis
Collectins SP-A and SP-D enhance clearance of apoptotic cells by macrophages.
## Complement Activation
Collectins are linked with activation of lectin pathway of complement activation. At the beginning, there is a binding of collectin to PAMPs or DAMPs. Collectin MBL is involved in activation of the lectin complement pathway. There are three serine proteases, MASP-1, 2 and 3 (MBL-associated serine proteases), which participate in activation of the lectin pathway. MASP-2 has a cleavage activity and it is essential for forming lectin C3 and C5 convertases and for activation of the complement.
# Reviews
For more informations and details see reviews. | Collectin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids which are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and also danger-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation[disambiguation needed], complement activation, opsonization, activation of phagocytosis or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.
# Structure
Functionally collectins are trimers. Monomeric subunit consists of four parts:
- A cysteine-rich domain at the N-terminus
- A collagen-like domain
- A coiled-coil neck domain
- A C-type lectin domain that is also called a carbohydrate recognition domain (CRD)
Recognition of specific parts of microorganism is mediated by CRD in presence of calcium.[1][2] Affinity of interaction between microbes and collectins depends on the degree of collectin oligomerization and also on the density of ligands on the surface of the microbe.[3]
# Types of Collectins
9 types of collectins have been defined to date:
- MBL = mannan-binding lectin (mannose-binding lectin)
- SP-A = surfactant protein A
- SP-D = surfactant protein D
- CL-L1 = collectin liver 1
- CL-P1 = collectin placenta 1
- CL-43 = conglutinin collectin of 43 kDa
- CL-46 = collectin of 46 kDa
- CL-K1 = collectin kidney 1
- Conglutinin
CL-43, CL-46 and conglutinin are found in bovine.
# Function
## Aggregation
Collectins can bind on the surface of the microorganism and between carbohydrate ligands can be made a bond. Due to those properties the interaction can result into aggregation.[4][5]
## Opsonization and Activation of Phagocytosis
Collectins can act as opsonins. There is a specific interaction between collectins and receptors on phagocytic cells which can lead to increased clearance of microorganisms.[6][7][8] MBL can bind to microorganisms and this interaction can lead to opsonization through complement activation,[9] or it can opsonize the microorganism directly.[10] SP-A and SP-D can also interact with microorganisms and phagocytic cells to enhance phagocytosis of the microorganism.[11]
## Inhibition of Microbial Growth
Collectins have effect on microorganism survival. SP-A and SP-D can bind to LPS (lipopolysaccharide) of both Gram-negative and Gram-positive bacteria. SP-A and SP-D can increase permeability of Gram-negative bacterial cell membrane.[12]
## Modulation of Inflammatory Responses
SP-A and SP-D can damp induction of inflammation by LPS or endotoxin. It can be caused by removing the LPS or by binding the LPS to CD14 receptor on macrophages which can block the inflammatory response.[13][14][15] SP-A can also bind to TLR2 (Toll-like receptor 2). This interaction causes decrease of TNF-α (Tumor necrosis factor-α) production by alveolar macrophages stimulated with peptidoglycan.[16] SP-A and SP-D can modulate cytokine production. They modulate the production of oxygen and nitrogen reactive species which are very important for phagocytic cells.[17][18][19] SP-A and SP-D has s function as chemoattractants for alveolar neutrophils and monocytes.[20] MBL can recognize peptidoglykan via N-acetylglukosamine. This interaction leads to inhibition of ligand-induced inflammatory by macrophage chemokine production.[21]
## Modulation of the Adaptive Immune System
SP-A and SP-D can suppress activated T-lymphocytes and IL-2 (interleukin-2) production.[22][23] SP-D increases bacterial antigen presentation by dendritic cells [24] whereas SP-A blocs differentation of the immature dendritic cells.[25]
## Modulation of Allergic Response
Collectins SP-A and SP-D have anti-allergic effect. They inhibit IgE binding to allergen, decrease histamin release from basophils and inhibit T-lymfocyte production in the late phase of the inflammation.[26][27][28]
## Apoptosis
Collectins SP-A and SP-D enhance clearance of apoptotic cells by macrophages.[29][30]
## Complement Activation
Collectins are linked with activation of lectin pathway of complement activation. At the beginning, there is a binding of collectin to PAMPs or DAMPs. Collectin MBL is involved in activation of the lectin complement pathway.[31][32] There are three serine proteases, MASP-1, 2 and 3 (MBL-associated serine proteases), which participate in activation of the lectin pathway. MASP-2 has a cleavage activity and it is essential for forming lectin C3 and C5 convertases and for activation of the complement.[33][34][35]
# Reviews
For more informations and details see reviews.[36][37][38] | https://www.wikidoc.org/index.php/Collectin | |
961f6060e5fd99d4e440691be7724986838f05e0 | wikidoc | Colocynth | Colocynth
The colocynth, also known as bitter apple, bitter cucumber, egusi, or vine of Sodom, is a viny plant native to the Mediterranean Basin and Asia, especially Turkey (especially in regions such as İzmir), Nubia, and Trieste. It originally bore the scientific name Colocynthis citrullus, but is now classified as Citrullus colocynthis.
Its fruit, which is lemon-sized, yellowish, green-mottled, spongy, and extremely bitter, is a powerful hepatic stimulant and hydragogue cathartic. It is used as a strong laxative. In overdoses, the fruit can cause violent, sharp pains in the bowels, with dangerous inflammation. Given that the colocynth grows wild in Israel, these symptoms would be consistent with the "wild gourd" mentioned in II Kings 4:39-40. It is seldom used alone, but in combination with other cathartics has been a standard remedy. It has been used alone in obstinate edema, amenorrhea, and in cerebral derangements. A normal dose of fluid extracted from the fruit pulp is 2 to 5 minims, and for the powdered extract, 1 to 2 grains.
Its seed, which is edible but similarly bitter, nutty-flavored, and rich in fat and protein, is eaten whole or used as an oilseed. The oil content of the seeds is 17-19% (w/w), consisting of 67-73% linoleic acid, 10-16% oleic acid, 5-8% stearic acid, and 9-12% palmitic acid. It is estimated that the oil yield is approximately 400 L/hectare.
The characteristic small seed of the colocynth have been found in several early archeological sites in northern Africa and the Near East, specifically at Neolithic Armant, Nagada (dated 3650-2850 BC), and Hierakonopolis (3500-3300 BC) in Egypt; at sites dating from 3800 BC to Roman times in Libya; and the pre-pottery Neolithic levels of the Nahal Hemar Caves in Israel. Zohary and Hopf speculate that "these finds indicate that the wild colocynth was very probably used by humans prior to its domestication."
Desert Bedouins are said to make a type of bread from the ground seeds. There is some confusion between this species and the closely-related watermelon, whose seeds may be used in much the same way. In particular the name "egusi" may refer to either or both plants (or more generically to other cucurbits) in their capacity as seed crops, or to a soup made from these seeds and popular in West Africa.
# Pre-modern medical uses
In pre-modern medicine it was an ingredient in the electuary called confectio hamech, or diacatholicon, and most other laxative pills; and in such cases as required purging, it was very successful. It is one of the most violent purgative drugs known; insomuch that it excoriates the passages to such a degree as to sometimes draw blood, and induce a so-called "superpurgation". Sometimes, it was taken boiled in water, or beer, in obstruction of the menses, which was considered successful in strong constitutions. Some women used it in the same manner, in the beginning of pregnancy, to cause an abortion, which often occurred due to the violence of its operation. Its usage for this purpose is documented in ancient times; for example, the following recipe was found in the Ebers medical papyrus in Egypt, dated to about 1550 BCE:
The powder of colocynth was sometimes used externally, with aloes, etc, in unguents, plasters, etc, with remarkable success against parasitic worms; and some, for the same purpose, recommended that the pulp be used as an enema. In iliac passion, enemas of colocynth were used effectively where most other pre-modern medicines had failed.
Troches, or lozenges, made of colocynth were called "troches of alhandal". They were prepared by cutting the colocynth to a small size, and reducing it to a fine powder in a mortar, rubbed with oil of sweet almonds; adding gum tragacanth, and mastic afterwards.
Remedies for counteracting colocynth have included emetics, such as zinc sulfate, and apomorphine, if caught early; later, demulcents and opiates, with stimulants to combat collapse. | Colocynth
The colocynth, also known as bitter apple, bitter cucumber, egusi, or vine of Sodom, is a viny plant native to the Mediterranean Basin and Asia, especially Turkey (especially in regions such as İzmir), Nubia, and Trieste. It originally bore the scientific name Colocynthis citrullus, but is now classified as Citrullus colocynthis.
Its fruit, which is lemon-sized, yellowish, green-mottled, spongy, and extremely bitter, is a powerful hepatic stimulant and hydragogue cathartic. It is used as a strong laxative. In overdoses, the fruit can cause violent, sharp pains in the bowels, with dangerous inflammation. Given that the colocynth grows wild in Israel, these symptoms would be consistent with the "wild gourd" mentioned in II Kings 4:39-40. It is seldom used alone, but in combination with other cathartics has been a standard remedy. It has been used alone in obstinate edema, amenorrhea, and in cerebral derangements. A normal dose of fluid extracted from the fruit pulp is 2 to 5 minims, and for the powdered extract, 1 to 2 grains.[1]
Its seed, which is edible but similarly bitter, nutty-flavored, and rich in fat and protein, is eaten whole or used as an oilseed. The oil content of the seeds is 17-19% (w/w), consisting of 67-73% linoleic acid, 10-16% oleic acid, 5-8% stearic acid, and 9-12% palmitic acid. It is estimated that the oil yield is approximately 400 L/hectare.[2]
The characteristic small seed of the colocynth have been found in several early archeological sites in northern Africa and the Near East, specifically at Neolithic Armant, Nagada (dated 3650-2850 BC), and Hierakonopolis (3500-3300 BC) in Egypt; at sites dating from 3800 BC to Roman times in Libya; and the pre-pottery Neolithic levels of the Nahal Hemar Caves in Israel.[3] Zohary and Hopf speculate that "these finds indicate that the wild colocynth was very probably used by humans prior to its domestication."[4]
Desert Bedouins are said to make a type of bread from the ground seeds. There is some confusion between this species and the closely-related watermelon, whose seeds may be used in much the same way. In particular the name "egusi" may refer to either or both plants (or more generically to other cucurbits) in their capacity as seed crops, or to a soup made from these seeds and popular in West Africa.
# Pre-modern medical uses
In pre-modern medicine it was an ingredient in the electuary called confectio hamech, or diacatholicon, and most other laxative pills; and in such cases as required purging, it was very successful. It is one of the most violent purgative drugs known; insomuch that it excoriates the passages to such a degree as to sometimes draw blood, and induce a so-called "superpurgation". Sometimes, it was taken boiled in water, or beer, in obstruction of the menses, which was considered successful in strong constitutions. Some women used it in the same manner, in the beginning of pregnancy, to cause an abortion, which often occurred due to the violence of its operation.[5] Its usage for this purpose is documented in ancient times; for example, the following recipe was found in the Ebers medical papyrus in Egypt, dated to about 1550 BCE:[6]
Template:"
The powder of colocynth was sometimes used externally, with aloes, etc, in unguents, plasters, etc, with remarkable success against parasitic worms; and some, for the same purpose, recommended that the pulp be used as an enema. In iliac passion, enemas of colocynth were used effectively where most other pre-modern medicines had failed.[5]
Troches, or lozenges, made of colocynth were called "troches of alhandal". They were prepared by cutting the colocynth to a small size, and reducing it to a fine powder in a mortar, rubbed with oil of sweet almonds; adding gum tragacanth, and mastic afterwards.[5]
Remedies for counteracting colocynth have included emetics, such as zinc sulfate, and apomorphine, if caught early; later, demulcents and opiates, with stimulants to combat collapse.[1] | https://www.wikidoc.org/index.php/Colocynth | |
aae26c44d0a8171433cae1e412cd17c83254fa37 | wikidoc | Colostomy | Colostomy
# Overview
A colostomy is a surgical procedure that involves connecting a part of the colon onto the anterior abdominal wall, leaving the patient with an opening on the abdomen called a stoma. This opening is formed from the end of the large intestine drawn out through the incision and sutured to the skin. After a colostomy, feces leave the patient's body through the stoma, and collect in a pouch attached to the patient's abdomen which is changed when necessary.
# Types of colostomy
- According to anatomic location
- According to function
- According to appearance
- According to duration
## According to anatomic location
- End sigmoid colostomy - Left iliac fossa
- End descending colon colostomy - Left iliac fossa
- Transverse colostomy - Above and right to umbilicus
- Caecostomy - Right iliac fossa
The appropriate stoma site must be selected pre-operatively for all the elective procedures and for most emergent operations.
## According to function that the colostomy is intended for
- Diverting colostomy : Any colostomy may be regarded as 'Diverting' if it is so constructed that faeces are prevented from entering the diseased bowel distal to it. They are of 2 types : temporary and permanent
Temporary diverting colostomy : Usually loop colostomy - the purpose is to provide temporary diversion of faeces for :
Protection of the compllicated and threatened distal anastomosis e.g, following anterior resection of rectal cancer
Grossly infected diverticulitis with or without perforation
Traumatic injuries of the colon or rectum
Multiple,complicated and high perianal fistulae
Temporary diverting end colostomy : hartmann's procedure
Permanent diverting colostomy : An end colostomy - the purpose is to provide permanent diversion of faeces for :
Perforated unresectable rectal cancer
Late and unresectable rectal or anal cancer
Unrepairable lesion of rectum and anal canal following trauma, crohn's disease, hidradenitis suppurativa
- Temporary diverting colostomy : Usually loop colostomy - the purpose is to provide temporary diversion of faeces for :
Protection of the compllicated and threatened distal anastomosis e.g, following anterior resection of rectal cancer
Grossly infected diverticulitis with or without perforation
Traumatic injuries of the colon or rectum
Multiple,complicated and high perianal fistulae
- Protection of the compllicated and threatened distal anastomosis e.g, following anterior resection of rectal cancer
- Grossly infected diverticulitis with or without perforation
- Traumatic injuries of the colon or rectum
- Multiple,complicated and high perianal fistulae
- Temporary diverting end colostomy : hartmann's procedure
- Permanent diverting colostomy : An end colostomy - the purpose is to provide permanent diversion of faeces for :
Perforated unresectable rectal cancer
Late and unresectable rectal or anal cancer
Unrepairable lesion of rectum and anal canal following trauma, crohn's disease, hidradenitis suppurativa
- Perforated unresectable rectal cancer
- Late and unresectable rectal or anal cancer
- Unrepairable lesion of rectum and anal canal following trauma, crohn's disease, hidradenitis suppurativa
- Decompression colostomy
The purpose is to provide decompression of hugely dilated large bowel proximal to obstructing growth of the rectum or sigmoid colon
Frequently done on emergency basis to prevent impending rupture of the dilated colon proximal to obstruction.
Useful and life-saving
Provides opportunity for a subsequent definitive cancer surgery without compromise of the principles of cancer surgery.
Types of decompression colostomy:
A loop transverse colube'ostomy
'Blow hole' stoma constructed in the caecum or transverse colon.
Tube type colostomy
- The purpose is to provide decompression of hugely dilated large bowel proximal to obstructing growth of the rectum or sigmoid colon
- Frequently done on emergency basis to prevent impending rupture of the dilated colon proximal to obstruction.
- Useful and life-saving
- Provides opportunity for a subsequent definitive cancer surgery without compromise of the principles of cancer surgery.
Types of decompression colostomy:
A loop transverse colube'ostomy
'Blow hole' stoma constructed in the caecum or transverse colon.
Tube type colostomy
- Types of decompression colostomy:
A loop transverse colube'ostomy
'Blow hole' stoma constructed in the caecum or transverse colon.
Tube type colostomy
- A loop transverse colube'ostomy
- 'Blow hole' stoma constructed in the caecum or transverse colon.
- Tube type colostomy
## According to appearance of colostomy
- End colostomy
- Loop colostomy
- Double-barreled colostomy
- 'Blow hole' transverse colostomy
- 'Blow hole' caecostomy
- 'Tube' caecostomy
## According to duration
- Temporary colostomy :
Indications-
To relieve a distal obstruction of the sigmoid colon due to any cause , commonly carcinoma or diverticulitis.
Usually performed as an emergency procedure to relieve obstruction as it is quick and easy to make.
The resection of the diseased part is carried out later on in a completely defunctioned segment of the colon which is empty, inactive and relatively sterile.
To defunction the distal colon and thus to protect a distal anastomosis after a low colorectal anastomosis.
To prevent faecal peritonitis after perforation of the colon following obstructive cancer, diverticulitis colon, traumatic injuries of colon or rectum
To facilitate the operative repair of high fistula in ano.
To prevent spoiling of the urinary bladder in vesico-colic fistula or vagina in vagino-colic fistula
- Indications-
To relieve a distal obstruction of the sigmoid colon due to any cause , commonly carcinoma or diverticulitis.
Usually performed as an emergency procedure to relieve obstruction as it is quick and easy to make.
The resection of the diseased part is carried out later on in a completely defunctioned segment of the colon which is empty, inactive and relatively sterile.
To defunction the distal colon and thus to protect a distal anastomosis after a low colorectal anastomosis.
To prevent faecal peritonitis after perforation of the colon following obstructive cancer, diverticulitis colon, traumatic injuries of colon or rectum
To facilitate the operative repair of high fistula in ano.
To prevent spoiling of the urinary bladder in vesico-colic fistula or vagina in vagino-colic fistula
- To relieve a distal obstruction of the sigmoid colon due to any cause , commonly carcinoma or diverticulitis.
Usually performed as an emergency procedure to relieve obstruction as it is quick and easy to make.
The resection of the diseased part is carried out later on in a completely defunctioned segment of the colon which is empty, inactive and relatively sterile.
- Usually performed as an emergency procedure to relieve obstruction as it is quick and easy to make.
- The resection of the diseased part is carried out later on in a completely defunctioned segment of the colon which is empty, inactive and relatively sterile.
- To defunction the distal colon and thus to protect a distal anastomosis after a low colorectal anastomosis.
- To prevent faecal peritonitis after perforation of the colon following obstructive cancer, diverticulitis colon, traumatic injuries of colon or rectum
- To facilitate the operative repair of high fistula in ano.
- To prevent spoiling of the urinary bladder in vesico-colic fistula or vagina in vagino-colic fistula
- Permanent colostomy :
Types:
End sigmoid colostomy : Most common type.
End descending colon colostomy : When the inferior mesenteric artery is transected during an operation of rectal cancer.
Indications:
Usually performed after abdominoperineal resection (APR) for lower 1/3rd , middle 1/3rd , and upper 1/3rd of rectal cancer or anal cancer : APR +left iliac colostomy is commonly done.
- Types:
End sigmoid colostomy : Most common type.
End descending colon colostomy : When the inferior mesenteric artery is transected during an operation of rectal cancer.
- End sigmoid colostomy : Most common type.
- End descending colon colostomy : When the inferior mesenteric artery is transected during an operation of rectal cancer.
- Indications:
Usually performed after abdominoperineal resection (APR) for lower 1/3rd , middle 1/3rd , and upper 1/3rd of rectal cancer or anal cancer : APR +left iliac colostomy is commonly done.
- Usually performed after abdominoperineal resection (APR) for lower 1/3rd , middle 1/3rd , and upper 1/3rd of rectal cancer or anal cancer : APR +left iliac colostomy is commonly done.
Note : In the upper 1/3rd rectal cancer, anterior resection can be performed in selected cases by experienced surgeons.
# Indications
There are many reasons for this procedure: a section of the colon has had to be removed, e.g. due to colon cancer requiring a total mesorectal excision, diverticulitis, injury, etc, so that it is no longer possible for feces to pass out via the anus; or a portion of the colon (or ileum) has been operated upon and needs to be 'rested' until it is healed. In the latter case, the colostomy is often temporary and is usually reversed at a later date, leaving the patient with a small scar where the stoma was.
# Options
Colostomies are viewed negatively due to the misconception that it is difficult to hide the pouch and the smell of feces, or to keep the pouch securely attached. However, modern colostomy pouches are well-designed, odor-proof, and allow stoma patients to continue normal activities. Latex-free tape is available for ensuring a secure attachment.
Colostomates (people with colostomies) who have ostomies of the sigmoid colon or descending colon may have the option of irrigation, which allows for the person to not wear a pouch, but rather just a gauze cap over the stoma. By irrigating, a catheter is placed inside the stoma, and flushed with water, which allows the feces to come out of the body into an irrigation sleeve. Most colostomates irrigate once a day or every other day, though this depends on the person, their food intake, and their health.
Placement of the stoma on the abdomen can occur at any location along the colon, the majority being on the lower left side near or in the sigmoid colon, other locations include; the ascending, transverse, and descending sections of the colon. Colostomy surgery that can be planned ahead often has a higher rate of long-term success and satisfaction than those done in emergency surgery.
# Living with a colostomy
People with colostomies must wear an ostomy pouching system to collect intestinal waste. Ordinarily the pouch must be emptied or changed several times a day depending on the frequency of activity; in general the further from the anus the ostomy is located the greater the output and more frequent the need to empty or change the pouch.
# Alternatives
In some rare situations it may be possible to opt for an internal colo-anal pouch which eliminates the need for an external pouch. In place of an external appliance, an internal ileo-anal pouch is constructed using a portion of the patient's lower intestine, to act as a new rectum to replace the removed original. | Colostomy
Template:Interventions infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Assistant Editor-in-Chief: Soumya Sachdeva
# Overview
A colostomy is a surgical procedure that involves connecting a part of the colon onto the anterior abdominal wall, leaving the patient with an opening on the abdomen called a stoma. This opening is formed from the end of the large intestine drawn out through the incision and sutured to the skin. After a colostomy, feces leave the patient's body through the stoma, and collect in a pouch attached to the patient's abdomen which is changed when necessary.
# Types of colostomy
- According to anatomic location
- According to function
- According to appearance
- According to duration
## According to anatomic location
- End sigmoid colostomy - Left iliac fossa
- End descending colon colostomy - Left iliac fossa
- Transverse colostomy - Above and right to umbilicus
- Caecostomy - Right iliac fossa
The appropriate stoma site must be selected pre-operatively for all the elective procedures and for most emergent operations.
## According to function that the colostomy is intended for
- Diverting colostomy : Any colostomy may be regarded as 'Diverting' if it is so constructed that faeces are prevented from entering the diseased bowel distal to it. They are of 2 types : temporary and permanent
Temporary diverting colostomy : Usually loop colostomy - the purpose is to provide temporary diversion of faeces for :
Protection of the compllicated and threatened distal anastomosis e.g, following anterior resection of rectal cancer
Grossly infected diverticulitis with or without perforation
Traumatic injuries of the colon or rectum
Multiple,complicated and high perianal fistulae
Temporary diverting end colostomy : hartmann's procedure
Permanent diverting colostomy : An end colostomy - the purpose is to provide permanent diversion of faeces for :
Perforated unresectable rectal cancer
Late and unresectable rectal or anal cancer
Unrepairable lesion of rectum and anal canal following trauma, crohn's disease, hidradenitis suppurativa
- Temporary diverting colostomy : Usually loop colostomy - the purpose is to provide temporary diversion of faeces for :
Protection of the compllicated and threatened distal anastomosis e.g, following anterior resection of rectal cancer
Grossly infected diverticulitis with or without perforation
Traumatic injuries of the colon or rectum
Multiple,complicated and high perianal fistulae
- Protection of the compllicated and threatened distal anastomosis e.g, following anterior resection of rectal cancer
- Grossly infected diverticulitis with or without perforation
- Traumatic injuries of the colon or rectum
- Multiple,complicated and high perianal fistulae
- Temporary diverting end colostomy : hartmann's procedure
- Permanent diverting colostomy : An end colostomy - the purpose is to provide permanent diversion of faeces for :
Perforated unresectable rectal cancer
Late and unresectable rectal or anal cancer
Unrepairable lesion of rectum and anal canal following trauma, crohn's disease, hidradenitis suppurativa
- Perforated unresectable rectal cancer
- Late and unresectable rectal or anal cancer
- Unrepairable lesion of rectum and anal canal following trauma, crohn's disease, hidradenitis suppurativa
- Decompression colostomy
The purpose is to provide decompression of hugely dilated large bowel proximal to obstructing growth of the rectum or sigmoid colon
Frequently done on emergency basis to prevent impending rupture of the dilated colon proximal to obstruction.
Useful and life-saving
Provides opportunity for a subsequent definitive cancer surgery without compromise of the principles of cancer surgery.
Types of decompression colostomy:
A loop transverse colube'ostomy
'Blow hole' stoma constructed in the caecum or transverse colon.
Tube type colostomy
- The purpose is to provide decompression of hugely dilated large bowel proximal to obstructing growth of the rectum or sigmoid colon
- Frequently done on emergency basis to prevent impending rupture of the dilated colon proximal to obstruction.
- Useful and life-saving
- Provides opportunity for a subsequent definitive cancer surgery without compromise of the principles of cancer surgery.
Types of decompression colostomy:
A loop transverse colube'ostomy
'Blow hole' stoma constructed in the caecum or transverse colon.
Tube type colostomy
- Types of decompression colostomy:
A loop transverse colube'ostomy
'Blow hole' stoma constructed in the caecum or transverse colon.
Tube type colostomy
- A loop transverse colube'ostomy
- 'Blow hole' stoma constructed in the caecum or transverse colon.
- Tube type colostomy
## According to appearance of colostomy
- End colostomy
- Loop colostomy
- Double-barreled colostomy
- 'Blow hole' transverse colostomy
- 'Blow hole' caecostomy
- 'Tube' caecostomy
## According to duration
- Temporary colostomy :
Indications-
To relieve a distal obstruction of the sigmoid colon due to any cause , commonly carcinoma or diverticulitis.
Usually performed as an emergency procedure to relieve obstruction as it is quick and easy to make.
The resection of the diseased part is carried out later on in a completely defunctioned segment of the colon which is empty, inactive and relatively sterile.
To defunction the distal colon and thus to protect a distal anastomosis after a low colorectal anastomosis.
To prevent faecal peritonitis after perforation of the colon following obstructive cancer, diverticulitis colon, traumatic injuries of colon or rectum
To facilitate the operative repair of high fistula in ano.
To prevent spoiling of the urinary bladder in vesico-colic fistula or vagina in vagino-colic fistula
- Indications-
To relieve a distal obstruction of the sigmoid colon due to any cause , commonly carcinoma or diverticulitis.
Usually performed as an emergency procedure to relieve obstruction as it is quick and easy to make.
The resection of the diseased part is carried out later on in a completely defunctioned segment of the colon which is empty, inactive and relatively sterile.
To defunction the distal colon and thus to protect a distal anastomosis after a low colorectal anastomosis.
To prevent faecal peritonitis after perforation of the colon following obstructive cancer, diverticulitis colon, traumatic injuries of colon or rectum
To facilitate the operative repair of high fistula in ano.
To prevent spoiling of the urinary bladder in vesico-colic fistula or vagina in vagino-colic fistula
- To relieve a distal obstruction of the sigmoid colon due to any cause , commonly carcinoma or diverticulitis.
Usually performed as an emergency procedure to relieve obstruction as it is quick and easy to make.
The resection of the diseased part is carried out later on in a completely defunctioned segment of the colon which is empty, inactive and relatively sterile.
- Usually performed as an emergency procedure to relieve obstruction as it is quick and easy to make.
- The resection of the diseased part is carried out later on in a completely defunctioned segment of the colon which is empty, inactive and relatively sterile.
- To defunction the distal colon and thus to protect a distal anastomosis after a low colorectal anastomosis.
- To prevent faecal peritonitis after perforation of the colon following obstructive cancer, diverticulitis colon, traumatic injuries of colon or rectum
- To facilitate the operative repair of high fistula in ano.
- To prevent spoiling of the urinary bladder in vesico-colic fistula or vagina in vagino-colic fistula
- Permanent colostomy :
Types:
End sigmoid colostomy : Most common type.
End descending colon colostomy : When the inferior mesenteric artery is transected during an operation of rectal cancer.
Indications:
Usually performed after abdominoperineal resection (APR) for lower 1/3rd , middle 1/3rd , and upper 1/3rd of rectal cancer or anal cancer : APR +left iliac colostomy is commonly done.
- Types:
End sigmoid colostomy : Most common type.
End descending colon colostomy : When the inferior mesenteric artery is transected during an operation of rectal cancer.
- End sigmoid colostomy : Most common type.
- End descending colon colostomy : When the inferior mesenteric artery is transected during an operation of rectal cancer.
- Indications:
Usually performed after abdominoperineal resection (APR) for lower 1/3rd , middle 1/3rd , and upper 1/3rd of rectal cancer or anal cancer : APR +left iliac colostomy is commonly done.
- Usually performed after abdominoperineal resection (APR) for lower 1/3rd , middle 1/3rd , and upper 1/3rd of rectal cancer or anal cancer : APR +left iliac colostomy is commonly done.
Note : In the upper 1/3rd rectal cancer, anterior resection can be performed in selected cases by experienced surgeons.
# Indications
There are many reasons for this procedure: a section of the colon has had to be removed, e.g. due to colon cancer requiring a total mesorectal excision, diverticulitis, injury, etc, so that it is no longer possible for feces to pass out via the anus; or a portion of the colon (or ileum) has been operated upon and needs to be 'rested' until it is healed. In the latter case, the colostomy is often temporary and is usually reversed at a later date, leaving the patient with a small scar where the stoma was.
# Options
Colostomies are viewed negatively due to the misconception that it is difficult to hide the pouch and the smell of feces, or to keep the pouch securely attached. However, modern colostomy pouches are well-designed, odor-proof, and allow stoma patients to continue normal activities. Latex-free tape is available for ensuring a secure attachment.
Colostomates (people with colostomies) who have ostomies of the sigmoid colon or descending colon may have the option of irrigation, which allows for the person to not wear a pouch, but rather just a gauze cap over the stoma. By irrigating, a catheter is placed inside the stoma, and flushed with water, which allows the feces to come out of the body into an irrigation sleeve. Most colostomates irrigate once a day or every other day, though this depends on the person, their food intake, and their health.
Placement of the stoma on the abdomen can occur at any location along the colon, the majority being on the lower left side near or in the sigmoid colon, other locations include; the ascending, transverse, and descending sections of the colon. Colostomy surgery that can be planned ahead often has a higher rate of long-term success and satisfaction than those done in emergency surgery.
# Living with a colostomy
People with colostomies must wear an ostomy pouching system to collect intestinal waste. Ordinarily the pouch must be emptied or changed several times a day depending on the frequency of activity; in general the further from the anus the ostomy is located the greater the output and more frequent the need to empty or change the pouch.
# Alternatives
In some rare situations it may be possible to opt for an internal colo-anal pouch which eliminates the need for an external pouch. In place of an external appliance, an internal ileo-anal pouch is constructed using a portion of the patient's lower intestine, to act as a new rectum to replace the removed original. | https://www.wikidoc.org/index.php/Colostomies | |
8b7865f1216e5a3b6fe1e2e424c1c83b94a8a2c9 | wikidoc | Colostrum | Colostrum
Colostrum (also known as beestings or first milk) is a form of milk produced by the mammary glands in late pregnancy and the few days after giving birth.
Human and bovine colostrums are thick, sticky and yellowish. In humans, it has high concentrations of nutrients and antibodies, but it is small in quantity.
Colostrum is high in carbohydrates, high in protein, high in antibodies, and low in fat (as human newborns may find fat difficult to digest). Newborns have very small digestive systems, and colostrum delivers its nutrients in a very concentrated low-volume form. It has a mild laxative effect, encouraging the passing of the baby's first stool, which is called meconium. This clears excess bilirubin, a waste product of dead red blood cells which is produced in large quantities at birth due to blood volume reduction, from the infant's body and helps prevent jaundice.
Colostrum contains large numbers of antibodies called "secretory immunoglobulin" (IgA) that help protect the mucous membranes in the throat, lungs, and intestines of the infant. Leukocytes are also present in large numbers; these begin protecting the infant from harmful viruses and bacteria. Ingesting colostrum establishes beneficial bacteria in the digestive tract.
Premature babies tend to fare better on human colostrum than commercial infant formulas. Ambesh Patel is made of colostrum. Human milk contains special components, called growth modulators, that help the premature baby's digestive system adjust to oral feedings (Davies 1989). Research (Schlanler 1999b; Gross and Slagle 1993; Lucas 1987; Lucas 1984) indicate that premature babies fed formula tend to vomit more and continue tube feeding longer than those fed human colostrum and breast milk.
Bovine colostrum is sometimes used by humans as a dietary supplement. It has been attributed with curative powers and used as an ingredient in food dishes for the ill or invalid (Davidson, 1999). Purified bovine colostrum extract is also sometimes used in protein supplements used by athletes and bodybuilders.
Colostrum can start as early as the second trimester for some women.
Colostrum is also called "Palethi" in Punjabi. (more citation needed) | Colostrum
Colostrum (also known as beestings or first milk) is a form of milk produced by the mammary glands in late pregnancy and the few days after giving birth.
Human and bovine colostrums are thick, sticky and yellowish. In humans, it has high concentrations of nutrients and antibodies, but it is small in quantity.
Colostrum is high in carbohydrates, high in protein, high in antibodies, and low in fat (as human newborns may find fat difficult to digest). Newborns have very small digestive systems, and colostrum delivers its nutrients in a very concentrated low-volume form. It has a mild laxative effect, encouraging the passing of the baby's first stool, which is called meconium. This clears excess bilirubin, a waste product of dead red blood cells which is produced in large quantities at birth due to blood volume reduction, from the infant's body and helps prevent jaundice.
Colostrum contains large numbers of antibodies called "secretory immunoglobulin" (IgA) that help protect the mucous membranes in the throat, lungs, and intestines of the infant. Leukocytes are also present in large numbers; these begin protecting the infant from harmful viruses and bacteria. Ingesting colostrum establishes beneficial bacteria in the digestive tract.
Premature babies tend to fare better on human colostrum than commercial infant formulas. Ambesh Patel is made of colostrum. Human milk contains special components, called growth modulators, that help the premature baby's digestive system adjust to oral feedings (Davies 1989). Research (Schlanler 1999b; Gross and Slagle 1993; Lucas 1987; Lucas 1984) indicate that premature babies fed formula tend to vomit more and continue tube feeding longer than those fed human colostrum and breast milk.
Bovine colostrum is sometimes used by humans as a dietary supplement. It has been attributed with curative powers and used as an ingredient in food dishes for the ill or invalid (Davidson, 1999). Purified bovine colostrum extract is also sometimes used in protein supplements used by athletes and bodybuilders.
Colostrum can start as early as the second trimester for some women.
Colostrum is also called "Palethi" in Punjabi. (more citation needed) | https://www.wikidoc.org/index.php/Colostrum | |
f4f6f0bd0224b8e96917fcd389da42becc967932 | wikidoc | Coltsfoot | Coltsfoot
Coltsfoot (Tussilago farfara) is a plant in the family Asteraceae.
It has been used medicinally as a cough suppressant. The name "tussilago" itself means "cough suppressant." The plant has been used since at least historical times to treat lung ailments such as asthma as well as various coughs by way of smoking. Crushed flowers supposedly cured skin conditions, and the plant has been consumed as a food item.
Coltsfoot is a perennial herbaceous plant that spreads by seeds and rhizomes. Tussilago is often found in colonies of dozens of plants. The flowers, which superficially resemble dandelions, appear in early spring before dandelions. Leaves do not appear usually until after the seeds are set. The plant is typically between 10 - 30cm.
Coltsfoot is native to several locations in Europe and Asia. It is also a common plant in North America and South America where it has been introduced, most likely by settlers as a medicinal item. The plant is often found in waste and disturbed places and along roadsides and paths. In some areas it is considered an invasive species.
Coltsfoot is used as a food plant by the larvae of some Lepidoptera species including The Gothic and Small Angle Shades. The Coltsfoot is also worked by the honey bee (apis mellifera mellifera), this species provided a lot of pollen for the honey bee.
Other common names include Ass's foot, Bull's foot, Butterbur, Coughwort, Farfara, Foal's foot, Foalswort, Horse Foot and Winter heliotrope. | Coltsfoot
Coltsfoot (Tussilago farfara) is a plant in the family Asteraceae.
It has been used medicinally as a cough suppressant. The name "tussilago" itself means "cough suppressant." The plant has been used since at least historical times to treat lung ailments such as asthma as well as various coughs by way of smoking. Crushed flowers supposedly cured skin conditions, and the plant has been consumed as a food item.
Coltsfoot is a perennial herbaceous plant that spreads by seeds and rhizomes. Tussilago is often found in colonies of dozens of plants. The flowers, which superficially resemble dandelions, appear in early spring before dandelions. Leaves do not appear usually until after the seeds are set. The plant is typically between 10 - 30cm.
Coltsfoot is native to several locations in Europe and Asia. It is also a common plant in North America and South America where it has been introduced, most likely by settlers as a medicinal item. The plant is often found in waste and disturbed places and along roadsides and paths. In some areas it is considered an invasive species.
Coltsfoot is used as a food plant by the larvae of some Lepidoptera species including The Gothic and Small Angle Shades. The Coltsfoot is also worked by the honey bee (apis mellifera mellifera), this species provided a lot of pollen for the honey bee.
Other common names include Ass's foot, Bull's foot, Butterbur, Coughwort, Farfara, Foal's foot, Foalswort, Horse Foot and Winter heliotrope.
# External links
- Coltsfoot information
- Coltsfoot Flowers Sorbet | https://www.wikidoc.org/index.php/Coltsfoot | |
4f226fef1ae97ae2c1d89d3e7d946e4a7a494755 | wikidoc | Colza oil | Colza oil
Colza oil is a non-drying oil obtained from the seeds of Brassica campestris, var. oleifera, a variety of the plant that produces Swedish turnips. Colza is extensively cultivated in France, Belgium, the Netherlands and Germany; and, especially in France, the expression of the oil is an important industry. In commerce, colza is classed with rape oil, to which it is very closely allied in both source and properties. It is a comparatively inodorous oil of a yellow color, having a specific gravity varying between 0.912 to 0.920. The cake left after expression of the oil is a valuable feeding substance for cattle. Colza oil is extensively used as a lubricant for machinery, and for burning in lamps.
In France it is used also as a substitute for fine oil in restaurants, as the oil part in a carpaccio, or as the high temperature boiling oil in beef bourguignon. Its taste is different from olive oil. Colza oil, with added color and flavor, has also been fraudulently labeled and sold as olive oil by unscrupulous Italian companies.
Colza oil was also used in Gombault's Caustic Balsam; a popular horse and human liniment at the turn of the 20th century.
Among the more unusual applications of colza oil is the calming of choppy seas, where the oil modifies the surface tension of the water and rapidly smoothes the surface. Rescue and recovery operations have been made far less risky in this way.
More recently, colza has been cultivated in France as an ingredient for biodiesel fuels. | Colza oil
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Colza oil is a non-drying oil obtained from the seeds of Brassica campestris, var. oleifera, a variety of the plant that produces Swedish turnips. Colza is extensively cultivated in France, Belgium, the Netherlands and Germany; and, especially in France, the expression of the oil is an important industry. In commerce, colza is classed with rape oil, to which it is very closely allied in both source and properties. It is a comparatively inodorous oil of a yellow color, having a specific gravity varying between 0.912 to 0.920. The cake left after expression of the oil is a valuable feeding substance for cattle. Colza oil is extensively used as a lubricant for machinery, and for burning in lamps.
In France it is used also as a substitute for fine oil in restaurants, as the oil part in a carpaccio, or as the high temperature boiling oil in beef bourguignon. Its taste is different from olive oil. Colza oil, with added color and flavor, has also been fraudulently labeled and sold as olive oil by unscrupulous Italian companies.[1]
Colza oil was also used in Gombault's Caustic Balsam; a popular horse and human liniment at the turn of the 20th century. [Note that the ingredients listed in this link are similar but not the same as the list on the actual bottle.]
Among the more unusual applications of colza oil is the calming of choppy seas, where the oil modifies the surface tension of the water and rapidly smoothes the surface. Rescue and recovery operations have been made far less risky in this way.[2]
More recently, colza has been cultivated in France as an ingredient for biodiesel fuels. | https://www.wikidoc.org/index.php/Colza_oil | |
a94bc8e24e4d696aaf1fb50c52d5a4eb8c5d0063 | wikidoc | Enflurane | Enflurane
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# Overview
Enflurane is a general anesthetic that is FDA approved for the {{{indicationType}}} of analgesia for labor/delivery, for vaginal delivery, anesthesia - obstetric procedure, as supplement to other general anesthetic agents during cesarean section, general anesthesia.. Common adverse reactions include gastrointestinal: nausea, vomiting, musculoskeletal: involuntary movement, neurologic: shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Analgesia for labor/delivery, for vaginal delivery: for vaginal delivery, 0.25 to 1% concentration.
- Anesthesia - Obstetric procedure, As supplement to other general anesthetic agents during Cesarean section: during cesarean section, 0.5 to 1% concentration (to supplement other anesthetics).
- General anesthesia: induction, 2 to 4.5% concentration via vaporizer; with oxygen or combination with oxygen-nitrous oxide mixtures.
- General anesthesia: maintenance, 0.5 to 3% concentration; max 3%
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- General anesthesia - Surgical procedure on eye proper
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Enflurane in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Enflurane FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Enflurane in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Enflurane in pediatric patients.
# Contraindications
- Seizure disorders (see Warnings)
- Known sensitivity to Enflurane or other halogenated anesthetics. Known or suspected genetic susceptibility to malignant hyperthermia
# Warnings
- Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria.
- Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.
- In susceptible individuals, enflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecificsigns may appear with light anesthesia, acute hypoxia, etc. The syndrome of malignant hyperthermia secondary to enflurane appears to be rare; by March 1980, 35 cases had been reported in North America for an approximate incidence of 1:725,000 enflurane anesthetics.) An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot cannister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., enflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangement. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible.
- Increasing depth of anesthesia with Enflurane may produce a change in the electroencephalogram characterized by high voltage, fast frequency, progressing through spike-dome complexes alternating with periods of electrical silence to frank seizure activity. The latter may or may not be associated with motor movement. Motor activity, when encountered, generally consists of twitching or “jerks” of various muscle groups; it is self-limiting and can be terminated by lowering the anesthetic concentration. This electroencephalographic pattern associated with deep anesthesia is exacerbated by low arterial carbon dioxide tension. A reduction in ventilation and anesthetic concentrations usually suffices to eliminate seizure activity. Cerebral blood flow and metabolism studies in normal volunteers immediately following seizure activity show no evidence of cerebral hypoxia. Mental function testing does not reveal any impairment of performance following prolonged enflurane anesthesia associated with or not associated with seizure activity.
- Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used.
- Hypotension and respiratory exchange can serve as a guide to depth of anesthesia. Deep levels of anesthesia may produce marked hypotension and respiratory depression When previous exposure to a halogenated anesthetic is known to have been followed by evidence of unexplained hepatic dysfunction, consideration should be given to use of an agent other than enflurane.
# Adverse Reactions
## Clinical Trials Experience
- Malignant hyperthermia (see Warnings).
- Motor activity exemplified by movements of various muscle groups and/or seizures may be encountered with deep levels of enflurane anesthesia, or light levels with hypocapnia.
- Hypotension, respiratory depression and hypoxia have been reported.
- Arrhythmias, shivering, nausea and vomiting have been reported.
- Elevation of the white blood count has been observed.
- Mild, moderate and severe liver injury, including hepatic failure, may rarely follow anesthesia with enflurane.
- Serum transaminases may be increased and histologic evidence of injury may be found. The histologic changes are neither unique nor consistent. In several of these cases, it has not been possible to exclude enflurane as the cause or as a contributing cause to liver injury. The incidence of unexplained hepatotoxicity following the administration of enflurane is unknown, but it appears to be rare and not dose related. Enflurane has also been associated with perioperative hyperkalemia (see Warnings). There have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anesthetic agents, including Enflurane. Due to the spontaneous nature of these reports, the actual incidence and relationship of Enflurane to these events cannot be established with certainty
## Postmarketing Experience
There is limited information regarding Enflurane Postmarketing Experience in the drug label.
# Drug Interactions
- The action of nondepolarizing relaxants is augmented by enflurane. Less than the usual amounts of these drugs should be used. If the usual amounts of nondepolarizing relaxants are given, the time for recovery from neuromuscular blockade will be longer in the presence of enflurane than when halothane or nitrous oxide with a balanced technique are used.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to enflurane. There are, however, no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enflurane in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Enflurane during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when enflurane is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Enflurane in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Enflurane in geriatric settings.
### Gender
There is no FDA guidance on the use of Enflurane with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Enflurane with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Enflurane in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Enflurane in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enflurane in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enflurane in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Enflurane Administration in the drug label.
### Monitoring
There is limited information regarding Enflurane Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Enflurane and IV administrations.
# Overdosage
- In the event of overdosage, or what may appear to be overdosage, the following action should be taken: Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen.
# Pharmacology
## Mechanism of Action
There is limited information regarding Enflurane Mechanism of Action in the drug label.
## Structure
- Enflurane, USP, a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether, (CHF2OCF2CHFCl). The boiling point is 56.5°C at 760 mm Hg, and the vapor pressure (in mm Hg) is 175 at 20°C, 218 at 25°C, and 345 at 36°C. Vapor pressures can be calculated using the equation:
- Enflurane is a clear, colorless, stable liquid whose purity exceeds 99.9% (area percent by gas chromatography). No stabilizers are added as these have been found, through controlled laboratory tests, to be unnecessary even in the presence of ultraviolet light. Enflurane is stable to strong base, does not decompose in contact with soda lime (at normal operating temperatures) and does not react with aluminum, tin, brass, iron or copper. The partition coefficients of enflurane at 25°C are 74 in conductive rubber and 120 in polyvinyl chloride.
## Pharmacodynamics
- Enflurane is an inhalation anesthetic. The MAC (minimum alveolar concentration) in man is 1.68% in pure oxygen, 0.57 in 70% nitrous oxide, 30% oxygen, and 1.17 in 30% nitrous oxide, 70% oxygen.Induction of and recovery from anesthesia with enflurane are rapid. Enflurane has a mild sweet odor. Enflurane may provide a mild stimulus to salivation or tracheobronchial secretions. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia can be changed rapidly by changing the inspired enflurane concentration. Enflurane reduces ventilation as depth of anesthesia increases. High PaCO2 levels can be obtained at deeper levels of anesthesia if ventilation is not supported. Enflurane provokes a sigh response reminiscent of that seen with diethyl ether. There is a decrease in blood pressure with induction of anesthesia, followed by a return to near normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding increases in hypotension. Heart rate remains relatively constant without significant bradycardia. Electrocardiographic monitoring or recordings indicate that cardiac rhythm remains stable. Elevation of the carbon dioxide level in arterial blood does not alter cardiac rhythm.
- Studies in man indicate a considerable margin of safety in the administration of Epinephrine containing solutions during enflurane anesthesia. Enflurane anesthesia has been used in excision of pheochromocytoma in man without ventricular arrhythmias. On the basis of studies in patients anesthetized with enflurane and injected with epinephrine-containing solutions to achieve hemostasis in a highly vascular area (transsphenoidal surgery), up to 2 micrograms per kilogram (2 μg/kg) of epinephrine may be injected subcutaneously over a 10 minute period in patients judged to have ordinary tolerance to epinephrine administration. This would represent up to 14 mL of 1:100,000 epinephrine-containing solution (10 μg/mL), or the equivalent quantity, in a 70 kilogram patient. This may be repeated up to 3 times per hour (total 42 mL per hour).The concomitant administration of lidocaine enhances the safety of the use of epinephrine during enflurane anesthesia. This effect of lidocain is dose related.All customary precautions in the use of vasoconstrictor substances should be observed. Muscle relaxation may be adequate for intra-abdominal operations at normal levels of anesthesia. Muscle relaxants may be used to achieve greater relaxation and all commonly used muscle relaxants are compatible with enflurane. The Nondepolarizing Muscle Relaxants Are Potentiated. In the normal 70 kg adult, 6 to 9 mg of d-tubocurarine or 1 to 1.5 mg of pancuronium will produce a 90% or greater depression of twitch height. Neostigmine does not reverse the direct effect of enflurane. Enflurane 0.25 to 1% (average 0.5%) provides analgesia equal to that produced by 30 to 60% (average 40%) nitrous oxide for vaginal delivery. With either agent, patients remain awake, cooperative and oriented. Maternal blood losses are comparable. These clinical approaches produce normal Apgar scores. Serial neurobehavioral testing of the newborn during the first 24 hours of life reveals that neither enflurane nor nitrous oxide analgesia is associated with obvious neurobehavioral alterations. Neither enflurane nor nitrous oxide when used for obstetrical analgesia alters BUN, creatinine, uric acid or osmolality.The only difference in the use of these two agents for obstetrical analgesia appears to be higher inspired oxygen concentration that may be used with enflurane. Analgetic doses of enflurane, up to approximately 1.0%, do not significantly depress the rate or force of uterine contraction during labor and delivery. A slowing of the rate of uterine contraction and a diminution of the force of uterine contraction is noted between the administration of 1.0 to 2.0% delivered enflurane; concentrations somewhere between 2.0 and 3.0% delivered enflurane may abolish uterine contractions. Enflurane displaces the myometrial response curve to oxytocin so that at lower concentrations of enflurane oxytocin will restore uterine contractions; however, as the dose of enflurane progresses (somewhere between 1.5 and 3% delivered enflurane) the response to oxytocin is diminished and then abolished. Uterine bleeding may be increased when enflurane is used in higher concentrations for vaginal delivery or to facilitate delivery by Cesarean section; however, this has not been demonstrated within the recommended dosage range (see Dosage And Administration section).
- Mean estimated blood loss in patients anesthetized for therapeutic termination of pregnancy with 1.0% enflurane in 70% nitrous oxide with oxygen is approximately twice that noted following therapeutic termination of pregnancy performed with the use of a local anesthetic technique (40 mL versus 20 mL).
## Pharmacokinetics
- Biotransformation of enflurane in man results in low peak levels of serum fluoride averaging 15 μmol/L. These levels are well below the 50 μmol/L threshold level, which can produce minimal renal damage in normal subjects. However, patients chronically ingesting isoniazid or other hydrazine-containing compounds may metabolize greater amounts of enflurane. Although no significant renal dysfunction
has been found thus far in such patients, peak serum fluoride levels can exceed 50 μmol/L, particularly when anesthesia goes beyond 2 MAC hours. Depression of lymphocyte transformation does notfollow prolonged enflurane anesthesia in man in the absence of surgery. Thus enflurane does not depress this aspect of the immune response.
## Nonclinical Toxicology
There is limited information regarding Enflurane Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Enflurane Clinical Studies in the drug label.
# How Supplied
- Enflurane, USP is packaged in 250 mL amber-colored bottles.250mL - NDC 66794-010-25
## Storage
- Store at room controlled room temperature 15° to 30°C (59° to 86°F). Enflurane, USP contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Enflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for several days following administration.
# Precautions with Alcohol
Alcohol-Enflurane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Enflurane Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Enflurane Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Enflurane
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
# Disclaimer
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# Overview
Enflurane is a general anesthetic that is FDA approved for the {{{indicationType}}} of analgesia for labor/delivery, for vaginal delivery, anesthesia - obstetric procedure, as supplement to other general anesthetic agents during cesarean section, general anesthesia.. Common adverse reactions include gastrointestinal: nausea, vomiting, musculoskeletal: involuntary movement, neurologic: shivering.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Analgesia for labor/delivery, for vaginal delivery: for vaginal delivery, 0.25 to 1% concentration.
- Anesthesia - Obstetric procedure, As supplement to other general anesthetic agents during Cesarean section: during cesarean section, 0.5 to 1% concentration (to supplement other anesthetics).
- General anesthesia: induction, 2 to 4.5% concentration via vaporizer; with oxygen or combination with oxygen-nitrous oxide mixtures.
- General anesthesia: maintenance, 0.5 to 3% concentration; max 3%
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- General anesthesia - Surgical procedure on eye proper
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Enflurane in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Enflurane FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Enflurane in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Enflurane in pediatric patients.
# Contraindications
- Seizure disorders (see Warnings)
- Known sensitivity to Enflurane or other halogenated anesthetics. Known or suspected genetic susceptibility to malignant hyperthermia
# Warnings
- Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria.
- Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.
- In susceptible individuals, enflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. (It should also be noted that many of these nonspecificsigns may appear with light anesthesia, acute hypoxia, etc. The syndrome of malignant hyperthermia secondary to enflurane appears to be rare; by March 1980, 35 cases had been reported in North America for an approximate incidence of 1:725,000 enflurane anesthetics.) An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO2 absorption system (hot cannister). PaO2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., enflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangement. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible.
- Increasing depth of anesthesia with Enflurane may produce a change in the electroencephalogram characterized by high voltage, fast frequency, progressing through spike-dome complexes alternating with periods of electrical silence to frank seizure activity. The latter may or may not be associated with motor movement. Motor activity, when encountered, generally consists of twitching or “jerks” of various muscle groups; it is self-limiting and can be terminated by lowering the anesthetic concentration. This electroencephalographic pattern associated with deep anesthesia is exacerbated by low arterial carbon dioxide tension. A reduction in ventilation and anesthetic concentrations usually suffices to eliminate seizure activity. Cerebral blood flow and metabolism studies in normal volunteers immediately following seizure activity show no evidence of cerebral hypoxia. Mental function testing does not reveal any impairment of performance following prolonged enflurane anesthesia associated with or not associated with seizure activity.
- Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used.
- Hypotension and respiratory exchange can serve as a guide to depth of anesthesia. Deep levels of anesthesia may produce marked hypotension and respiratory depression When previous exposure to a halogenated anesthetic is known to have been followed by evidence of unexplained hepatic dysfunction, consideration should be given to use of an agent other than enflurane.
# Adverse Reactions
## Clinical Trials Experience
- Malignant hyperthermia (see Warnings).
- Motor activity exemplified by movements of various muscle groups and/or seizures may be encountered with deep levels of enflurane anesthesia, or light levels with hypocapnia.
- Hypotension, respiratory depression and hypoxia have been reported.
- Arrhythmias, shivering, nausea and vomiting have been reported.
- Elevation of the white blood count has been observed.
- Mild, moderate and severe liver injury, including hepatic failure, may rarely follow anesthesia with enflurane.
- Serum transaminases may be increased and histologic evidence of injury may be found. The histologic changes are neither unique nor consistent. In several of these cases, it has not been possible to exclude enflurane as the cause or as a contributing cause to liver injury. The incidence of unexplained hepatotoxicity following the administration of enflurane is unknown, but it appears to be rare and not dose related. Enflurane has also been associated with perioperative hyperkalemia (see Warnings). There have been rare post-marketing reports of hepatic failure and hepatic necrosis associated with the use of potent volatile anesthetic agents, including Enflurane. Due to the spontaneous nature of these reports, the actual incidence and relationship of Enflurane to these events cannot be established with certainty
## Postmarketing Experience
There is limited information regarding Enflurane Postmarketing Experience in the drug label.
# Drug Interactions
- The action of nondepolarizing relaxants is augmented by enflurane. Less than the usual amounts of these drugs should be used. If the usual amounts of nondepolarizing relaxants are given, the time for recovery from neuromuscular blockade will be longer in the presence of enflurane than when halothane or nitrous oxide with a balanced technique are used.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to enflurane. There are, however, no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enflurane in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Enflurane during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when enflurane is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Enflurane in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Enflurane in geriatric settings.
### Gender
There is no FDA guidance on the use of Enflurane with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Enflurane with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Enflurane in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Enflurane in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enflurane in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enflurane in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Enflurane Administration in the drug label.
### Monitoring
There is limited information regarding Enflurane Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Enflurane and IV administrations.
# Overdosage
- In the event of overdosage, or what may appear to be overdosage, the following action should be taken: Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen.
# Pharmacology
## Mechanism of Action
There is limited information regarding Enflurane Mechanism of Action in the drug label.
## Structure
- Enflurane, USP, a nonflammable liquid administered by vaporizing, is a general inhalation anesthetic drug. It is 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether, (CHF2OCF2CHFCl). The boiling point is 56.5°C at 760 mm Hg, and the vapor pressure (in mm Hg) is 175 at 20°C, 218 at 25°C, and 345 at 36°C. Vapor pressures can be calculated using the equation:
- Enflurane is a clear, colorless, stable liquid whose purity exceeds 99.9% (area percent by gas chromatography). No stabilizers are added as these have been found, through controlled laboratory tests, to be unnecessary even in the presence of ultraviolet light. Enflurane is stable to strong base, does not decompose in contact with soda lime (at normal operating temperatures) and does not react with aluminum, tin, brass, iron or copper. The partition coefficients of enflurane at 25°C are 74 in conductive rubber and 120 in polyvinyl chloride.
## Pharmacodynamics
- Enflurane is an inhalation anesthetic. The MAC (minimum alveolar concentration) in man is 1.68% in pure oxygen, 0.57 in 70% nitrous oxide, 30% oxygen, and 1.17 in 30% nitrous oxide, 70% oxygen.Induction of and recovery from anesthesia with enflurane are rapid. Enflurane has a mild sweet odor. Enflurane may provide a mild stimulus to salivation or tracheobronchial secretions. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia can be changed rapidly by changing the inspired enflurane concentration. Enflurane reduces ventilation as depth of anesthesia increases. High PaCO2 levels can be obtained at deeper levels of anesthesia if ventilation is not supported. Enflurane provokes a sigh response reminiscent of that seen with diethyl ether. There is a decrease in blood pressure with induction of anesthesia, followed by a return to near normal with surgical stimulation. Progressive increases in depth of anesthesia produce corresponding increases in hypotension. Heart rate remains relatively constant without significant bradycardia. Electrocardiographic monitoring or recordings indicate that cardiac rhythm remains stable. Elevation of the carbon dioxide level in arterial blood does not alter cardiac rhythm.
- Studies in man indicate a considerable margin of safety in the administration of Epinephrine containing solutions during enflurane anesthesia. Enflurane anesthesia has been used in excision of pheochromocytoma in man without ventricular arrhythmias. On the basis of studies in patients anesthetized with enflurane and injected with epinephrine-containing solutions to achieve hemostasis in a highly vascular area (transsphenoidal surgery), up to 2 micrograms per kilogram (2 μg/kg) of epinephrine may be injected subcutaneously over a 10 minute period in patients judged to have ordinary tolerance to epinephrine administration. This would represent up to 14 mL of 1:100,000 epinephrine-containing solution (10 μg/mL), or the equivalent quantity, in a 70 kilogram patient. This may be repeated up to 3 times per hour (total 42 mL per hour).The concomitant administration of lidocaine enhances the safety of the use of epinephrine during enflurane anesthesia. This effect of lidocain is dose related.All customary precautions in the use of vasoconstrictor substances should be observed. Muscle relaxation may be adequate for intra-abdominal operations at normal levels of anesthesia. Muscle relaxants may be used to achieve greater relaxation and all commonly used muscle relaxants are compatible with enflurane. The Nondepolarizing Muscle Relaxants Are Potentiated. In the normal 70 kg adult, 6 to 9 mg of d-tubocurarine or 1 to 1.5 mg of pancuronium will produce a 90% or greater depression of twitch height. Neostigmine does not reverse the direct effect of enflurane. Enflurane 0.25 to 1% (average 0.5%) provides analgesia equal to that produced by 30 to 60% (average 40%) nitrous oxide for vaginal delivery. With either agent, patients remain awake, cooperative and oriented. Maternal blood losses are comparable. These clinical approaches produce normal Apgar scores. Serial neurobehavioral testing of the newborn during the first 24 hours of life reveals that neither enflurane nor nitrous oxide analgesia is associated with obvious neurobehavioral alterations. Neither enflurane nor nitrous oxide when used for obstetrical analgesia alters BUN, creatinine, uric acid or osmolality.The only difference in the use of these two agents for obstetrical analgesia appears to be higher inspired oxygen concentration that may be used with enflurane. Analgetic doses of enflurane, up to approximately 1.0%, do not significantly depress the rate or force of uterine contraction during labor and delivery. A slowing of the rate of uterine contraction and a diminution of the force of uterine contraction is noted between the administration of 1.0 to 2.0% delivered enflurane; concentrations somewhere between 2.0 and 3.0% delivered enflurane may abolish uterine contractions. Enflurane displaces the myometrial response curve to oxytocin so that at lower concentrations of enflurane oxytocin will restore uterine contractions; however, as the dose of enflurane progresses (somewhere between 1.5 and 3% delivered enflurane) the response to oxytocin is diminished and then abolished. Uterine bleeding may be increased when enflurane is used in higher concentrations for vaginal delivery or to facilitate delivery by Cesarean section; however, this has not been demonstrated within the recommended dosage range (see Dosage And Administration section).
- Mean estimated blood loss in patients anesthetized for therapeutic termination of pregnancy with 1.0% enflurane in 70% nitrous oxide with oxygen is approximately twice that noted following therapeutic termination of pregnancy performed with the use of a local anesthetic technique (40 mL versus 20 mL).
## Pharmacokinetics
- Biotransformation of enflurane in man results in low peak levels of serum fluoride averaging 15 μmol/L. These levels are well below the 50 μmol/L threshold level, which can produce minimal renal damage in normal subjects. However, patients chronically ingesting isoniazid or other hydrazine-containing compounds may metabolize greater amounts of enflurane. Although no significant renal dysfunction
has been found thus far in such patients, peak serum fluoride levels can exceed 50 μmol/L, particularly when anesthesia goes beyond 2 MAC hours. Depression of lymphocyte transformation does notfollow prolonged enflurane anesthesia in man in the absence of surgery. Thus enflurane does not depress this aspect of the immune response.
## Nonclinical Toxicology
There is limited information regarding Enflurane Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Enflurane Clinical Studies in the drug label.
# How Supplied
- Enflurane, USP is packaged in 250 mL amber-colored bottles.250mL - NDC 66794-010-25
## Storage
- Store at room controlled room temperature 15° to 30°C (59° to 86°F). Enflurane, USP contains no additives and has been demonstrated to be stable at room temperature for periods in excess of five years.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Enflurane, as well as other general anesthetics, may cause a slight decrease in intellectual function for 2 or 3 days following anesthesia. As with other anesthetics, small changes in moods and symptoms may persist for several days following administration.
# Precautions with Alcohol
Alcohol-Enflurane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Enflurane Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Enflurane Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Compound_374 | |
807cd88ff32a859e401960f2a122e4744d14c2f0 | wikidoc | Oniomania | Oniomania
# Overview
Oniomania is a medical typer term (from Greek onios = "for sale," mania = insanity) for the compulsive desire to shop. Oniomania is the technical term for the compulsive desire to shop, more commonly referred to as compulsive shopping, compulsive buying, shopping addiction or shopaholism. First described by Bleuler in 1915, and then Kraepelin in 1924, as oneomania from the Greek oneomai, to buy, included among other pathological and reactive impulses, compulsive buying went largely ignored for nearly sixty years.
# Disorders
Psychiatrists often call oniomania a disorder, but it has only been accepted as a disorder by the Deutsche Gesellschaft Zwangserkrankungen (German organization for obsessive-compulsive disorders), for several years. In the United States, impulsive-compulsive buying behavior may be diagnosed as an Impulse-Control Disorder - Not Otherwise Specified in the DSM-IV-TR. It may be under consideration for inclusion as a separate specific Impulse-Control Disorder in the next edition of the Diagnostic and Statistical Manual of Mental Disorders.
Only in the past twenty years has specific and persistent inquiry into the disorder occurred. Although the study of compulsive buying is still in its infancy compared with some of its psychological siblings—alcoholism, eating disorders or drug abuse—there is more and more evidence that it poses a serious and worsening problem, one with significant emotional, social, occupational, and financial consequences. As many as 8.9 percent of the American population may be full-fledged compulsive buyers. (Ridgway, et al., 2008), and the problem is fast becoming a global one.
The terms compulsive shopping, compulsive buying, and compulsive spending are often used interchangeably, but the behaviors they represent are in fact distinctly different (Nataraajan and Goff 1992). However, one may buy without shopping or certainly shop without buying. Most current researchers use the term compulsive buying and subscribe to an exceptionally specific definition proposed by McElroy and her colleagues (1994) as follows:
1. Compulsive buying is a maladaptive preoccupation with buying or shopping, or maladaptive buying or shopping impulses or behavior, as indicated by either: frequent preoccupation with buying or impulses to buy that is/are experienced as irresistible, intrusive, and/or senseless, or frequent buying items that are not needed or cannot be afforded or shopping for longer periods of time than intended.
2. The buying preoccupations, impulses, or behaviors cause marked distress, are time-consuming, significantly interfere with social or occupational functioning, or result in financial problems, and they do not occur exclusively during periods of hypomania or mania.
# Symptoms
Similar to other compulsive behaviors, sufferers often experience the highs and lows associated with addiction. Victims often experience moods of satisfaction when they are in the process of purchasing, which seems to give their life meaning while letting them forget about their sorrows. Once leaving the environment where the purchasing occurred, the feeling of a personal reward has already gone. To compensate, the addicted person goes shopping again. Eventually a feeling of suppression will overcome the person. For example, cases have shown that the bought goods will be hidden or destroyed, because the person concerned feels ashamed of their addiction and tries to conceal it.
# Causes
The addicted person gets into a vicious circle that consists of negative emotions like anger and stress, which lead to purchasing something. After the buying is over, the person is either regretful or depressed. In order to cope with the feelings, the addicted person resorts to another purchase.
Shopaholism often begins at an early age. Children who experience parental neglect often grow up with low self-esteem because throughout much of their childhood they experienced that they were not important as a person. As a result, they used toys to compensate for their feelings of loneliness. Adults that have depended on materials for emotional support when they were much younger are more likely to become addicted to shopping because of the ongoing sentiment of deprivation they endured as children. During adulthood, the purchase instead of the toy is substituted for affection. Shopaholics are unable to deal with their everyday problems, especially those that alter their self-esteem. Most of the issues in their lives are repressed by buying something.
Social conditions may also play an important role, especially in capitalist societies that are dominated by a consumerist economy where buying is an important part of daily life. Credit cards facilitate the spending of money as well as mail order via catalogues or the Internet. What differentiates oniomania from healthy shopping is the compulsive, destructive nature of the buying.
This disorder is often linked to emotional deprivations in childhood, an inability to tolerate negative feelings, the need to fill an internal void, excitement seeking, excessive dependency, approval seeking, perfectionism, general impulsiveness and compulsiveness, and the need to gain control (DeSarbo and Edwards 1996, Faber et al. 1987, Benson, 2000). Compulsive buying seems to represent a search for self in people whose identity is neither firmly felt nor dependable. Most shopaholics try to counteract feelings of low self-esteem through the emotional lift and momentary euphoria provided by compulsive shopping. These shoppers, who also experience a higher than normal rate of associated disorders—depression, anxiety, substance abuse, eating disorders, and impulse-control disorders—may be using their symptom to self-medicate. Underlying (or at least intensifying) the deeply felt need of problem shoppers is our nationwide outbreak of “affluenza,” the modern American plague of materialism and overconsumption.
# Consequences
The consequences of oniomania, which may persist long after a spree, can be devastating. They may include crushing consumer debt, theft or defalcation of money, defaulted loans, and general financial trouble. Sufferers often come into conflict with the law.
The “smiled upon addiction,” as Catalano and Sonnenberg have called it (1993), is smiled upon in two senses: it is at once a source of wry humor and at the same time a behavior much inflamed by our ever present marketing machinery. As a result, compulsive shopping may be an even greater source of guilt and shame than alcoholism or drug abuse.
# Self help groups
In the USA and Canada there are support groups for shopping-addicted people.
- Debtors Anonymous
- Shopping Addicts Only, Yahoo Group
- Stopping Overshopping Group Telephone Coaching Program | Oniomania
# Overview
Oniomania is a medical typer term (from Greek onios = "for sale," mania = insanity[1]) for the compulsive desire to shop. Oniomania is the technical term for the compulsive desire to shop, more commonly referred to as compulsive shopping, compulsive buying, shopping addiction or shopaholism. First described by Bleuler in 1915, and then Kraepelin in 1924, as oneomania from the Greek oneomai, to buy, included among other pathological and reactive impulses, compulsive buying went largely ignored for nearly sixty years.
# Disorders
Psychiatrists often call oniomania a disorder, but it has only been accepted as a disorder by the Deutsche Gesellschaft Zwangserkrankungen (German organization for obsessive-compulsive disorders), for several years[2]. In the United States, impulsive-compulsive buying behavior may be diagnosed as an Impulse-Control Disorder - Not Otherwise Specified in the DSM-IV-TR.[3] It may be under consideration for inclusion as a separate specific Impulse-Control Disorder in the next edition of the Diagnostic and Statistical Manual of Mental Disorders.
Only in the past twenty years has specific and persistent inquiry into the disorder occurred. Although the study of compulsive buying is still in its infancy compared with some of its psychological siblings—alcoholism, eating disorders or drug abuse—there is more and more evidence that it poses a serious and worsening problem, one with significant emotional, social, occupational, and financial consequences. As many as 8.9 percent of the American population may be full-fledged compulsive buyers. (Ridgway, et al., 2008), and the problem is fast becoming a global one.
The terms compulsive shopping, compulsive buying, and compulsive spending are often used interchangeably, but the behaviors they represent are in fact distinctly different (Nataraajan and Goff 1992). However, one may buy without shopping or certainly shop without buying. Most current researchers use the term compulsive buying and subscribe to an exceptionally specific definition proposed by McElroy and her colleagues (1994) as follows:
1. Compulsive buying is a maladaptive preoccupation with buying or shopping, or maladaptive buying or shopping impulses or behavior, as indicated by either: frequent preoccupation with buying or impulses to buy that is/are experienced as irresistible, intrusive, and/or senseless, or frequent buying items that are not needed or cannot be afforded or shopping for longer periods of time than intended.
2. The buying preoccupations, impulses, or behaviors cause marked distress, are time-consuming, significantly interfere with social or occupational functioning, or result in financial problems, and they do not occur exclusively during periods of hypomania or mania.
# Symptoms
Similar to other compulsive behaviors, sufferers often experience the highs and lows associated with addiction. Victims often experience moods of satisfaction when they are in the process of purchasing, which seems to give their life meaning while letting them forget about their sorrows. Once leaving the environment where the purchasing occurred, the feeling of a personal reward has already gone. To compensate, the addicted person goes shopping again. Eventually a feeling of suppression will overcome the person. For example, cases have shown that the bought goods will be hidden or destroyed, because the person concerned feels ashamed of their addiction and tries to conceal it.
# Causes
The addicted person gets into a vicious circle that consists of negative emotions like anger and stress, which lead to purchasing something. After the buying is over, the person is either regretful or depressed. In order to cope with the feelings, the addicted person resorts to another purchase.
Shopaholism often begins at an early age. Children who experience parental neglect often grow up with low self-esteem because throughout much of their childhood they experienced that they were not important as a person. As a result, they used toys to compensate for their feelings of loneliness. Adults that have depended on materials for emotional support when they were much younger are more likely to become addicted to shopping because of the ongoing sentiment of deprivation they endured as children. During adulthood, the purchase instead of the toy is substituted for affection. Shopaholics are unable to deal with their everyday problems, especially those that alter their self-esteem. Most of the issues in their lives are repressed by buying something.
Social conditions may also play an important role, especially in capitalist societies that are dominated by a consumerist economy where buying is an important part of daily life. Credit cards facilitate the spending of money as well as mail order via catalogues or the Internet. What differentiates oniomania from healthy shopping is the compulsive, destructive nature of the buying.
This disorder is often linked to emotional deprivations in childhood, an inability to tolerate negative feelings, the need to fill an internal void, excitement seeking, excessive dependency, approval seeking, perfectionism, general impulsiveness and compulsiveness, and the need to gain control (DeSarbo and Edwards 1996, Faber et al. 1987, Benson, 2000). Compulsive buying seems to represent a search for self in people whose identity is neither firmly felt nor dependable. Most shopaholics try to counteract feelings of low self-esteem through the emotional lift and momentary euphoria provided by compulsive shopping. These shoppers, who also experience a higher than normal rate of associated disorders—depression, anxiety, substance abuse, eating disorders, and impulse-control disorders—may be using their symptom to self-medicate. Underlying (or at least intensifying) the deeply felt need of problem shoppers is our nationwide outbreak of “affluenza,” the modern American plague of materialism and overconsumption.
# Consequences
The consequences of oniomania, which may persist long after a spree, can be devastating. They may include crushing consumer debt, theft or defalcation of money, defaulted loans, and general financial trouble. Sufferers often come into conflict with the law.
The “smiled upon addiction,” as Catalano and Sonnenberg have called it (1993), is smiled upon in two senses: it is at once a source of wry humor and at the same time a behavior much inflamed by our ever present marketing machinery. As a result, compulsive shopping may be an even greater source of guilt and shame than alcoholism or drug abuse.
# Self help groups
In the USA and Canada there are support groups for shopping-addicted people.
- Debtors Anonymous
- Shopping Addicts Only, Yahoo Group
- Stopping Overshopping Group Telephone Coaching Program [1] | https://www.wikidoc.org/index.php/Compulsive_buying | |
9c2e52fe1aab278f0b55222b00dfb1c072f5570f | wikidoc | Diffusion | Diffusion
Diffusion is the spontaneous net movement of particles from an area of high concentration to an area of low concentration in a given volume of fluid (either liquid or gas) down the concentration gradient. For example, diffusing molecules will move randomly between areas of high and low concentration but because there are more molecules in the high concentration region, more molecules will leave the high concentration region than the low concentration one. Therefore, there will be a net movement of molecules from high to low concentration. Initially, a concentration gradient leaves a smooth decrease in concentration from high to low which will form between the two regions. As time progresses, the gradient will grow increasingly shallow until the concentrations are equalized.
Diffusion is a part of your body cells, a spontaneous process. It is simply the statistical outcome of random motion. Diffusion increases entropy, decreasing Gibbs free energy, and therefore is thermodynamically favorable. Diffusion operates within the boundaries of the Second Law of Thermodynamics because it demonstrates nature's tendency to wind down, as evidenced by increasing entropy.
The diffusion equation provides a mathematical description of diffusion. This equation is derived from Fick's law, which states that the net movement of diffusing substance per unit area of section (the flux) is proportional to the concentration gradient (how steeply the concentration changes in space), and is toward lower concentration. (Thus if the concentration is uniform there will be no net motion.) The constant of proportionality is the diffusion coefficient, which depends on the diffusing species and the material through which diffusion occurs. Fick's law is an assumption that may not hold for a given diffusive system (e.g., the diffusion may depend on concentration in addition to concentration gradient), in which case the motion would not be described by the normal (simple, Fickian) diffusion equation. An analogous statement of Fick's law, for heat instead of concentration, is Fourier's law.
The mechanism of diffusion is "Brownian motion" whereby a molecule makes a random walk about a central location since by kinetic theory the mean velocity of a particle is zero if it is not subject to any external forces. Due to collisions with neighboring molecules the motion of the particle is characterized by a mean free path which tends to confine the particle. But since there is no potential field acting to restore a particle to its original position, it is still free to move about the vessel or liquid in which it is located. The Laplacian in the diffusion equation indicates that the dispersion of the particles is second order effect, i.e., due to changes in the concentration gradient.
Diffusion is often important in systems experiencing an applied force. In a conducting material, the net motion of electrons in an electrical field quickly reaches a terminal velocity (resulting in a steady current described by Ohm's law) because of the thermal (diffusive) motions of atoms. The Einstein relation relates the diffusion coefficient to the mobility of particles.
In cell biology, diffusion is a main form of transport within cells and across cell membranes.
# Types of diffusion
The spreading of any quantity that can be described by the diffusion equation or a random walk model (e.g. concentration, heat, momentum, ideas, price) can be called diffusion. Some of the most important examples are listed below.
- Atomic diffusion
- Brownian motion, for example of a single particle in a solvent
- Collective diffusion, the diffusion of a large number of (possibly interacting) particles
- Effusion of a gas through small holes.
- Electron diffusion, resulting in electric current
- Facilitated diffusion, present in some organisms.
- Gaseous diffusion, used for isotope separation
- Heat flow
- Itō diffusion
- Knudsen diffusion
- Momentum diffusion, ex. the diffusion of the hydrodynamic velocity field
- Osmosis is the diffusion of water through a cell membrane.
- Photon diffusion
- Reverse diffusion
- Self-diffusion
- Surface diffusion
Metabolism and respiration rely in part upon diffusion in addition to bulk or active processes. For example, in the alveoli of mammalian lungs, due to differences in partial pressures across the alveolar-capillary membrane, oxygen diffuses into the blood and carbon dioxide diffuses out. Lungs contain a large surface area to facilitate this gas exchange process.
# An experiment to demonstrate diffusion
Diffusion is easy to observe, but care must be taken to avoid a mixture of diffusion and other transport processes.
It can be demonstrated with a wide glass tube, two corks, some cotton wool soaked in ammonia solution and some red litmus paper. By corking the two ends of the wide glass tube and plugging the wet cotton wool with one of the corks, and the litmus paper can be hung with a thread within the tube. It will be observed that the red litmus papers turn blue.
This is because the ammonia molecules travel by diffusion from the higher concentration in the cotton wool to the lower concentration in the rest of the glass tube. As the ammonia solution is alkaline, the red litmus papers turn blue. By changing the concentration of ammonia, the rate of color change of the litmus papers can be changed. | Diffusion
Diffusion is the spontaneous net movement of particles from an area of high concentration to an area of low concentration in a given volume of fluid (either liquid or gas) down the concentration gradient. For example, diffusing molecules will move randomly between areas of high and low concentration but because there are more molecules in the high concentration region, more molecules will leave the high concentration region than the low concentration one. Therefore, there will be a net movement of molecules from high to low concentration. Initially, a concentration gradient leaves a smooth decrease in concentration from high to low which will form between the two regions. As time progresses, the gradient will grow increasingly shallow until the concentrations are equalized.
Diffusion is a part of your body cells, a spontaneous process. It is simply the statistical outcome of random motion. Diffusion increases entropy, decreasing Gibbs free energy, and therefore is thermodynamically favorable. Diffusion operates within the boundaries of the Second Law of Thermodynamics because it demonstrates nature's tendency to wind down, as evidenced by increasing entropy.[1]
The diffusion equation provides a mathematical description of diffusion. This equation is derived from Fick's law, which states that the net movement of diffusing substance per unit area of section (the flux) is proportional to the concentration gradient (how steeply the concentration changes in space), and is toward lower concentration. (Thus if the concentration is uniform there will be no net motion.) The constant of proportionality is the diffusion coefficient, which depends on the diffusing species and the material through which diffusion occurs. Fick's law is an assumption that may not hold for a given diffusive system (e.g., the diffusion may depend on concentration in addition to concentration gradient), in which case the motion would not be described by the normal (simple, Fickian) diffusion equation. An analogous statement of Fick's law, for heat instead of concentration, is Fourier's law.
The mechanism of diffusion is "Brownian motion" whereby a molecule makes a random walk about a central location since by kinetic theory the mean velocity of a particle is zero if it is not subject to any external forces. Due to collisions with neighboring molecules the motion of the particle is characterized by a mean free path which tends to confine the particle. But since there is no potential field acting to restore a particle to its original position, it is still free to move about the vessel or liquid in which it is located. The Laplacian in the diffusion equation indicates that the dispersion of the particles is second order effect, i.e., due to changes in the concentration gradient.
Diffusion is often important in systems experiencing an applied force. In a conducting material, the net motion of electrons in an electrical field quickly reaches a terminal velocity (resulting in a steady current described by Ohm's law) because of the thermal (diffusive) motions of atoms. The Einstein relation relates the diffusion coefficient to the mobility of particles.
In cell biology, diffusion is a main form of transport within cells and across cell membranes.
# Types of diffusion
The spreading of any quantity that can be described by the diffusion equation or a random walk model (e.g. concentration, heat, momentum, ideas, price) can be called diffusion. Some of the most important examples are listed below.
- Atomic diffusion
- Brownian motion, for example of a single particle in a solvent
- Collective diffusion, the diffusion of a large number of (possibly interacting) particles
- Effusion of a gas through small holes.
- Electron diffusion, resulting in electric current
- Facilitated diffusion, present in some organisms.
- Gaseous diffusion, used for isotope separation
- Heat flow
- Itō diffusion
- Knudsen diffusion
- Momentum diffusion, ex. the diffusion of the hydrodynamic velocity field
- Osmosis is the diffusion of water through a cell membrane.
- Photon diffusion
- Reverse diffusion
- Self-diffusion
- Surface diffusion
Metabolism and respiration rely in part upon diffusion in addition to bulk or active processes. For example, in the alveoli of mammalian lungs, due to differences in partial pressures across the alveolar-capillary membrane, oxygen diffuses into the blood and carbon dioxide diffuses out. Lungs contain a large surface area to facilitate this gas exchange process.
# An experiment to demonstrate diffusion
Diffusion is easy to observe, but care must be taken to avoid a mixture of diffusion and other transport processes.
It can be demonstrated with a wide glass tube, two corks, some cotton wool soaked in ammonia solution and some red litmus paper. By corking the two ends of the wide glass tube and plugging the wet cotton wool with one of the corks, and the litmus paper can be hung with a thread within the tube. It will be observed that the red litmus papers turn blue.
This is because the ammonia molecules travel by diffusion from the higher concentration in the cotton wool to the lower concentration in the rest of the glass tube. As the ammonia solution is alkaline, the red litmus papers turn blue. By changing the concentration of ammonia, the rate of color change of the litmus papers can be changed. | https://www.wikidoc.org/index.php/Concentration_gradient | |
bf8c4b873308c9c03ae634d994a22525603cde25 | wikidoc | Turbinate | Turbinate
In anatomy, a turbinate (or nasal concha) is a long, narrow and curled bone shelf (shaped like an elongated sea-shell) which protrudes into the breathing passage of the nose. Turbinate bone refers to any of the scrolled spongy bones of the nasal passages in humans and other vertebrates.
In humans, the turbinates divide the nasal airway into three groove-like air passages –and are responsible for forcing inhaled air to flow in a steady, regular pattern around the largest possible surface of cilia and climate controlling tissue.
# Structure and functions of turbinates
Turbinates are composed of pseudo-stratified columnar ciliated respiratory epithelium with a thick, vascular and erectile glandular tissue layer.
The turbinates are located laterally in the nasal cavities, curling medially and downwards into the nasal airway. Each pair is composed of one turbinate in either side of the nasal cavity, divided by the septum.
The inferior turbinates are the largest turbinates, and can be as long as the index finger, and are responsible for the majority of airflow direction, humidification, heating, and filtering of air inhaled through the nose.
The middle turbinates are smaller, usually as long as the pinky finger. They project downwards over the openings of the maxillary and ethmoid sinuses, and act as buffers to protect the sinuses from coming in direct contact with pressurized nasal airflow. Most inhaled airflow travels between the inferior turbinate and the middle turbinate.
The superior turbinates are smaller structures, connected to the middle turbinates by nerve-endings, and serve to protect the olfactory bulb.
## Role of turbinates in the respiratory system
The turbinates compose most of the mucosal tissue of the nose and are required for functional respiration. The turbinates are enriched with airflow pressure and temperature sensing nerve receptors (linked to the “trigeminal” nerve route, the fifth cranial nerve), allowing for tremendous erectile capabilities of nasal congestion and decongestion (very much like the penis), in response to the climatic conditions and changing needs of the body.
The turbinates are also responsible for filtration, heating and humidification of air inhaled through the nose. Of these three, filtration is the most important reason to breathe through the nose. As air passes over the turbinate tissues it is heated to body temperature, humidified (up to 98% water saturation) and filtered.
## Role of turbinates as an immunological defense
The respiratory epithelium which covers the erectile tissue (or Lamina propria) of the turbinates, plays a major role in the body’s first line of immunological defense. The respiratory epithelium is partially composed of mucus producing goblet cells. This secreted mucus covers the nasal cavities, and serves as a filter, by trapping air-borne particles larger than 2 to 3 micrometers. The respiratory epithelium also serves as a means of access for the lymphatic system which protects the body from being infected by viruses or bacteria.
## Role of turbinates in olfaction
The turbinates provide, first and foremost, the humidity needed to preserve the delicate olfactory (smell) epithelium needed to keep the olfactory receptors healthy and alert. If the epithelial layer gets dry or irritated, it may cease to function. This is usually a temporary condition, but over time, may lead to chronic anosmia. The turbinates also increase the surface area of the inside of the nose, and by directing and deflecting airflow across the maximum mucosal surface of the inner nose, they are able to propel the inspired air. This, coupled with the humidity and filtration provided by the turbinates, helps to carry more scent molecules towards the higher, and very narrow regions of the nasal airways, where olfaction nerve receptors are located.
The superior turbinates literally hood-over, and protect the nerve axons piercing through the cribriform plate (a porous bone plate that separates the nose from the brain) into the nose. Some areas of the middle turbinates are also innervated by the olfactory bulb. All three turbinates are innervated by pain and temperature receptors, via the trigeminal nerve (or, the fifth cranial nerve). Research has shown that there is a strong connection between these nerve endings and activation of the olfactory receptors, but science has yet to fully explain this interaction.
# Turbinate dysfunction
Large, swollen turbinates may lead to blockage of nasal breathing. Allergies, exposure to environmental irritants, or a persistent inflammation within the sinuses, can lead to turbinate swelling. Deformity of the nasal septum can also result in enlarged turbinates.
Treatment of the underlying allergy or irritant may reduce turbinate swelling. In cases that do not resolve, or for treatment of deviated septum, turbinate reduction surgery may be required. Generally, because the turbinates are essential for respiration, only small amounts of turbinate tissue are removed. Extensive reduction of the inferior or middle turbinates can cause empty nose syndrome. | Turbinate
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In anatomy, a turbinate (or nasal concha) is a long, narrow and curled bone shelf (shaped like an elongated sea-shell) which protrudes into the breathing passage of the nose. Turbinate bone refers to any of the scrolled spongy bones of the nasal passages in humans and other vertebrates.
[1]
In humans, the turbinates divide the nasal airway into three groove-like air passages –and are responsible for forcing inhaled air to flow in a steady, regular pattern around the largest possible surface of cilia and climate controlling tissue.
# Structure and functions of turbinates
Turbinates are composed of pseudo-stratified columnar ciliated respiratory epithelium with a thick, vascular and erectile glandular tissue layer.
[2] The turbinates are located laterally in the nasal cavities, curling medially and downwards into the nasal airway. Each pair is composed of one turbinate in either side of the nasal cavity, divided by the septum.[2]
The inferior turbinates are the largest turbinates, and can be as long as the index finger, and are responsible for the majority of airflow direction, humidification, heating, and filtering of air inhaled through the nose.[1]
The middle turbinates are smaller, usually as long as the pinky finger. They project downwards over the openings of the maxillary and ethmoid sinuses, and act as buffers to protect the sinuses from coming in direct contact with pressurized nasal airflow. Most inhaled airflow travels between the inferior turbinate and the middle turbinate.[1]
The superior turbinates are smaller structures, connected to the middle turbinates by nerve-endings, and serve to protect the olfactory bulb.[1]
## Role of turbinates in the respiratory system
The turbinates compose most of the mucosal tissue of the nose and are required for functional respiration. The turbinates are enriched with airflow pressure and temperature sensing nerve receptors (linked to the “trigeminal” nerve route, the fifth cranial nerve), allowing for tremendous erectile capabilities of nasal congestion and decongestion (very much like the penis), in response to the climatic conditions and changing needs of the body.[2]
The turbinates are also responsible for filtration, heating and humidification of air inhaled through the nose. Of these three, filtration is the most important reason to breathe through the nose.[citation needed] As air passes over the turbinate tissues it is heated to body temperature, humidified (up to 98% water saturation) and filtered.[2]
## Role of turbinates as an immunological defense
The respiratory epithelium which covers the erectile tissue (or Lamina propria) of the turbinates, plays a major role in the body’s first line of immunological defense. The respiratory epithelium is partially composed of mucus producing goblet cells. This secreted mucus covers the nasal cavities, and serves as a filter, by trapping air-borne particles larger than 2 to 3 micrometers. The respiratory epithelium also serves as a means of access for the lymphatic system which protects the body from being infected by viruses or bacteria.[1]
## Role of turbinates in olfaction
The turbinates provide, first and foremost, the humidity needed to preserve the delicate olfactory (smell) epithelium needed to keep the olfactory receptors healthy and alert. If the epithelial layer gets dry or irritated, it may cease to function. This is usually a temporary condition, but over time, may lead to chronic anosmia[2]. The turbinates also increase the surface area of the inside of the nose, and by directing and deflecting airflow across the maximum mucosal surface of the inner nose, they are able to propel the inspired air. This, coupled with the humidity and filtration provided by the turbinates, helps to carry more scent molecules towards the higher, and very narrow regions of the nasal airways, where olfaction nerve receptors are located[1].
The superior turbinates literally hood-over, and protect the nerve axons piercing through the cribriform plate (a porous bone plate that separates the nose from the brain) into the nose. Some areas of the middle turbinates are also innervated by the olfactory bulb. All three turbinates are innervated by pain and temperature receptors, via the trigeminal nerve (or, the fifth cranial nerve)[2]. Research has shown that there is a strong connection between these nerve endings and activation of the olfactory receptors, but science has yet to fully explain this interaction.
# Turbinate dysfunction
Large, swollen turbinates may lead to blockage of nasal breathing. Allergies, exposure to environmental irritants, or a persistent inflammation within the sinuses, can lead to turbinate swelling. Deformity of the nasal septum can also result in enlarged turbinates.
[3]
Treatment of the underlying allergy or irritant may reduce turbinate swelling. In cases that do not resolve, or for treatment of deviated septum, turbinate reduction surgery may be required. Generally, because the turbinates are essential for respiration, only small amounts of turbinate tissue are removed. Extensive reduction of the inferior or middle turbinates can cause empty nose syndrome.[3] | https://www.wikidoc.org/index.php/Conch%C3%A6 | |
d4a45f78aa7e0a95572cea638d89f92a214e6d8f | wikidoc | Cone cell | Cone cell
# Overview
Cone cells, or cones, are cells in the retina of the eye which only function in relatively bright light. The cone cells gradually become more sparse towards the periphery of the retina.
A commonly cited figure of six million in the human eye was found by Osterberg in 1935. Oyster's textbook (1999) cites work by Curcio et al. (1990) indicating an average closer to 4.5 million cone cells and 90 million rod cells in the human retina.
Cones are less sensitive to light than the rod cells in the retina (which support vision at low light levels), but allow the perception of color. They are also able to perceive finer detail and more rapid changes in images, because their response times to stimuli are faster than those of rods. Because humans usually have three kinds of cones, with different photopsins, which have different response curves, and thus respond to variation in color in different ways, they have trichromatic vision. Being color blind can change this, and there have been reports of people with four or more types of cones, giving them tetrachromatic vision.
# Types
Humans normally have three kinds of cones. The first responds most to light of long wavelengths, peaking in the yellow region; this type is designated L for long. The second type responds most to light of medium-wavelength, peaking at green, and is abbreviated M for medium. The third type responds most to short-wavelength light, of a violet color, and is designated S for short. The three types have peak wavelengths near 564–580 nm, 534–545 nm, and 420–440 nm, respectively.
The difference in the signals received from the three cone types allows the brain to perceive all possible colors, through the opponent process of color vision.
The color yellow, for example, is perceived when the L cones are stimulated slightly more than the M cones, and the color red is perceived when the L cones are stimulated significantly more than the M cones. Similarly, blue and violet hues are perceived when the S receptor is stimulated more than the other two.
The S cones are most sensitive to light at wavelengths around 420 nm. However, the lens and cornea of the human eye are increasingly absorbative to smaller wavelengths, and this sets the lower wavelength limit of human-visible light to approximately 380 nm, which is therefore called 'ultraviolet' light. People with aphakia, a condition where the eye lacks a lens, sometimes report the ability to see into the ultraviolet range. At moderate to bright light levels where the cones functions, the eye is more sensitive to yellowish-green light than other colors because this stimulates the two most common of the three kinds of cones almost equally. At lower light levels, where only the rod cells function, the sensitivity is greatest at a blueish-green wavelength.
# Structure
Cone cells are larger than rods, and are much less numerous than rods in most parts of the retina, but greatly outnumber rods in the fovea. Structurally, cone cells have a cone-like shape at one end where a pigment filters incoming light, giving them their different response curves. They are typically 40-50 µm long, and their diameter varies from .50 to 4.0 µm, being smallest and most tightly packed at the center of the eye at the fovea. The S cones are a little larger than the others.
Photobleaching can be used to determine cone arrangement. This is done by exposing dark-adapted retina to a certain wavelength of light that paralyzes the particular type of cone sensitive to that wavelength for up to thirty minutes from being able to dark-adapt making it appear white in contrast to the grey dark-adapted cones when a picture of the retina is taken. The results illustrate that S cones are randomly placed and appear much less frequently than the M and L cones. The ratio of M and L cones varies greatly among different people with regular vision.
Like rods, each cone cell has a synaptic terminal, an inner segment, and an outer segment as well as an interior nucleus and various mitochondria. The synaptic terminal forms a synapse with a neuron such as a bipolar cell. The inner and outer segments are connected by a cilium. The inner segment contains organelles and the cell's nucleus, while the outer segment, which is pointed toward the back of the eye, contains the light-absorbing materials.
Like rods, the outer segments of cones have invaginations of their cell membranes that create stacks of membranous disks. Photopigments exist as transmembrane proteins within these disks, which provide more surface area for light to affect the pigments. In cones, these disks are attached to the outer membrane, whereas they are pinched off and exist separately in rods. Neither rods nor cones divide, but their membranous disks wear out and are sloughed off at the end of the outer segment, to be consumed and recycled by phagocytic cells.
# Response to light
Activation of a photoreceptor cell is actually a hyperpolarization; when they are not being stimulated, rods and cones depolarize and release a neurotransmitter spontaneously, and activation of photopigments by light sends a signal by preventing this. Depolarization occurs due to the fact that in the dark, cells have a relatively high concentration of cyclic guanosine 3'-5' monophosphate (cGMP), which opens ion channels (largely sodium channels, though Calcium can enter through these channels as well). The positive charges of the ions that enter the cell down its electrochemical gradient change the cell's membrane potential, cause depolarization, and lead to the release of the neurotransmitter glutamate. Glutamate can depolarize some neurons and hyperpolarize others, allowing photoreceptors to interact in an antagonistic manner.
When light hits photoreceptive pigments within the photoreceptor cell, the pigment changes shape. The pigment, called iodopsin (rhodopsin is found in rod cells) consists of a large protein called opsin (situated in the plasma membrane), attached to which is a covalently-bound prosthetic group: an organic molecule called retinal (a derivative of vitamin A). The retinal exists in the 11-cis-retinal form when in the dark, and stimulation by light causes its structure to change to all-trans-retinal. This structural change causes it to activate a regulatory protein called transducin, which leads to the activation of cGMP phosphodiesterase, which breaks cGMP down into 5'-GMP. Reduction in cGMP allows the ion channels to close, preventing the influx of positive ions, hyperpolarizing the cell, and stopping the release of neurotransmitters (Kandel et al., 2000). Though cone cells primarily use the transmitter substance acetyl choline, rod cells use a variety. The entire process by which light initiates a sensory response is called visual phototransduction.
## Table
Comparison of rod and cone cells, from Kandel. | Cone cell
# Overview
Cone cells, or cones, are cells in the retina of the eye which only function in relatively bright light. The cone cells gradually become more sparse towards the periphery of the retina.
A commonly cited figure of six million in the human eye was found by Osterberg in 1935. Oyster's textbook (1999) cites work by Curcio et al. (1990) indicating an average closer to 4.5 million cone cells and 90 million rod cells in the human retina.
Cones are less sensitive to light than the rod cells in the retina (which support vision at low light levels), but allow the perception of color. They are also able to perceive finer detail and more rapid changes in images, because their response times to stimuli are faster than those of rods.[1] Because humans usually have three kinds of cones, with different photopsins, which have different response curves, and thus respond to variation in color in different ways, they have trichromatic vision. Being color blind can change this, and there have been reports of people with four or more types of cones, giving them tetrachromatic vision.
# Types
Humans normally have three kinds of cones. The first responds most to light of long wavelengths, peaking in the yellow region; this type is designated L for long. The second type responds most to light of medium-wavelength, peaking at green, and is abbreviated M for medium. The third type responds most to short-wavelength light, of a violet color, and is designated S for short. The three types have peak wavelengths near 564–580 nm, 534–545 nm, and 420–440 nm, respectively.[2][3]
The difference in the signals received from the three cone types allows the brain to perceive all possible colors, through the opponent process of color vision.
The color yellow, for example, is perceived when the L cones are stimulated slightly more than the M cones, and the color red is perceived when the L cones are stimulated significantly more than the M cones. Similarly, blue and violet hues are perceived when the S receptor is stimulated more than the other two.
The S cones are most sensitive to light at wavelengths around 420 nm. However, the lens and cornea of the human eye are increasingly absorbative to smaller wavelengths, and this sets the lower wavelength limit of human-visible light to approximately 380 nm, which is therefore called 'ultraviolet' light. People with aphakia, a condition where the eye lacks a lens, sometimes report the ability to see into the ultraviolet range.[4] At moderate to bright light levels where the cones functions, the eye is more sensitive to yellowish-green light than other colors because this stimulates the two most common of the three kinds of cones almost equally. At lower light levels, where only the rod cells function, the sensitivity is greatest at a blueish-green wavelength.
# Structure
Cone cells are larger than rods, and are much less numerous than rods in most parts of the retina, but greatly outnumber rods in the fovea. Structurally, cone cells have a cone-like shape at one end where a pigment filters incoming light, giving them their different response curves. They are typically 40-50 µm long, and their diameter varies from .50 to 4.0 µm, being smallest and most tightly packed at the center of the eye at the fovea. The S cones are a little larger than the others.
Photobleaching can be used to determine cone arrangement. This is done by exposing dark-adapted retina to a certain wavelength of light that paralyzes the particular type of cone sensitive to that wavelength for up to thirty minutes from being able to dark-adapt making it appear white in contrast to the grey dark-adapted cones when a picture of the retina is taken. The results illustrate that S cones are randomly placed and appear much less frequently than the M and L cones. The ratio of M and L cones varies greatly among different people with regular vision.[5]
Like rods, each cone cell has a synaptic terminal, an inner segment, and an outer segment as well as an interior nucleus and various mitochondria. The synaptic terminal forms a synapse with a neuron such as a bipolar cell. The inner and outer segments are connected by a cilium.[1] The inner segment contains organelles and the cell's nucleus, while the outer segment, which is pointed toward the back of the eye, contains the light-absorbing materials.[1]
Like rods, the outer segments of cones have invaginations of their cell membranes that create stacks of membranous disks. Photopigments exist as transmembrane proteins within these disks, which provide more surface area for light to affect the pigments. In cones, these disks are attached to the outer membrane, whereas they are pinched off and exist separately in rods. Neither rods nor cones divide, but their membranous disks wear out and are sloughed off at the end of the outer segment, to be consumed and recycled by phagocytic cells.
# Response to light
Activation of a photoreceptor cell is actually a hyperpolarization; when they are not being stimulated, rods and cones depolarize and release a neurotransmitter spontaneously, and activation of photopigments by light sends a signal by preventing this. Depolarization occurs due to the fact that in the dark, cells have a relatively high concentration of cyclic guanosine 3'-5' monophosphate (cGMP), which opens ion channels (largely sodium channels, though Calcium can enter through these channels as well). The positive charges of the ions that enter the cell down its electrochemical gradient change the cell's membrane potential, cause depolarization, and lead to the release of the neurotransmitter glutamate. Glutamate can depolarize some neurons and hyperpolarize others, allowing photoreceptors to interact in an antagonistic manner.
When light hits photoreceptive pigments within the photoreceptor cell, the pigment changes shape. The pigment, called iodopsin (rhodopsin is found in rod cells) consists of a large protein called opsin (situated in the plasma membrane), attached to which is a covalently-bound prosthetic group: an organic molecule called retinal (a derivative of vitamin A). The retinal exists in the 11-cis-retinal form when in the dark, and stimulation by light causes its structure to change to all-trans-retinal. This structural change causes it to activate a regulatory protein called transducin, which leads to the activation of cGMP phosphodiesterase, which breaks cGMP down into 5'-GMP. Reduction in cGMP allows the ion channels to close, preventing the influx of positive ions, hyperpolarizing the cell, and stopping the release of neurotransmitters (Kandel et al., 2000). Though cone cells primarily use the transmitter substance acetyl choline, rod cells use a variety. The entire process by which light initiates a sensory response is called visual phototransduction.
## Table
Comparison of rod and cone cells, from Kandel.[1] | https://www.wikidoc.org/index.php/Cone_cell | |
bcca457af12a001f70811082ac8b4067b3051c0a | wikidoc | Flat feet | Flat feet
Flat feet, also called pes planus or fallen arches, is a condition in which the arch of the foot collapses, with the entire sole of the foot coming into complete or near-complete contact with the ground. In some individuals (an estimated 20-30% of the general population) the arch simply never develops in one foot (unilaterally) or both feet (bilaterally). It should be noted that being flatfooted does not decrease footspeed.
# Flat Feet in Children
The appearance of flat feet is normal and common in infants, partly due to "baby fat" which masks the developing arch and partly because the arch has not yet fully developed. The human arch develops in infancy and early childhood as part of normal muscle, tendon, ligament and bone growth. Training of the feet, especially by foot gymnastics and going barefoot on varying terrain, can facilitate the formation of arches during childhood, with a developed arch occurring for most by the age of four to six years.
Because young children are unlikely to suspect or identify flat feet on their own, it is a good idea for parents or other adult caregivers to check on this themselves. Besides visual inspection, parents should notice whether a child begins to walk oddly, for example on the outer edges of the feet, or to limp, during long walks, and to ask the child whether he or she feels foot pain (which some have described as feeling like a nail going through the foot) during such walks.
Children who complain about calf muscle pains or any other pains around the foot area, are likely to have flat feet. Recent medical research indicates that arch support inserts and certain heel cups, inserted into a growing child's shoes, can facilitate the proper development of the longitudinal arch, by holding the foot in the correct neutral position while it is growing. There is little debate, however, that going barefoot, particularly over terrain such as a beach where muscles are given a good workout, is good for all but the most extremely flatfooted, or those with certain related conditions such as plantar fasciitis. One medical study in India with a large sample size of children who had grown up wearing shoes and others going barefoot, found that the longitudinal arches of the barefooters were generally strongest and highest as a group, and that flat feet were less common in children who had grown up wearing sandals or slippers than among those who had worn closed-toe shoes.
# Flat Feet in Adults
Flat feet can also develop as an adult ("adult acquired flatfoot") due to injury, illness, unusual or prolonged stress to the foot, faulty biomechanics, or as part of the normal aging process. Flat feet can also occur in pregnant women as a result of temporary changes, due to increased elastin (elasticity) during pregnancy. However, if developed by adulthood, flat feet generally remain flat permanently.
If a youth or adult appears flatfooted while standing in a full weight-bearing position, but an arch appears when the person dorsiflexes (stands on tip-toe or pulls the toes back with the rest of the foot flat on the floor), this condition is called flexible flatfoot. Muscular training of the feet, while generally helpful, will usually not result in increased arch height in adults, because the muscles in the human foot are so short that exercise will generally not make much difference, regardless of the variety or amount of exercise. However, as long as the foot is still growing, there is still a possibility that a lasting arch can be created.
# Diagnosis and Treatment
A podiatrist can easily diagnose a flat foot condition during an office visit. An easy and traditional home diagnosis is the "wet foot" test, performed by wetting the feet in water and then standing on a surface such as cement or heavy paper. If the impression that the wet foot leaves does not show a dry area where the arch should be, it is a good indication of flat feet.
Most flexible flat feet are asymptomatic; not painful. In these cases there is no real cause for concern. Rigid flatfoot, a condition where the sole of the foot is rigidly flat even when a person is not standing, can be legitimate cause for concern, however. Other flatfoot-related conditions, such as various forms of tarsal coalition (two or more bones in the midfoot or hindfoot abnormally joined) or an accessory navicular (extra bone on the side of the foot) should be treated promptly, usually by the very early teen years, before a child's bone structure firms up permanently as a young adult. Both tarsal coalition and an accessory navicular can be confirmed by x-ray.
Treatment of flat feet may also be appropriate if there is associated foot or lower leg pain, or if the condition affects the knees or the back. Treatment may include using arch supports/orthotics, foot gymnastics or other exercises as recommended by a podiatrist or other physician. Surgery, while a last resort, can provide lasting relief, and even create an arch where none existed before, but is usually very costly.
Several studies of soldiers explored the link between arch height and stress fractures. One study of 287 Israeli Defense Force recruits found that those with high arches suffered almost four times as many stress fractures as those with the lowest arches. One later study of 449 US naval special warfare trainees found no significant difference in the incidence of stress fractures among soldiers with different arch heights and another was inconclusive. | Flat feet
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Flat feet, also called pes planus or fallen arches, is a condition in which the arch of the foot collapses, with the entire sole of the foot coming into complete or near-complete contact with the ground. In some individuals (an estimated 20-30% of the general population) the arch simply never develops in one foot (unilaterally) or both feet (bilaterally). It should be noted that being flatfooted does not decrease footspeed.
# Flat Feet in Children
The appearance of flat feet is normal and common in infants, partly due to "baby fat" which masks the developing arch and partly because the arch has not yet fully developed. The human arch develops in infancy and early childhood as part of normal muscle, tendon, ligament and bone growth. Training of the feet, especially by foot gymnastics and going barefoot on varying terrain, can facilitate the formation of arches during childhood, with a developed arch occurring for most by the age of four to six years.
Because young children are unlikely to suspect or identify flat feet on their own, it is a good idea for parents or other adult caregivers to check on this themselves. Besides visual inspection, parents should notice whether a child begins to walk oddly, for example on the outer edges of the feet, or to limp, during long walks, and to ask the child whether he or she feels foot pain (which some have described as feeling like a nail going through the foot) during such walks.
Children who complain about calf muscle pains or any other pains around the foot area, are likely to have flat feet. Recent medical research indicates that arch support inserts and certain heel cups, inserted into a growing child's shoes, can facilitate the proper development of the longitudinal arch, by holding the foot in the correct neutral position while it is growing. There is little debate, however, that going barefoot, particularly over terrain such as a beach where muscles are given a good workout, is good for all but the most extremely flatfooted, or those with certain related conditions such as plantar fasciitis. One medical study in India with a large sample size of children who had grown up wearing shoes and others going barefoot, found that the longitudinal arches of the barefooters were generally strongest and highest as a group, and that flat feet were less common in children who had grown up wearing sandals or slippers than among those who had worn closed-toe shoes.[1]
# Flat Feet in Adults
Flat feet can also develop as an adult ("adult acquired flatfoot") due to injury, illness, unusual or prolonged stress to the foot, faulty biomechanics, or as part of the normal aging process. Flat feet can also occur in pregnant women as a result of temporary changes, due to increased elastin (elasticity) during pregnancy. However, if developed by adulthood, flat feet generally remain flat permanently.
If a youth or adult appears flatfooted while standing in a full weight-bearing position, but an arch appears when the person dorsiflexes (stands on tip-toe or pulls the toes back with the rest of the foot flat on the floor), this condition is called flexible flatfoot. Muscular training of the feet, while generally helpful, will usually not result in increased arch height in adults, because the muscles in the human foot are so short that exercise will generally not make much difference, regardless of the variety or amount of exercise. However, as long as the foot is still growing, there is still a possibility that a lasting arch can be created.
# Diagnosis and Treatment
A podiatrist can easily diagnose a flat foot condition during an office visit. An easy and traditional home diagnosis is the "wet foot" test, performed by wetting the feet in water and then standing on a surface such as cement or heavy paper. If the impression that the wet foot leaves does not show a dry area where the arch should be, it is a good indication of flat feet.
Most flexible flat feet are asymptomatic; not painful. In these cases there is no real cause for concern. Rigid flatfoot, a condition where the sole of the foot is rigidly flat even when a person is not standing, can be legitimate cause for concern, however. Other flatfoot-related conditions, such as various forms of tarsal coalition (two or more bones in the midfoot or hindfoot abnormally joined) or an accessory navicular (extra bone on the side of the foot) should be treated promptly, usually by the very early teen years, before a child's bone structure firms up permanently as a young adult. Both tarsal coalition and an accessory navicular can be confirmed by x-ray.
Treatment of flat feet may also be appropriate if there is associated foot or lower leg pain, or if the condition affects the knees or the back. Treatment may include using arch supports/orthotics, foot gymnastics or other exercises as recommended by a podiatrist or other physician. Surgery, while a last resort, can provide lasting relief, and even create an arch where none existed before, but is usually very costly.
Several studies of soldiers explored the link between arch height and stress fractures. One study of 287 Israeli Defense Force recruits found that those with high arches suffered almost four times as many stress fractures as those with the lowest arches. One later study of 449 US naval special warfare trainees found no significant difference in the incidence of stress fractures among soldiers with different arch heights and another was inconclusive.[2] | https://www.wikidoc.org/index.php/Congenital_pes_planus | |
2988bd4f041f0b665699301bf77edbb0db1ed56d | wikidoc | Congo red | Congo red
Congo red is the sodium salt of benzidinediazo-bis-1-naphtylamine-4-sulfonic acid (formula: C32H22N6Na2O6S2; molecular weight: 696.66 g/mol). It is a secondary diazo dye. Congo red is water soluble, yielding a red colloidal solution; its solubility is better in organic solvents such as ethanol.
It has a strong, though apparently non-covalent affinity to cellulose fibres. However, the use of congo red in the cellulose industries (cotton textile, wood pulp & paper) has long been abandoned, mainly because of its toxicity.
# Behaviour in solution
Due to a color change from blue to red at pH 3.0-5.2, congo red can be used as a pH indicator. Since this color change is an approximate inverse of that of litmus, it can be used with litmus paper in a simple parlor trick: add a drop or two of congo red to both an acid solution and a base solution. Dipping red litmus paper in the red solution will turn it blue, while dipping blue litmus paper in the blue solution will turn it red.
Congo red has a propensity to aggregate in aqueous and organic solutions. The proposed mechanisms suggest hydrophobic interactions between the aromatic rings of the dye molecules, leading to a pi-pi stacking phenomenon. Although these aggregates are present under various sizes and shapes, the "ribbon-like micelles" of a few molecules seem to be the predominant form (even if the "micelle" term is not totally appropriate here). This aggregation phenomenon is more important for high congo red concentrations, at high salinity and/or low pH.
# Dyeing activity
As suggested by its intense red color, congo red has important spectrophotometric properties. Indeed, its UV-visible absorption spectrum shows a characteristic, intense peak around 498 nm in aqueous solution, at low dye concentration. Congo red molar extinction coefficient is about 45000 /. in these conditions. Aggregation of the dye tends to red-shift the absorption spectrum, whereas binding to cellulose fibres or amyloid fibrils has the opposite effect.
Congo red also shows a fluorescent activity when bound to amyloid fibrils, which tends to be used as a sensitive diagnosis tool for amyloidosis, instead of the traditional histological birefringence test.
# Diagnostic use
In biochemistry and histology, congo red is used to stain microscopic preparates, especially as a cytoplasm and erythrocyte stain. Apple-green birefringence of Congo red stained preparates under polarized light is indicative for the presence of amyloid fibrils.
de:Kongorot | Congo red
Template:Chembox new
Congo red is the sodium salt of benzidinediazo-bis-1-naphtylamine-4-sulfonic acid (formula: C32H22N6Na2O6S2; molecular weight: 696.66 g/mol). It is a secondary diazo dye. Congo red is water soluble, yielding a red colloidal solution; its solubility is better in organic solvents such as ethanol.
It has a strong, though apparently non-covalent affinity to cellulose fibres. However, the use of congo red in the cellulose industries (cotton textile, wood pulp & paper) has long been abandoned, mainly because of its toxicity.
# Behaviour in solution
Template:PH indicator template
Due to a color change from blue to red at pH 3.0-5.2, congo red can be used as a pH indicator. Since this color change is an approximate inverse of that of litmus, it can be used with litmus paper in a simple parlor trick: add a drop or two of congo red to both an acid solution and a base solution. Dipping red litmus paper in the red solution will turn it blue, while dipping blue litmus paper in the blue solution will turn it red.
Congo red has a propensity to aggregate in aqueous and organic solutions. The proposed mechanisms suggest hydrophobic interactions between the aromatic rings of the dye molecules, leading to a pi-pi stacking phenomenon. Although these aggregates are present under various sizes and shapes, the "ribbon-like micelles" of a few molecules seem to be the predominant form (even if the "micelle" term is not totally appropriate here). This aggregation phenomenon is more important for high congo red concentrations, at high salinity and/or low pH.
# Dyeing activity
As suggested by its intense red color, congo red has important spectrophotometric properties. Indeed, its UV-visible absorption spectrum shows a characteristic, intense peak around 498 nm in aqueous solution, at low dye concentration. Congo red molar extinction coefficient is about 45000 [L]/[mol].[cm] in these conditions. Aggregation of the dye tends to red-shift the absorption spectrum, whereas binding to cellulose fibres or amyloid fibrils has the opposite effect.
Congo red also shows a fluorescent activity when bound to amyloid fibrils, which tends to be used as a sensitive diagnosis tool for amyloidosis, instead of the traditional histological birefringence test.
# Diagnostic use
In biochemistry and histology, congo red is used to stain microscopic preparates, especially as a cytoplasm and erythrocyte stain. Apple-green birefringence of Congo red stained preparates under polarized light is indicative for the presence of amyloid fibrils.
de:Kongorot
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Congo_red | |
b38bb24661476e45cd03a35d33ae0488c0834b52 | wikidoc | Pinophyta | Pinophyta
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The conifers, division Pinophyta, also known as division Coniferae, are one of 13 or 14 division level taxa within the Kingdom Plantae. They are cone-bearing seed plants with vascular tissue; all extant conifers are woody plants, the great majority being trees with just a few being shrubs. Typical examples of conifers include cedars, douglas-firs, cypresses, firs, junipers, kauris, larches, pines, redwoods, spruces, and yews. Species of conifers can be found growing naturally in almost all parts of the world, and are frequently dominant plants in their habitats, as in the taiga, for example. Conifers are of immense economic value, primarily for timber and paper production; the wood of conifers is known as softwood. The division contains approximately 630 living species.
# Evolution
The earliest Conifers date back to the late Carboniferous (Pennsylvanian) period.
# Taxonomy and naming
The division name Pinophyta conforms to the rules of the ICBN, which state (Article 16.1) that the names of higher taxa in plants (above the rank of family) are either formed from the name of an included family (usually the most common and/or representative), in this case Pinaceae (the pine family), or are descriptive. In the latter case the name for the conifers (at whatever rank is chosen) is Coniferae (Art 16 Ex 2), which is also in widespread use. Older scientific names (no longer allowed) are Coniferophyta and Coniferales.
According to the ICBN it is possible to use a name formed by replacing the termination -aceae in the name of an included family, in this case preferably Pinaceae, by the appropriate termination, in the case of this division -ophyta. Alternatively, "descriptive botanical names" may also be used at any rank above family. Both are allowed.
This means that if the conifers are regarded to be a division they may be called Pinophyta or Coniferae (if regarded as a class they may be called Pinopsida or Coniferae; if regarded as an order they may be called Pinales or Coniferae (but see also Coniferales)).
Commonly the conifers are considered equivalent to the Gymnosperms, particularly in areas with a temperate climate where they may be the only commonly occurring gymnosperms. However, these are two different levels of grouping: conifers are the largest and economically most important component group of the gymnosperms, but nevertheless they comprise only one of the four groups.
The division Pinophyta consists of just one class, Pinopsida, which includes both living and fossil taxa. Subdivision of the living conifers into two or more orders has been proposed from time to time. The most commonly seen in the past was a split into two orders, Taxales (Taxaceae only) and Pinales (the rest), but recent research into DNA sequences suggests that this interpretation leaves the Pinales without Taxales as paraphyletic, and the latter order is no longer regarded as distinct. A more accurate subdivision would be to split the class into three orders, Pinales containing only Pinaceae, Araucariales containing Araucariaceae and Podocarpaceae, and Cupressales containing the remaining families (including Taxaceae), but there has not been any significant support for such a split, with the majority of opinion preferring retention of all the families within a single order Pinales, despite their antiquity and diverse morphology.
The conifers are now accepted as comprising six to eight families, with a total of 65-70 genera and 600-630 species (696 accepted names) . The seven most distinct families are linked in the box above right and phylogenetic diagram left. In other interpretations, the Cephalotaxaceae may be better included within the Taxaceae, and some authors additionally recognise Phyllocladaceae as distinct from Podocarpaceae (in which it is included here). The family Taxodiaceae is here included in family Cupressaceae, but was widely recognised in the past and can still be found in many field guides.
The conifers are an ancient group, with a fossil record extending back about 300 million years to the Paleozoic in the late Carboniferous period; even many of the modern genera are recognisable from fossils 60-120 million years old. Other classes and orders, now long extinct, also occur as fossils, particularly from the late Paleozoic and Mesozoic eras. Fossil conifers included many diverse forms, the most dramatically distinct from modern conifers being some herbaceous conifers with no woody stems. Major fossil orders of conifers or conifer-like plants include the Cordaitales, Vojnovskyales, Voltziales and perhaps also the Czekanowskiales (possibly more closely related to the Ginkgophyta).
# Morphology
All living conifers are woody plants, and most are trees, the majority having monopodial growth form (a single, straight trunk with side branches) with strong apical dominance. The size of mature conifers varies from less than one meter, to over 100 metres. The world's tallest, largest, thickest and oldest living things are all conifers. The tallest is a Coast Redwood (Sequoia sempervirens), with a height of 115.2 metres. The largest is a Giant Sequoia (Sequoiadendron giganteum), with a volume 1486.9 cubic metres. The thickest, or tree with the greatest trunk diameter, is a Montezuma Cypress (Taxodium mucronatum), 11.42 metres in diameter. The oldest is a Great Basin Bristlecone Pine (Pinus longaeva), 4,700 years old.
## Foliage
The leaves of many conifers are long, thin and and have a needle like look about them, but others, including most of the Cupressaceae and some of the Podocarpaceae, have flat, triangular scale-like leaves. Some, notably Agathis in Araucariaceae and Nageia in Podocarpaceae, have broad, flat strap-shaped leaves. In the majority of conifers, the leaves are arranged spirally, exceptions being most of Cupressaceae and one genus in Podocarpaceae, where they are arranged in decussate opposite pairs or whorls of 3 (-4). In many species with spirally arranged leaves, the leaf bases are twisted to present the leaves in a flat plane for maximum light capture (see e.g. photo of Grand Fir Abies grandis). Leaf size varies from 2 mm in many scale-leaved species, up to 400 mm long in the needles of some pines (e.g. Apache Pine Pinus engelmannii). The stomata are in lines or patches on the leaves, and can be closed when it is very dry or cold. The leaves are often dark green in colour which may help absorb a maximum of energy from weak sunshine at high latitudes or under forest canopy shade. Conifers from hotter areas with high sunlight levels (e.g. Turkish Pine Pinus brutia) often have yellower-green leaves, while others (e.g. Blue Spruce Picea pungens) have a very strong glaucous wax bloom to reflect ultraviolet light. In the great majority of genera the leaves are evergreen, usually remaining on the plant for several (2-40) years before falling, but five genera (Larix, Pseudolarix, Glyptostrobus, Metasequoia and Taxodium) are deciduous, shedding the leaves in autumn and leafless through the winter. The seedlings of many conifers, including most of the Cupressaceae, and Pinus in Pinaceae, have a distinct juvenile foliage period where the leaves are different, often markedly so, from the typical adult leaves.
## Reproduction
See conifer cones for a more detailed discussion.
Most conifers are monoecious, but some are subdioecious or dioecious; all are wind-pollinated. Conifer seeds develop inside a protective cone called a strobilus (or, very loosely, "pine cones", which technically occur only on pines, not other conifers!). The cones take from four months to three years to reach maturity, and vary in size from 2 mm to 600 mm long.
In Pinaceae, Araucariaceae, Sciadopityaceae and most Cupressaceae, the cones are woody, and when mature the scales usually spread open allowing the seeds to fall out and be dispersed by the wind. In some (e.g. firs and cedars), the cones disintegrate to release the seeds, and in others (e.g. the pines that produce pine nuts) the nut-like seeds are dispersed by birds (mainly nutcrackers and jays) which break up the specially adapted softer cones. Ripe cones may remain on the plant for a varied amount of time before falling to the ground; in some fire-adapted pines, the seeds may be stored in closed cones for up to 60-80 years, being released only when a fire kills the parent tree.
In the families Podocarpaceae, Cephalotaxaceae, Taxaceae, and one Cupressaceae genus (Juniperus), the scales are soft, fleshy, sweet and brightly coloured, and are eaten by fruit-eating birds, which then pass the seeds in their droppings. These fleshy scales are (except in Juniperus) known as arils. In some of these conifers (e.g. most Podocarpaceae), the cone consists of several fused scales, while in others (e.g. Taxaceae), the cone is reduced to just one seed scale or (e.g. Cephalotaxaceae) the several scales of a cone develop into individual arils, giving the appearance of a cluster of berries.
The male cones have structures called microsporangia which produce yellowish pollen. Pollen is released and carried by the wind to female cones. Pollen grains from living pinophyte species produce pollen tubes, much like those of angiosperms. When a pollen grain lands near a female gametophyte, it undergoes meiosis and fertilizes the female gametophyte. The resulting zygote develops into an embryo, which along with its surrounding integument, becomes a seed. Eventually the seed may fall to the ground and, if conditions permit, grows into a new plant.
In forestry, the terminology of flowering plants has commonly though inaccurately been applied to cone-bearing trees as well. The male cone and unfertilized female cone are called "male flower" and "female flower", respectively. After fertilization, the female cone is termed "fruit", which undergoes "ripening" (maturation).
## Life cycle
- To fertilize the ovum, the male cone releases pollen that is carried on the wind to the female cone.
- A fertilized female gamete (called a zygote) develops into an embryo.
- Along with integument cells surrounding the embryo, a seed develops containing the embryo.
- Mature seed drops out of cone onto the ground.
- Seed germinates and seedling grows into a mature plant.
- When mature, the adult plant produces cones.
# Other facts
Although the total number of species is relatively small, conifers are of immense ecological importance. They are the dominant plants over huge areas of land, most notably the boreal forests of the northern hemisphere, but also in similar cool climates in mountains further south.
Many conifers have distinctly scented resin, secreted to protect the tree against insect infestation and fungal infection of wounds. Fossilised resin hardens into amber.
They Might Be Giants recorded a song about conifers called C Is for Conifers on their 2005 album Here Come The ABCs.
# Notes
- ↑ Jump up to: 1.0 1.1 Catalogue of Life : 2007 Annual checklist - Conifer database
# Image Gallery
- Longleaf Pine
Longleaf Pine | Pinophyta
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The conifers, division Pinophyta, also known as division Coniferae, are one of 13 or 14 division level taxa within the Kingdom Plantae. They are cone-bearing seed plants with vascular tissue; all extant conifers are woody plants, the great majority being trees with just a few being shrubs. Typical examples of conifers include cedars, douglas-firs, cypresses, firs, junipers, kauris, larches, pines, redwoods, spruces, and yews. Species of conifers can be found growing naturally in almost all parts of the world, and are frequently dominant plants in their habitats, as in the taiga, for example. Conifers are of immense economic value, primarily for timber and paper production; the wood of conifers is known as softwood. The division contains approximately 630 living species. [1]
# Evolution
The earliest Conifers date back to the late Carboniferous (Pennsylvanian) period.
Template:Sectstub
# Taxonomy and naming
The division name Pinophyta conforms to the rules of the ICBN, which state (Article 16.1) that the names of higher taxa in plants (above the rank of family) are either formed from the name of an included family (usually the most common and/or representative), in this case Pinaceae (the pine family), or are descriptive. In the latter case the name for the conifers (at whatever rank is chosen) is Coniferae (Art 16 Ex 2), which is also in widespread use. Older scientific names (no longer allowed) are Coniferophyta and Coniferales.
According to the ICBN it is possible to use a name formed by replacing the termination -aceae in the name of an included family, in this case preferably Pinaceae, by the appropriate termination, in the case of this division -ophyta. Alternatively, "descriptive botanical names" may also be used at any rank above family. Both are allowed.
This means that if the conifers are regarded to be a division they may be called Pinophyta or Coniferae (if regarded as a class they may be called Pinopsida or Coniferae; if regarded as an order they may be called Pinales or Coniferae (but see also Coniferales)).
Commonly the conifers are considered equivalent to the Gymnosperms, particularly in areas with a temperate climate where they may be the only commonly occurring gymnosperms. However, these are two different levels of grouping: conifers are the largest and economically most important component group of the gymnosperms, but nevertheless they comprise only one of the four groups.
The division Pinophyta consists of just one class, Pinopsida, which includes both living and fossil taxa. Subdivision of the living conifers into two or more orders has been proposed from time to time. The most commonly seen in the past was a split into two orders, Taxales (Taxaceae only) and Pinales (the rest), but recent research into DNA sequences suggests that this interpretation leaves the Pinales without Taxales as paraphyletic, and the latter order is no longer regarded as distinct. A more accurate subdivision would be to split the class into three orders, Pinales containing only Pinaceae, Araucariales containing Araucariaceae and Podocarpaceae, and Cupressales containing the remaining families (including Taxaceae), but there has not been any significant support for such a split, with the majority of opinion preferring retention of all the families within a single order Pinales, despite their antiquity and diverse morphology.
The conifers are now accepted as comprising six to eight families, with a total of 65-70 genera and 600-630 species (696 accepted names) [1] . The seven most distinct families are linked in the box above right and phylogenetic diagram left. In other interpretations, the Cephalotaxaceae may be better included within the Taxaceae, and some authors additionally recognise Phyllocladaceae as distinct from Podocarpaceae (in which it is included here). The family Taxodiaceae is here included in family Cupressaceae, but was widely recognised in the past and can still be found in many field guides.
The conifers are an ancient group, with a fossil record extending back about 300 million years to the Paleozoic in the late Carboniferous period; even many of the modern genera are recognisable from fossils 60-120 million years old. Other classes and orders, now long extinct, also occur as fossils, particularly from the late Paleozoic and Mesozoic eras. Fossil conifers included many diverse forms, the most dramatically distinct from modern conifers being some herbaceous conifers with no woody stems. Major fossil orders of conifers or conifer-like plants include the Cordaitales, Vojnovskyales, Voltziales and perhaps also the Czekanowskiales (possibly more closely related to the Ginkgophyta).
# Morphology
All living conifers are woody plants, and most are trees, the majority having monopodial growth form (a single, straight trunk with side branches) with strong apical dominance. The size of mature conifers varies from less than one meter, to over 100 metres. The world's tallest, largest, thickest and oldest living things are all conifers. The tallest is a Coast Redwood (Sequoia sempervirens), with a height of 115.2 metres. The largest is a Giant Sequoia (Sequoiadendron giganteum), with a volume 1486.9 cubic metres. The thickest, or tree with the greatest trunk diameter, is a Montezuma Cypress (Taxodium mucronatum), 11.42 metres in diameter. The oldest is a Great Basin Bristlecone Pine (Pinus longaeva), 4,700 years old.
## Foliage
The leaves of many conifers are long, thin and and have a needle like look about them, but others, including most of the Cupressaceae and some of the Podocarpaceae, have flat, triangular scale-like leaves. Some, notably Agathis in Araucariaceae and Nageia in Podocarpaceae, have broad, flat strap-shaped leaves. In the majority of conifers, the leaves are arranged spirally, exceptions being most of Cupressaceae and one genus in Podocarpaceae, where they are arranged in decussate opposite pairs or whorls of 3 (-4). In many species with spirally arranged leaves, the leaf bases are twisted to present the leaves in a flat plane for maximum light capture (see e.g. photo of Grand Fir Abies grandis). Leaf size varies from 2 mm in many scale-leaved species, up to 400 mm long in the needles of some pines (e.g. Apache Pine Pinus engelmannii). The stomata are in lines or patches on the leaves, and can be closed when it is very dry or cold. The leaves are often dark green in colour which may help absorb a maximum of energy from weak sunshine at high latitudes or under forest canopy shade. Conifers from hotter areas with high sunlight levels (e.g. Turkish Pine Pinus brutia) often have yellower-green leaves, while others (e.g. Blue Spruce Picea pungens) have a very strong glaucous wax bloom to reflect ultraviolet light. In the great majority of genera the leaves are evergreen, usually remaining on the plant for several (2-40) years before falling, but five genera (Larix, Pseudolarix, Glyptostrobus, Metasequoia and Taxodium) are deciduous, shedding the leaves in autumn and leafless through the winter. The seedlings of many conifers, including most of the Cupressaceae, and Pinus in Pinaceae, have a distinct juvenile foliage period where the leaves are different, often markedly so, from the typical adult leaves.
## Reproduction
See conifer cones for a more detailed discussion.
Most conifers are monoecious, but some are subdioecious or dioecious; all are wind-pollinated. Conifer seeds develop inside a protective cone called a strobilus (or, very loosely, "pine cones", which technically occur only on pines, not other conifers!). The cones take from four months to three years to reach maturity, and vary in size from 2 mm to 600 mm long.
In Pinaceae, Araucariaceae, Sciadopityaceae and most Cupressaceae, the cones are woody, and when mature the scales usually spread open allowing the seeds to fall out and be dispersed by the wind. In some (e.g. firs and cedars), the cones disintegrate to release the seeds, and in others (e.g. the pines that produce pine nuts) the nut-like seeds are dispersed by birds (mainly nutcrackers and jays) which break up the specially adapted softer cones. Ripe cones may remain on the plant for a varied amount of time before falling to the ground; in some fire-adapted pines, the seeds may be stored in closed cones for up to 60-80 years, being released only when a fire kills the parent tree.
In the families Podocarpaceae, Cephalotaxaceae, Taxaceae, and one Cupressaceae genus (Juniperus), the scales are soft, fleshy, sweet and brightly coloured, and are eaten by fruit-eating birds, which then pass the seeds in their droppings. These fleshy scales are (except in Juniperus) known as arils. In some of these conifers (e.g. most Podocarpaceae), the cone consists of several fused scales, while in others (e.g. Taxaceae), the cone is reduced to just one seed scale or (e.g. Cephalotaxaceae) the several scales of a cone develop into individual arils, giving the appearance of a cluster of berries.
The male cones have structures called microsporangia which produce yellowish pollen. Pollen is released and carried by the wind to female cones. Pollen grains from living pinophyte species produce pollen tubes, much like those of angiosperms. When a pollen grain lands near a female gametophyte, it undergoes meiosis and fertilizes the female gametophyte. The resulting zygote develops into an embryo, which along with its surrounding integument, becomes a seed. Eventually the seed may fall to the ground and, if conditions permit, grows into a new plant.
In forestry, the terminology of flowering plants has commonly though inaccurately been applied to cone-bearing trees as well. The male cone and unfertilized female cone are called "male flower" and "female flower", respectively. After fertilization, the female cone is termed "fruit", which undergoes "ripening" (maturation).
## Life cycle
- To fertilize the ovum, the male cone releases pollen that is carried on the wind to the female cone.
- A fertilized female gamete (called a zygote) develops into an embryo.
- Along with integument cells surrounding the embryo, a seed develops containing the embryo.
- Mature seed drops out of cone onto the ground.
- Seed germinates and seedling grows into a mature plant.
- When mature, the adult plant produces cones.
# Other facts
Although the total number of species is relatively small, conifers are of immense ecological importance. They are the dominant plants over huge areas of land, most notably the boreal forests of the northern hemisphere, but also in similar cool climates in mountains further south.
Many conifers have distinctly scented resin, secreted to protect the tree against insect infestation and fungal infection of wounds. Fossilised resin hardens into amber.
They Might Be Giants recorded a song about conifers called C Is for Conifers on their 2005 album Here Come The ABCs.
# Notes
- ↑ Jump up to: 1.0 1.1 Catalogue of Life : 2007 Annual checklist - Conifer database
# Image Gallery
- Longleaf Pine
Longleaf Pine
# External links
- ToLweb: Conifers
- Pinophyta - The Gymnosperm Database
- 300 million-year-old conifer in Illinois - 4/2007
Template:Pinophyta
bg:Иглолистни
ca:Pinòpsid
cs:Nahosemenné
cy:Conwydden
da:Nåletræ
de:Nadelholzgewächse
et:Paljasseemnetaimed
eo:Pinofitoj
fa:مخروطیان
ko:구과식물
id:Tumbuhan berdaun jarum
it:Pinophyta
he:מחטניים
lv:Kailsēkļi
lt:Pušūnai
mk:Четинар
nl:Coniferen
no:Bartrær
sk:borovicorasty
sl:Iglavci
fi:Paljassiemeniset
sv:Barrväxter
to:ʻakau paini | https://www.wikidoc.org/index.php/Conifer | |
730dcd23550138c32d96341e974f306abfaae756 | wikidoc | Estimator | Estimator
In statistics, an estimator is a function of the observable sample data that is used to estimate an unknown population parameter; an estimate is the result from the actual application of the function to a particular set of data. Many different estimators are possible for any given parameter. Some criterion is used to choose between the estimators, although it is often the case that a criterion cannot be used to clearly pick one estimator over another.
To estimate a parameter of interest (e.g., a population mean, a binomial proportion, a difference between two population means, or a ratio of two population standard deviation), the usual procedure is as follows:
- Select a random sample from the population of interest.
- Calculate the point estimate of the parameter.
- Calculate a measure of its variability, often a confidence interval.
- Associate with this estimate a measure of variability.
There are two types of estimators: point estimators and interval estimators.
# Point estimators
Suppose \widehat{\theta} is an estimator of a parameter \theta \ . That is, \widehat{\theta} is a function that maps each sample s \ to its sample estimate \widehat{\theta}(s) \ .
- For a given sample s \ , the error of the estimator \widehat{\theta} is defined as \widehat{\theta}(s) - \theta, where \widehat{\theta}(s) \ is the estimate for sample \ s , and \theta \ is the parameter being estimated. Note that the error depends not only on the estimator (the estimation formula or procedure), but on the sample.
- The mean squared error of \widehat{\theta} is defined as the expected value (probability-weighted average, over all samples) of the squared errors; that is, \operatorname{MSE}(\widehat{\theta}) = \operatorname{E}. It is used to indicate how far, on average, the collection of estimates are from the single parameter being estimated. Consider the following analogy. Suppose the parameter is the bull's-eye of a target, the estimator is the process of shooting arrows at the target, and the individual arrows are estimates. Then high MSE means the average distance of the arrows from the target is high, and low MSE means the average distance from the target is low. The arrows may or may not be clustered. For example, even if all arrows hit the same point, yet grossly miss the target, the MSE is still relatively large. Note, however, that if the MSE is relatively low, then the arrows are likely more highly clustered (than highly dispersed).
- For a given sample s \ , the sampling deviation of the estimator \widehat{\theta} is defined as \widehat{\theta}(s) - \operatorname{E}( \widehat{\theta} ) , where \widehat{\theta}(s) \ is the estimate for sample \ s , and \operatorname{E}( \widehat{\theta} ) is the expected value of the estimator. Note that the sampling deviation depends not only on the estimator, but on the sample.
- The variance of \widehat{\theta} is simply the expected value of the squared sampling deviations; that is, \operatorname{var}(\widehat{\theta}) = \operatorname{E}. It is used to indicate how far, on average, the collection of estimates are from the expected value of the estimates. Note the difference between MSE and variance. If the parameter is the bull's-eye of a target, and the arrows are estimates, then a relatively high variance means the arrows are dispersed, and a relatively low variance means the arrows are clustered. Some things to note: even if the variance is low, the cluster of arrows may still be far off-target, and even if the variance is high, the diffuse collection of arrows may still be unbiased. Finally, note that even if all arrows grossly miss the target, if they nevertheless all hit the same point, the variance is zero.
- The bias of \widehat{\theta} is defined as B(\widehat{\theta}) = \operatorname{E}(\widehat{\theta}) - \theta. It is the distance between the average of the collection of estimates, and the single parameter being estimated. It also is the expected value of the error, since \operatorname{E}(\widehat{\theta}) - \theta = \operatorname{E}(\widehat{\theta} - \theta ) . If the parameter is the bull's-eye of a target, and the arrows are estimates, then a relatively high absolute value for the bias means the average position of the arrows is off-target, and a relatively low absolute bias means the average position of the arrows is on target. They may be dispersed, or may be clustered. The relationship between bias and variance is analogous to the relationship between accuracy and precision.
- \widehat{\theta} is an unbiased estimator of \theta \ if and only if B(\widehat{\theta}) = 0, for all values of θ in the parameter space or, equivalently, if and only if \operatorname{E}_\theta(\widehat{\theta}) remains equal to θ regardless of the value of θ. Note that bias is a property of the estimator, not of the estimate. Often, people refer to a "biased estimate" or an "unbiased estimate," but they really are talking about an "estimate from a biased estimator," or an "estimate from an unbiased estimator." Also, people often confuse the "error" of a single estimate with the "bias" of an estimator. Just because the error for one estimate is large, does not mean the estimator is biased. In fact, even if all estimates have astronomical absolute values for their errors, if the expected value of the error is zero, the estimator is unbiased. Also, just because an estimator is biased, does not preclude the error of an estimate from being zero (we may have gotten lucky). The ideal situation, of course, is to have an unbiased estimator with low variance, and also try to limit the number of samples where the error is extreme (that is, have few outliers). Yet unbiasedness is not essential. Often, if we permit just a little bias, then we can find an estimator with lower MSE and/or fewer outlier sample estimates.
- The MSE, variance, and bias, are related: \operatorname{MSE}(\widehat{\theta}) = \operatorname{var}(\widehat\theta) + (B(\widehat{\theta}))^2,
The standard deviation of an estimator of θ (the square root of the variance), or an estimate of the standard deviation of an estimator of θ, is called the standard error of θ.
# Consistency
A consistent estimator is an estimator that converges in probability to the quantity being estimated as the sample size grows without bound.
An estimator t_n (where n is the sample size) is a consistent estimator for parameter \theta if and only if, for all \epsilon > 0, no matter how small, we have
\lim_{n\to\infty}\Pr\left\{
\left|
t_n-\theta\right|<\epsilon
\right\}=1.
It is called strongly consistent, if it converges almost surely to the true value.
# Asymptotic normality
An asymptotically normal estimator is a consistent estimator whose distribution around the true parameter \theta approaches a normal distribution with standard deviation shrinking in proportion to 1/\sqrt{n} as the sample size n grows. Using \xrightarrow{D} to denote convergence in distribution, t_n is asymptotically normal if
for some V, which is called the asymptotic variance of the estimator.
Central limit theorem implies asymptotic normality of the sample mean \bar x as an estimator of the true mean.
# Efficiency
The quality of an estimator is generally judged by its mean squared error.
However, occasionally one chooses the unbiased estimator with the lowest variance.
Efficient estimators are those that have the lowest possible variance among all unbiased estimators. In some cases, a biased estimator may have a uniformly smaller mean squared error than does any unbiased estimator, so one should not make too much of this concept. For that and other reasons, it is sometimes preferable not to limit oneself to unbiased estimators; see estimator bias. Concerning such "best unbiased estimators", see also Cramér-Rao bound, Gauss-Markov theorem, Lehmann-Scheffé theorem, Rao-Blackwell theorem.
# Robustness
See: Robust estimator, Robust statistics
# Other properties
Sometimes, estimators should satisfy further restrictions (restricted estimators) - eg, one might require an estimated probability
to be between zero and one, or an estimated variance to be nonnegative. Sometimes this conflicts with the requirement of unbiasedness,
see the example in estimator bias concerning the estimation of the exponent of minus twice lambda based on a sample of size one from the Poisson distribution with mean lambda. | Estimator
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In statistics, an estimator is a function of the observable sample data that is used to estimate an unknown population parameter; an estimate is the result from the actual application of the function to a particular set of data. Many different estimators are possible for any given parameter. Some criterion is used to choose between the estimators, although it is often the case that a criterion cannot be used to clearly pick one estimator over another.
To estimate a parameter of interest (e.g., a population mean, a binomial proportion, a difference between two population means, or a ratio of two population standard deviation), the usual procedure is as follows:
- Select a random sample from the population of interest.
- Calculate the point estimate of the parameter.
- Calculate a measure of its variability, often a confidence interval.
- Associate with this estimate a measure of variability.
There are two types of estimators: point estimators and interval estimators.
# Point estimators
Suppose <math>\widehat{\theta}</math> is an estimator of a parameter <math> \theta \ </math>. That is, <math>\widehat{\theta}</math> is a function that maps each sample <math> s \ </math> to its sample estimate <math>\widehat{\theta}(s) \ </math>.
- For a given sample <math> s \ </math>, the error of the estimator <math>\widehat{\theta}</math> is defined as <math>\widehat{\theta}(s) - \theta</math>, where <math>\widehat{\theta}(s) \ </math> is the estimate for sample <math> \ s </math>, and <math>\theta \ </math> is the parameter being estimated. Note that the error depends not only on the estimator (the estimation formula or procedure), but on the sample.
- The mean squared error of <math>\widehat{\theta}</math> is defined as the expected value (probability-weighted average, over all samples) of the squared errors; that is, <math>\operatorname{MSE}(\widehat{\theta}) = \operatorname{E}[(\widehat{\theta} - \theta)^2]</math>. It is used to indicate how far, on average, the collection of estimates are from the single parameter being estimated. Consider the following analogy. Suppose the parameter is the bull's-eye of a target, the estimator is the process of shooting arrows at the target, and the individual arrows are estimates. Then high MSE means the average distance of the arrows from the target is high, and low MSE means the average distance from the target is low. The arrows may or may not be clustered. For example, even if all arrows hit the same point, yet grossly miss the target, the MSE is still relatively large. Note, however, that if the MSE is relatively low, then the arrows are likely more highly clustered (than highly dispersed).
- For a given sample <math> s \ </math>, the sampling deviation of the estimator <math>\widehat{\theta}</math> is defined as <math>\widehat{\theta}(s) - \operatorname{E}( \widehat{\theta} ) </math>, where <math>\widehat{\theta}(s) \ </math> is the estimate for sample <math> \ s </math>, and <math> \operatorname{E}( \widehat{\theta} ) </math> is the expected value of the estimator. Note that the sampling deviation depends not only on the estimator, but on the sample.
- The variance of <math>\widehat{\theta}</math> is simply the expected value of the squared sampling deviations; that is, <math>\operatorname{var}(\widehat{\theta}) = \operatorname{E}[(\widehat{\theta} - \operatorname{E}(\widehat{\theta}) )^2]</math>. It is used to indicate how far, on average, the collection of estimates are from the expected value of the estimates. Note the difference between MSE and variance. If the parameter is the bull's-eye of a target, and the arrows are estimates, then a relatively high variance means the arrows are dispersed, and a relatively low variance means the arrows are clustered. Some things to note: even if the variance is low, the cluster of arrows may still be far off-target, and even if the variance is high, the diffuse collection of arrows may still be unbiased. Finally, note that even if all arrows grossly miss the target, if they nevertheless all hit the same point, the variance is zero.
- The bias of <math>\widehat{\theta}</math> is defined as <math>B(\widehat{\theta}) = \operatorname{E}(\widehat{\theta}) - \theta</math>. It is the distance between the average of the collection of estimates, and the single parameter being estimated. It also is the expected value of the error, since <math> \operatorname{E}(\widehat{\theta}) - \theta = \operatorname{E}(\widehat{\theta} - \theta ) </math>. If the parameter is the bull's-eye of a target, and the arrows are estimates, then a relatively high absolute value for the bias means the average position of the arrows is off-target, and a relatively low absolute bias means the average position of the arrows is on target. They may be dispersed, or may be clustered. The relationship between bias and variance is analogous to the relationship between accuracy and precision.
- <math>\widehat{\theta}</math> is an unbiased estimator of <math> \theta \ </math> if and only if <math>B(\widehat{\theta}) = 0</math>, for all values of θ in the parameter space or, equivalently, if and only if <math>\operatorname{E}_\theta(\widehat{\theta})</math> remains equal to θ regardless of the value of θ. Note that bias is a property of the estimator, not of the estimate. Often, people refer to a "biased estimate" or an "unbiased estimate," but they really are talking about an "estimate from a biased estimator," or an "estimate from an unbiased estimator." Also, people often confuse the "error" of a single estimate with the "bias" of an estimator. Just because the error for one estimate is large, does not mean the estimator is biased. In fact, even if all estimates have astronomical absolute values for their errors, if the expected value of the error is zero, the estimator is unbiased. Also, just because an estimator is biased, does not preclude the error of an estimate from being zero (we may have gotten lucky). The ideal situation, of course, is to have an unbiased estimator with low variance, and also try to limit the number of samples where the error is extreme (that is, have few outliers). Yet unbiasedness is not essential. Often, if we permit just a little bias, then we can find an estimator with lower MSE and/or fewer outlier sample estimates.
- The MSE, variance, and bias, are related: <math>\operatorname{MSE}(\widehat{\theta}) = \operatorname{var}(\widehat\theta) + (B(\widehat{\theta}))^2,</math>
The standard deviation of an estimator of θ (the square root of the variance), or an estimate of the standard deviation of an estimator of θ, is called the standard error of θ.
# Consistency
A consistent estimator is an estimator that converges in probability to the quantity being estimated as the sample size grows without bound.
An estimator <math>t_n</math> (where n is the sample size) is a consistent estimator for parameter <math>\theta</math> if and only if, for all <math>\epsilon > 0</math>, no matter how small, we have
\lim_{n\to\infty}\Pr\left\{
\left|
t_n-\theta\right|<\epsilon
\right\}=1.
</math>
It is called strongly consistent, if it converges almost surely to the true value.
# Asymptotic normality
An asymptotically normal estimator is a consistent estimator whose distribution around the true parameter <math>\theta</math> approaches a normal distribution with standard deviation shrinking in proportion to <math>1/\sqrt{n}</math> as the sample size <math>n</math> grows. Using <math>\xrightarrow{D}</math> to denote convergence in distribution, <math>t_n</math> is asymptotically normal if
for some <math>V</math>, which is called the asymptotic variance of the estimator.
Central limit theorem implies asymptotic normality of the sample mean <math>\bar x</math> as an estimator of the true mean.
# Efficiency
The quality of an estimator is generally judged by its mean squared error.
However, occasionally one chooses the unbiased estimator with the lowest variance.
Efficient estimators are those that have the lowest possible variance among all unbiased estimators. In some cases, a biased estimator may have a uniformly smaller mean squared error than does any unbiased estimator, so one should not make too much of this concept. For that and other reasons, it is sometimes preferable not to limit oneself to unbiased estimators; see estimator bias. Concerning such "best unbiased estimators", see also Cramér-Rao bound, Gauss-Markov theorem, Lehmann-Scheffé theorem, Rao-Blackwell theorem.
# Robustness
See: Robust estimator, Robust statistics
# Other properties
Sometimes, estimators should satisfy further restrictions (restricted estimators) - eg, one might require an estimated probability
to be between zero and one, or an estimated variance to be nonnegative. Sometimes this conflicts with the requirement of unbiasedness,
see the example in estimator bias concerning the estimation of the exponent of minus twice lambda based on a sample of size one from the Poisson distribution with mean lambda. | https://www.wikidoc.org/index.php/Consistency_(statistics) | |
bef2292156406fde827649d8e9d607d249889361 | wikidoc | Keratitis | Keratitis
# Overview
Keratitis is a condition in which the eye's cornea is inflamed. Superficial keratitis involves the superficial layers of the cornea. After healing, this form of keratitis does not generally leave a scar. Deep keratitis involves the deeper layers of the cornea, leaving a scar upon healing that impairs vision if on or near the visual axis. Keratitis has multiple causes, one of which is an infection of a present or previous herpes simplex virus secondary to an upper respiratory infection, involving cold sores. Symptoms of keratitis include red eyes, sensitivity to light, and uncomfortable eyes. In the later stages of more severe cases, there can be strong pain, loss of vision, blurry vision, and pus. Microbial keratitis should be managed as bacterial keratitis until proven otherwise. Steroids are indicated in the management of keratitis to reduce inflammation that may damage the eye.
# Classification
Superficial keratitis involves the superficial layers of the cornea. After healing, this form of keratitis does not generally leave a scar.
Deep keratitis involves deeper layers of the cornea, leaving a scar upon healing that impairs vision if on or near the visual axis.
# Pathophysiology
Keratitis has multiple causes, one of which is an infection of a present or previous herpes simplex virus secondary to an upper respiratory infection, involving cold sores.
## Pathogens
- Amoebic keratitis. Amoebic infection of the cornea is the most serious corneal infection, usually affecting soft contact lens wearers. It is usually caused by Acanthamoeba. On May 25, 2007, the CDC issued a health advisory due to increased risk of Acanthamoeba keratitis (AK)infection associated with use of Advanced Medical Optics (AMO) Complete Moisture Plus Multi-Purpose eye solution. See CDC Advisory
- Bacterial keratitis. Bacterial infection of the cornea can follow from an injury or from wearing contact lenses. The bacteriums usually involved are Staphylococcus aureus and for contact lens wearers Pseudomonas aeruginosa.
- Fungal keratitis (cf. Fusarium, causing recent incidences of keratitis through the possible vector of Bausch & Lomb ReNu with MoistureLoc contact lens solution)
- Viral keratitis
- Herpes simplex keratitis. Viral infection of the cornea is often caused by the herpes simplex virus which frequently leaves what is called a 'dendritic ulcer'.
- Herpes zoster keratitis
## Other
- Exposure keratitis
- Photokeratitis - keratitis due to intense ultraviolet radiation exposure (e.g. snow blindness or welder's arc eye.)
- Ulcerative keratitis
- Contact lens acute red eye (CLARE) - a non-ulcerative sterile keratitis associated with colonization of Gram-negative bacteria on contact lenses
- Severe allergic response may lead to corneal inflammation and ulceration (i.e. vernal keratoconjunctivitis).
- Drug Induced - Afatinib, Cyclopentolate, Diclofenac (ophthalmic), Doxorubicin Hydrochloride, Emedastine Difumarate, Moxifloxacin ophthalmic, Naphazoline , Nitisinone, Panitumumab, Pramipexole
# Causes
## Life Threatening Causes
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.
- Small pox
## Common Causes
- Adenovirus
- Contact lens
- Herpes simplex virus
- Injury
## Causes by Organ System
## Causes in Alphabetical Order
- Acanthamoeba
- Aciclovir
- Adenovirus
- Afatinib
- Amaurosis fugax
- Arc eye
- Aspergillus fumigatus
- Atopic dermatitis
- Bacillus cereus
- Balamuthia mandrillaris
- Behcet disease
- Betaxolol (ophthalmic)
- Bimatoprost
- Brimonidine (ophthalmic)
- Bromfenac
- Brucellosis
- Candida
- Canine herpesvirus
- Cogan syndrome
- Confocal laser scanning microscopy
- Congenital syphilis
- Conjunctivitis
- Connexin
- Contact lens
- Contact lens acute red eye
- Contaminated water
- Corneal dystrophy
- Corneal transplantation
- Corneal ulcer
- Corynebacterium diphtheriae
- Crab louse
- Cyclopentolate
- Dendritic ulcer
- Diclofenac (ophthalmic)
- Dorzolamide
- Doxorubicin hydrochloride
- Dry eyes
- Ectrodactyly-ectodermal dysplasia-cleft syndrome
- Ectropion
- Emedastine difumarate
- Enterobacteria
- Enterovirus
- Epidermolysis bullosa
- Epinastine
- Erythema elevatum diutinum
- Erythema multiforme
- Exophthalmos
- Facial nerve paralysis
- Facioscapulohumeral muscular dystrophy
- Feline viral rhinotracheitis
- Fungal keratitis
- Fusarium
- Graves' disease
- Graves ophthalmopathy
- Haemophilus influenzae
- Henoch-Schönlein purpura
- Herpes simplex keratitis
- Herpes simplex virus infection
- Herpes zoster
- Herpesviridae
- Herpetic keratitis
- Hydroxypropyl cellulose
- Ichthyosis
- Immune reconstitution inflammatory syndrome
- Incontinentia pigmenti
- Injury
- Jellyfish stings
- Keratitis-ichthyosis-deafness syndrome
- Keratoconjunctivitis
- Keratoconjunctivitis sicca
- KID syndrome
- Lagophthalmos
- LASIK
- Latanoprost
- Late congenital syphilitic oculopathy
- Lepromatous leprosy
- Listeria
- Lyme disease
- Mansonella ozzardi
- Measles
- Microsporidiosis
- Moraxella
- Moxifloxacin ophthalmic
- Mycobacterium
- Mycobacterium boenickei
- Mycobacterium brisbanense
- Mycobacterium houstonense
- Mycobacterium neworleansense
- Naegleria infection
- Naphazoline
- Natamycin
- Neisseria gonorrhea
- Nepafenac
- Nitisinone
- Nocardiosis
- Non-steroidal anti-inflammatory drug (topical)
- Ocular rosacea
- Oculotect
- Oculovestibuloauditory syndrome
- Olopatadine
- Onchocerciasis
- Orthokeratology
- Orthopoxvirus
- Panitumumab
- Pannus
- Parechovirus
- Phlyctenular keratoconjunctivitis
- Phosgene oxime
- Photokeratitis
- Phycomycosis
- Pityriasis rubra pilaris
- Plesiomonas shigelloides
- Pramipexole
- Pseudomonas aeruginosa
- Psittacosis
- Radial keratotomy
- Reactive arthritis
- Reiter's syndrome
- Relapsing polychondritis
- ReNu
- Rheumatoid arthritis
- Rheumatoid vasculitis
- Ribonucleotide reductase
- Scedosporium apiospermum
- Scleritis
- Scopolamine
- Serratia marcescens
- Shigella
- Sicca syndrome
- Sjögren's syndrome
- Smallpox
- Snow blindness
- Staphylococcus aureus
- Staphylococcus epidermidis
- Stevens-Johnson syndrome
- Streptococcus pneumoniae
- Superior limbic keratoconjunctivitis
- Syphilis
- Systemic lupus erythematosus
- Thygeson's superficial punctate keratopathy
- Topical anesthetic
- Toxic epidermal necrolysis
- Trachoma
- Travoprost
- Trifluridine
- Type II tyrosinemia
- Ultraviolet radiation
- Unoprostone
- Vaccinia
- Varicella-zoster virus
- Vasculitis
- Vernal keratoconjunctivitis
- Vidarabine
- Vitamin A deficiency
- Xeroderma pigmentosum
# Symptoms
The symptoms are often very similar to those of conjunctivitis, an inflammation of the conjunctiva, and photophobia. The eye turns very red and there may be sensitivity to light, and the eye may feel uncomfortable. In the later stages of more severe cases, there can be strong pain, loss of vision/blurriness, and pus may form.
# Diagnosis
Effective diagnosis is important in detecting this condition and subsequent treatment as keratitis is sometimes mistaken for an allergic conjunctivitis.
# Treatment
- Treatment depends on the cause of the keratitis.
- Microbial keratitis should be managed as bacterial keratitis until proven otherwise.
- Steroids are indicated in the management of keratitis to reduce inflammation that may damage the eye.
## Antimicrobial regimens
### Bacterial Keratitis
- 1. Causative pathogens
- Pseudomonas aeruginosa
- Staphylococcus epidermidis
- Staphylococcus aureus
- Streptococcus pneumoniae
- Serratia spp.
- Hemophilus spp.
- Moraxella spp.
- Neisseria gonorrhea
- Corynebacterium diphtheriae
- Listeria spp.
- Shigella spp.
- Nocardia spp.
- Mycobacterium spp.
- 2. Empiric antimicrobial therapy
- Preferred regimen (1): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (2): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (3): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (4): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (5): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q2h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14 OR Gentamicin 1.5% ophthalmic ointment q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14)
- Alternative regimen (1), unresponsive keratitis: Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Alternative regimen (2): Erythromycin 0.5% ophthalmic ointment qhs for 1 week AND (Amikacin 5% AND/OR Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14)
- Note (1) : Subconjunctival antibiotics may be helpful where there is imminent scleral spread or perforation or in cases where adherence to the treatment regimen is questionable.
- Note (2) : Systemic therapy is necessary for suspected gonococcal infection.
- 3. Pathogen-directed antimicrobial therapy
- 3.1 Non-streptococcal gram-positive bacteria
- Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14
- 3.2 Streptococcus pneumoniae
- Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Alternative regimen (unresponsive keratitis): Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- 3.3 Nocardia spp.
- Preferred regimen (1): Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (2): Erythromycin 0.5% ophthalmic ointment qhs for 1 week AND (Amikacin 5% AND/OR Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14)
- 3.4 Gram-negative bacteria
- Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14
- 3.5 Anaerobes
- Preferred regimen (1): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (2): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (3): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
### Fungal (mycotic) Keratitis
- 1. Causative Pathogens.
- Candida spp.
- Fusarium spp.
- Aspergillus spp.
- Curvularia spp.
- 2. Empiric antimicrobial therapy
- Preferred regimen (1): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks
- Preferred regimen (2): Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks
- Preferred regimen (3): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks
- Alternative regimen (1), unresponsive: Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks
- Alternative regimen (2), unresponsive: Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks
- 3. Special considerations
- Immunocompromised status, spreading ulcer, impending perforation, true perforation
- Preferred regimen (1): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks AND (Ketoconazole IV 200-400 mg q12h for 2-3 weeks OR Fluconazole IV 200 mg q12h for 2-3 weeks
- Preferred regimen (2): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks AND (Ketoconazole IV 200-400 mg q12h for 2-3 weeks OR Fluconazole IV 200 mg q12h for 2-3 weeks
- Note: Bacterial superinfection must be treated using Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14 OR (Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14)
### Protozoal Keratitis
- 1. Causative pathogens
- Acanthamoeba spp.
- Microsporidia spp.
- 2. Empiric antimicrobial therapy
- Preferred regimen (1): Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks AND Chlorhexidine 0.02% ophthalmic ointment q1h for 1-2 weeks AND/OR (Propamidine 0.1% ophthalmic ointment q1h for 1-2 weeks OR Hexamidine 0.1% ophthalmic ointment q1h for 2 days then q1h for another 3 days)
- Preferred regimen (2): Propamidine 0.1% ophthalmic ointment q1h for 1-2 weeks AND Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks
- Preferred regimen (4): Propamidine ophthalmic ointment q1h for 1-2 weeks AND Chlorhexidine ophthalmic ointment q1h for 1-2 weeks
- Preferred regimen (4): Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks AND Hexamidine 0.1% ophthalmic ointment q1h for 2 days then q1h for another 3 days
### Viral Keratitis
- 1. Causative pathogens
- Herpes simplex virus (HSV)
- 2. Empiric antimicrobial therapy
- Preferred regimen (1): Acyclovir 3% ophthalmic ointment q5h for 2-3 weeks AND Homatropine 2% ophthalmic solution bid for 2-3 weeks
- Preferred regimen (2): Idoxuridine 0.1% ophthalmic solution q1h in daytime and 0.5% ophthalmic ointment qhs for 1 week then 0.1% ophthalmic solution q2h in daytime and 0.5% ophthalmic ointment qhs for 2-3 weeks AND Homatropine 2% ophthalmic solution bid for 2-3 weeks
### Contraindicated medications
Epithelial herpes simplex keratitis is considered an absolute contraindication to the use of the following medications:
- Fluorometholone
- Loteprednol
- Rimexolone
- Suprofen | Keratitis
Template:DiseaseDisorder infobox
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamed Moubarak, M.D. [2], Ogheneochuko Ajari, MB.BS, MS [3], Faizan Sheraz, M.D. [4]
# Overview
Keratitis is a condition in which the eye's cornea is inflamed. Superficial keratitis involves the superficial layers of the cornea. After healing, this form of keratitis does not generally leave a scar. Deep keratitis involves the deeper layers of the cornea, leaving a scar upon healing that impairs vision if on or near the visual axis. Keratitis has multiple causes, one of which is an infection of a present or previous herpes simplex virus secondary to an upper respiratory infection, involving cold sores. Symptoms of keratitis include red eyes, sensitivity to light, and uncomfortable eyes. In the later stages of more severe cases, there can be strong pain, loss of vision, blurry vision, and pus. Microbial keratitis should be managed as bacterial keratitis until proven otherwise. Steroids are indicated in the management of keratitis to reduce inflammation that may damage the eye.
# Classification
Superficial keratitis involves the superficial layers of the cornea. After healing, this form of keratitis does not generally leave a scar.
Deep keratitis involves deeper layers of the cornea, leaving a scar upon healing that impairs vision if on or near the visual axis.
# Pathophysiology
Keratitis has multiple causes, one of which is an infection of a present or previous herpes simplex virus secondary to an upper respiratory infection, involving cold sores.
## Pathogens
- Amoebic keratitis. Amoebic infection of the cornea is the most serious corneal infection, usually affecting soft contact lens wearers. It is usually caused by Acanthamoeba. On May 25, 2007, the CDC issued a health advisory due to increased risk of Acanthamoeba keratitis (AK)infection associated with use of Advanced Medical Optics (AMO) Complete Moisture Plus Multi-Purpose eye solution. See CDC Advisory
- Bacterial keratitis. Bacterial infection of the cornea can follow from an injury or from wearing contact lenses. The bacteriums usually involved are Staphylococcus aureus and for contact lens wearers Pseudomonas aeruginosa.
- Fungal keratitis (cf. Fusarium, causing recent incidences of keratitis through the possible vector of Bausch & Lomb ReNu with MoistureLoc contact lens solution)
- Viral keratitis
- Herpes simplex keratitis. Viral infection of the cornea is often caused by the herpes simplex virus which frequently leaves what is called a 'dendritic ulcer'.
- Herpes zoster keratitis
## Other
- Exposure keratitis
- Photokeratitis - keratitis due to intense ultraviolet radiation exposure (e.g. snow blindness or welder's arc eye.)
- Ulcerative keratitis
- Contact lens acute red eye (CLARE) - a non-ulcerative sterile keratitis associated with colonization of Gram-negative bacteria on contact lenses
- Severe allergic response may lead to corneal inflammation and ulceration (i.e. vernal keratoconjunctivitis).[5]
- Drug Induced - Afatinib, Cyclopentolate, Diclofenac (ophthalmic), Doxorubicin Hydrochloride, Emedastine Difumarate, Moxifloxacin ophthalmic, Naphazoline , Nitisinone, Panitumumab, Pramipexole
# Causes
## Life Threatening Causes
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.
- Small pox
## Common Causes
- Adenovirus
- Contact lens
- Herpes simplex virus
- Injury
## Causes by Organ System
## Causes in Alphabetical Order
- Acanthamoeba
- Aciclovir
- Adenovirus
- Afatinib
- Amaurosis fugax
- Arc eye
- Aspergillus fumigatus
- Atopic dermatitis
- Bacillus cereus
- Balamuthia mandrillaris
- Behcet disease
- Betaxolol (ophthalmic)
- Bimatoprost
- Brimonidine (ophthalmic)
- Bromfenac
- Brucellosis
- Candida
- Canine herpesvirus
- Cogan syndrome
- Confocal laser scanning microscopy
- Congenital syphilis
- Conjunctivitis
- Connexin
- Contact lens
- Contact lens acute red eye
- Contaminated water
- Corneal dystrophy
- Corneal transplantation
- Corneal ulcer
- Corynebacterium diphtheriae
- Crab louse
- Cyclopentolate
- Dendritic ulcer
- Diclofenac (ophthalmic)
- Dorzolamide
- Doxorubicin hydrochloride
- Dry eyes
- Ectrodactyly-ectodermal dysplasia-cleft syndrome
- Ectropion
- Emedastine difumarate
- Enterobacteria
- Enterovirus
- Epidermolysis bullosa
- Epinastine
- Erythema elevatum diutinum
- Erythema multiforme
- Exophthalmos
- Facial nerve paralysis
- Facioscapulohumeral muscular dystrophy
- Feline viral rhinotracheitis
- Fungal keratitis
- Fusarium
- Graves' disease
- Graves ophthalmopathy
- Haemophilus influenzae
- Henoch-Schönlein purpura
- Herpes simplex keratitis
- Herpes simplex virus infection
- Herpes zoster
- Herpesviridae
- Herpetic keratitis
- Hydroxypropyl cellulose
- Ichthyosis
- Immune reconstitution inflammatory syndrome
- Incontinentia pigmenti
- Injury
- Jellyfish stings
- Keratitis-ichthyosis-deafness syndrome
- Keratoconjunctivitis
- Keratoconjunctivitis sicca
- KID syndrome
- Lagophthalmos
- LASIK
- Latanoprost
- Late congenital syphilitic oculopathy
- Lepromatous leprosy
- Listeria
- Lyme disease
- Mansonella ozzardi
- Measles
- Microsporidiosis
- Moraxella
- Moxifloxacin ophthalmic
- Mycobacterium
- Mycobacterium boenickei
- Mycobacterium brisbanense
- Mycobacterium houstonense
- Mycobacterium neworleansense
- Naegleria infection
- Naphazoline
- Natamycin
- Neisseria gonorrhea
- Nepafenac
- Nitisinone
- Nocardiosis
- Non-steroidal anti-inflammatory drug (topical)
- Ocular rosacea
- Oculotect
- Oculovestibuloauditory syndrome
- Olopatadine
- Onchocerciasis
- Orthokeratology
- Orthopoxvirus
- Panitumumab
- Pannus
- Parechovirus
- Phlyctenular keratoconjunctivitis
- Phosgene oxime
- Photokeratitis
- Phycomycosis
- Pityriasis rubra pilaris
- Plesiomonas shigelloides
- Pramipexole
- Pseudomonas aeruginosa
- Psittacosis
- Radial keratotomy
- Reactive arthritis
- Reiter's syndrome
- Relapsing polychondritis
- ReNu
- Rheumatoid arthritis
- Rheumatoid vasculitis
- Ribonucleotide reductase
- Scedosporium apiospermum
- Scleritis
- Scopolamine
- Serratia marcescens
- Shigella
- Sicca syndrome
- Sjögren's syndrome
- Smallpox
- Snow blindness
- Staphylococcus aureus
- Staphylococcus epidermidis
- Stevens-Johnson syndrome
- Streptococcus pneumoniae
- Superior limbic keratoconjunctivitis
- Syphilis
- Systemic lupus erythematosus
- Thygeson's superficial punctate keratopathy
- Topical anesthetic
- Toxic epidermal necrolysis
- Trachoma
- Travoprost
- Trifluridine
- Type II tyrosinemia
- Ultraviolet radiation
- Unoprostone
- Vaccinia
- Varicella-zoster virus
- Vasculitis
- Vernal keratoconjunctivitis
- Vidarabine
- Vitamin A deficiency
- Xeroderma pigmentosum
# Symptoms
The symptoms are often very similar to those of conjunctivitis, an inflammation of the conjunctiva, and photophobia. The eye turns very red and there may be sensitivity to light, and the eye may feel uncomfortable. In the later stages of more severe cases, there can be strong pain, loss of vision/blurriness, and pus may form.
# Diagnosis
Effective diagnosis is important in detecting this condition and subsequent treatment as keratitis is sometimes mistaken for an allergic conjunctivitis.
# Treatment
- Treatment depends on the cause of the keratitis.
- Microbial keratitis should be managed as bacterial keratitis until proven otherwise.
- Steroids are indicated in the management of keratitis to reduce inflammation that may damage the eye.
## Antimicrobial regimens
### Bacterial Keratitis[1]
- 1. Causative pathogens
- Pseudomonas aeruginosa
- Staphylococcus epidermidis
- Staphylococcus aureus
- Streptococcus pneumoniae
- Serratia spp.
- Hemophilus spp.
- Moraxella spp.
- Neisseria gonorrhea
- Corynebacterium diphtheriae
- Listeria spp.
- Shigella spp.
- Nocardia spp.
- Mycobacterium spp.
- 2. Empiric antimicrobial therapy
- Preferred regimen (1): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (2): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (3): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (4): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (5): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q2h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14 OR Gentamicin 1.5% ophthalmic ointment q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14)
- Alternative regimen (1), unresponsive keratitis: Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Alternative regimen (2): Erythromycin 0.5% ophthalmic ointment qhs for 1 week AND (Amikacin 5% AND/OR Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14)
- Note (1) : Subconjunctival antibiotics may be helpful where there is imminent scleral spread or perforation or in cases where adherence to the treatment regimen is questionable.
- Note (2) : Systemic therapy is necessary for suspected gonococcal infection.
- 3. Pathogen-directed antimicrobial therapy
- 3.1 Non-streptococcal gram-positive bacteria
- Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14
- 3.2 Streptococcus pneumoniae
- Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Alternative regimen (unresponsive keratitis): Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- 3.3 Nocardia spp.
- Preferred regimen (1): Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14 AND Amikacin 5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (2): Erythromycin 0.5% ophthalmic ointment qhs for 1 week AND (Amikacin 5% AND/OR Vancomycin 5% q30 min on day 1 then q2h on day 2 then q4h on days 3-14)
- 3.4 Gram-negative bacteria
- Preferred regimen (1): Moxifloxacin 0.5% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (2): Gatifloxacin 0.3% q1h on day 1 then q2h on day 2 then q4h on days 3-14
- Preferred regimen (3): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (4): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (5): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (6): Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14
- 3.5 Anaerobes
- Preferred regimen (1): Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14
- Preferred regimen (2): Ofloxacin 0.3% ophthalmic ointment q2h for 2-3 weeks
- Preferred regimen (3): Levofloxacin 1.5% ophthalmic ointment q2h for 2-3 weeks
### Fungal (mycotic) Keratitis[2]
- 1. Causative Pathogens.
- Candida spp.
- Fusarium spp.
- Aspergillus spp.
- Curvularia spp.
- 2. Empiric antimicrobial therapy
- Preferred regimen (1): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks
- Preferred regimen (2): Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks
- Preferred regimen (3): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks
- Alternative regimen (1), unresponsive: Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks
- Alternative regimen (2), unresponsive: Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks
- 3. Special considerations
- Immunocompromised status, spreading ulcer, impending perforation, true perforation
- Preferred regimen (1): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Fluconazole 1% ophthalmic suspension q1h for 2-3 weeks AND (Ketoconazole IV 200-400 mg q12h for 2-3 weeks OR Fluconazole IV 200 mg q12h for 2-3 weeks
- Preferred regimen (2): Natamycin 5% ophthalmic suspension q30min to q1h for 2-3 weeks AND Amphotericin B 0.15-0.25% prepared in distilled water q15min-q30min on day 1-2 then q1h to q2h for 2-3 weeks AND (Ketoconazole IV 200-400 mg q12h for 2-3 weeks OR Fluconazole IV 200 mg q12h for 2-3 weeks
- Note: Bacterial superinfection must be treated using Ciprofloxacin 0.3% ophthalmic ointment q15min for 6 hours then q30min for the remainder of day 1 then q1h on day 2, then q4h on days 3-14 OR (Cefazolin 5% q30min to q1h on day 1 then q1h on day 2 then q4h on days 3-14 AND Tobramycin 5% ophthalmic ointment q1h on day 1 then q2h on day 2 then q4h on days 3-14)
### Protozoal Keratitis[2][3]
- 1. Causative pathogens
- Acanthamoeba spp.
- Microsporidia spp.
- 2. Empiric antimicrobial therapy
- Preferred regimen (1): Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks AND Chlorhexidine 0.02% ophthalmic ointment q1h for 1-2 weeks AND/OR (Propamidine 0.1% ophthalmic ointment q1h for 1-2 weeks OR Hexamidine 0.1% ophthalmic ointment q1h for 2 days then q1h for another 3 days)
- Preferred regimen (2): Propamidine 0.1% ophthalmic ointment q1h for 1-2 weeks AND Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks
- Preferred regimen (4): Propamidine ophthalmic ointment q1h for 1-2 weeks AND Chlorhexidine ophthalmic ointment q1h for 1-2 weeks
- Preferred regimen (4): Polyhexamethylene biguanide 0.02% ophthalmic ointment q1h for 1-2 weeks AND Hexamidine 0.1% ophthalmic ointment q1h for 2 days then q1h for another 3 days
### Viral Keratitis[2]
- 1. Causative pathogens
- Herpes simplex virus (HSV)
- 2. Empiric antimicrobial therapy
- Preferred regimen (1): Acyclovir 3% ophthalmic ointment q5h for 2-3 weeks AND Homatropine 2% ophthalmic solution bid for 2-3 weeks
- Preferred regimen (2): Idoxuridine 0.1% ophthalmic solution q1h in daytime and 0.5% ophthalmic ointment qhs for 1 week then 0.1% ophthalmic solution q2h in daytime and 0.5% ophthalmic ointment qhs for 2-3 weeks AND Homatropine 2% ophthalmic solution bid for 2-3 weeks
### Contraindicated medications
Epithelial herpes simplex keratitis is considered an absolute contraindication to the use of the following medications:
- Fluorometholone
- Loteprednol
- Rimexolone
- Suprofen | https://www.wikidoc.org/index.php/Contact_lens_acute_red_eye | |
8872f140ffb91e6eebb43405e7fc309d16ef2c04 | wikidoc | Coomassie | Coomassie
Coomassie (also known as Coomassie Blue, Brilliant Blue, Brilliant Blue G, Acid Blue 90, C.I. 42655, or Brilliant Blue G 250) is a blue dye commonly used in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The gel is soaked in dye for thirty minutes and then destained for thirty minutes or more. This treatment allows the visualization of bands indicating the protein content of the gel. The gel usually contains a set of molecular weight marker(proteins of pre-determined weight) so that protein molecular weight can be determined in an unknown solution during the visualization.
# Variations
Shown at right is Coomassie G250. A similar but distinct dye, known as Coomassie R-250, also exists.
# Laboratory usage
Coomassie dye is an integral component of the Bradford Method for determining protein concentration in a solution. The Coomassie dye binds to proteins via physisorptionto arginine, the aromatic amino acids, and histidine. When Coomassie Brilliant Blue G-250 binds to proteins in acid solution, it has an absorbance shift from 465 nm to 595 nm. The absorbance data can then be used in Beer's law to determine protein concentration and ultimately the actual amount of protein in a given solution.
## Coomassie stain and destain solution formulas
For staining solution:
For destaining solution:
(Can also be destained using only distilled water and heating, though at a much slower pace)
Common mix for Bradford reagent:
Methanol has been used in the past and can be replaced by ethanol at all steps resulting in slightly safer reagents (methanol is a neurotoxin) while the efficiency of the procedure remains the same.
# Name
Like many dyes, Coomassie blue dye is named after an African locale, in this case the city of Kumasi, now in Ghana. It was developed as an acid wool dye and was named to commemorate the 1896 British occupation of the Ashanti capital, then known as Coomassie. | Coomassie
Template:Chembox new
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Coomassie (also known as Coomassie Blue, Brilliant Blue, Brilliant Blue G, Acid Blue 90, C.I. 42655, or Brilliant Blue G 250) is a blue dye commonly used in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The gel is soaked in dye for thirty minutes and then destained for thirty minutes or more. This treatment allows the visualization of bands indicating the protein content of the gel. The gel usually contains a set of molecular weight marker(proteins of pre-determined weight) so that protein molecular weight can be determined in an unknown solution during the visualization.
# Variations
Shown at right is Coomassie G250. A similar but distinct dye, known as Coomassie R-250, also exists.
# Laboratory usage
Coomassie dye is an integral component of the Bradford Method for determining protein concentration in a solution. The Coomassie dye binds to proteins via physisorptionto arginine, the aromatic amino acids, and histidine. When Coomassie Brilliant Blue G-250 binds to proteins in acid solution, it has an absorbance shift from 465 nm to 595 nm. The absorbance data can then be used in Beer's law to determine protein concentration and ultimately the actual amount of protein in a given solution.
## Coomassie stain and destain solution formulas
For staining solution:
For destaining solution:
(Can also be destained using only distilled water and heating, though at a much slower pace)
Common mix for Bradford reagent:
Methanol has been used in the past and can be replaced by ethanol at all steps resulting in slightly safer reagents (methanol is a neurotoxin) while the efficiency of the procedure remains the same.
# Name
Like many dyes, Coomassie blue dye is named after an African locale, in this case the city of Kumasi, now in Ghana. It was developed as an acid wool dye and was named to commemorate the 1896 British occupation of the Ashanti capital, then known as Coomassie.[1] | https://www.wikidoc.org/index.php/Coomassie | |
f6a1a2e8eaea0f3586857b1ba088440dda75d0a7 | wikidoc | Ribavirin | Ribavirin
# Disclaimer
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# Black Box Warning
# Overview
Ribavirin is a nucleoside analogue that is FDA approved for the treatment of chronic hepatitis C (CHC) virus infection in combination with peginterferon alfa-2a in adults with compensated liver disease not previously treated with interferon alpha, and in CHC patients coinfected with HIV-1. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reaction, pruritus, weight decrease, diarrhea, gastrointestinal symptoms, loss of appetite, nausea, vomiting, neutropenia, asthenia, dizziness, excluding vertigo, headache, insomnia, fatigue and influenza-like illness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: 800-1200 mg/day, administered in two divided doses, for 24-48 week. Administer with food. Exact dose depends on the genotype of the Hepatitis C Virus (HCV) and weight of the patients.
- Dosage: peg-interferon alfa-2a 180 mcg subcutaneous once weekly and ribavirin tablets, 800 mg PO daily for a total duration of 48 weeks, regardless of HCV genotype. Ribavirin tablets should be taken with food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Ribavirin 15 mg/kg orally three times daily for 4 days, then 8 mg/kg three times daily for up to 10 days.
### Non–Guideline-Supported Use
- Dosage: 400 mg 4 times a day for 3 days followed by 400 mg twice a day for 5 days.
- Dosage: 6 g/day in 3 divided doses for 5 to 7 days (Aerosol RIbavirin).
- Dosage: 1200 as initial dose, repeated at 1 and 2 hours; maintaining doses of 1200 mg were given every 12 hours during 2 days. In total, 8.4g in 2 days.
- Dosage:
Loading dose: 30 mg/kg IV once (maximum 2 g)
Maintenance
First Stage: 6 mg/kg IV (maximum 1 g/dose) every 6 hours for 4 days.
- Loading dose: 30 mg/kg IV once (maximum 2 g)
- Maintenance
First Stage: 6 mg/kg IV (maximum 1 g/dose) every 6 hours for 4 days.
- First Stage: 6 mg/kg IV (maximum 1 g/dose) every 6 hours for 4 days.
Second Stage: 8 mg/kg IV (maximum 500 mg/dose) every 8 hours for 6 days.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosage: The recommended treatment regimen is 20 mg/mL RIbavirin as the starting solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration for 12-18 hours per day for 3 to 7 days. Using the recommended drug concentration of 20 mg/mL the average aerosol concentration for a 12 hour delivery period would be 190 micrograms/liter of air. Aerosolized Ribavirin should not be administered in a mixture for combined aerosolization or simultaneously with other aerosolized medications.
- Dosage: 2 g 3 PO times daily.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Ribavirin 15 mg/kg orally three times daily for 4 days, then 8 mg/kg three times daily for up to 10 days.
Hepatitis C virus treatment is indicated for all children with HIV/HCV co-infection 3 years or older.
- Dosage
Regardless of HCV Genotype
Peginterferon-2-alfa 180 micrograms/1.73 m2 (Max 180 micrograms) or (peginterferon-2-beta 60 micrograms/m2 body surface area) subcutaneous once weekly
Oral ribavirin 7.5 mg/kg twice daily for 48 weeks
- Regardless of HCV Genotype
Peginterferon-2-alfa 180 micrograms/1.73 m2 (Max 180 micrograms) or (peginterferon-2-beta 60 micrograms/m2 body surface area) subcutaneous once weekly
Oral ribavirin 7.5 mg/kg twice daily for 48 weeks
- Peginterferon-2-alfa 180 micrograms/1.73 m2 (Max 180 micrograms) or (peginterferon-2-beta 60 micrograms/m2 body surface area) subcutaneous once weekly
- Oral ribavirin 7.5 mg/kg twice daily for 48 weeks
### Non–Guideline-Supported Use
- Dosage: 400 mg 4 times a day for 3 days followed by 400 mg twice a day for 5 days.
- Dosage: 25 mg/kg/day orally .
# Contraindications
Ribavirin tablets are contraindicated in:
- Women who are pregnant. Ribavirin tablets may cause fetal harm when administered to a pregnant woman. *Ribavirin tablets are contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Men whose female partners are pregnant.
- Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
- In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.
Ribavirin tablets and peginterferon alfa-2a combination therapy is contraindicated in patients with:
- Autoimmune hepatitis.
- Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment
- Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment
Ribavirin is contraindicated in individuals who have shown hypersensitivity to the drug or its components, and in women who are or may become pregnant during exposure to the drug. Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted (rodents and rabbits). Therefore, although clinical studies have not been performed, it should be assumed that ribavirin may cause fetal harm in humans. Studies in which the drug has been administered systemically demonstrate that ribavirin is concentrated in the red blood cells and persists for the life of the erythrocyte.
# Warnings
- Ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin.
- Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during ribavirin therapy and for 6 months after therapy has stopped.
- The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin/peginterferon alfa-2a-treated subjects in clinical trials. Anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding)
- Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with preexisting cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin
- Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961, among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with ribavirin/peginterferon alfa-2a should be discontinued immediately in patients with hepatic decompensation.
- Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and ribavirin should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy.
- Ribavirin should not be used in patients with creatinine clearance < 50 mL/min.
- Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with ribavirin and interferon. Occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, patients should be closely monitored and, if appropriate, combination ribavirin/peginterferon alfa-2a treatment should be discontinued.
- Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n = 8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Peginterferon alfa-2a, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine.
- Ribavirin and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.
- Before beginning peginterferon alfa-2a/ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have preexisting cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/ribavirin.
- After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.
The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:
- Platelet count ≥ 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV patients with cirrhosis or 70,000 cells/mm3 in patients with CHC and HIV)
- Absolute neutrophil count (ANC) ≥ 1500 cells/mm3
- TSH and T4 within normal limits or adequately controlled thyroid function
- CD4+ cell count ≥ 200 cells/μL or CD4+ cell count ≥ 100 cells/μL but < 200 cells/μL and HIV-1 RNA < 5000 copies/mL in patients coinfected with HIV
- Hemoglobin ≥ 12 g/dL for women and ≥ 13 g/dL for men in CHC monoinfected patients
- Hemoglobin ≥ 11 g/dL for women and ≥ 12 g/dL for men in patients with CHC and HIV
# Adverse Reactions
## Clinical Trials Experience
- Injection Site Reaction
- Hypothyroidism
- Fatigue/Asthenia
- Pyrexia
- Rigors
- Pain
- Nausea/Vomiting
- Diarrhea
- Abdominal pain
- Dry Mouth
- Dyspepsia
- Lymphopenia
- Anemia
- Neutropenia
- Thrombocytopenia
- Anorexia
- Weight decrease
- Myalgia
- Arthralgia
- Back pain
- Headache
- Dizziness (excluding vertigo)
- Memory impairment
- Irritability/Anxiety/Nervousness
- Insomnia
- Depression
- Concentration impairment
- Mood alteration
- Dyspnea
- Cough
- Dyspnea exertional
- Alopecia
- Pruritus
- Dermatitis
- Dry Skin
- Rash
- Sweating increased
- Eczema
- Vision Blurred
## Postmarketing Experience
- Pure red cell aplasia
- Hearing impairment
- Hearing loss
- Serous retinal detachment
- Renal graft rejection
- Liver graft rejection
- Dehydration
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
# Drug Interactions
Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin.
In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HCV/HIV coinfected patients. In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed.
Patients receiving peginterferon alfa-2a/ribavirin and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a, ribavirin or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh ≥ 6).
Coadministration of ribavirin and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) concentrations are increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.
In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin developed severe neutropenia (ANC < 500) and severe anemia (hemoglobin < 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.
In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.
The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced.
In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended daily human dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended daily human dose of ribavirin).
Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.
Ribavirin should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post therapy.
A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ribavirin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ribavirin during labor and delivery.
### Nursing Mothers
It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with ribavirin, based on the importance of the therapy to the mother.
### Pediatric Use
- Pharmacokinetic evaluations in pediatric patients have not been performed.
- Safety and effectiveness of ribavirin have not been established in patients below the age of 18.
### Geriatic Use
Clinical studies of ribavirin and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. Ribavirin should not be administered to patients with creatinine clearance < 50 mL/min.
### Gender
No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects.
Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.
### Race
A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n = 14), Hispanic (n = 13) and Caucasian (n = 15) subjects.
### Renal Impairment
The pharmacokinetics of ribavirin following administration of ribavirin have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin in patients with creatinine clearance < 50 mL/min. Therefore, patients with creatinine clearance < 50 mL/min should not be treated with ribavirin.
### Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child-Pugh class A disease.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ribavirin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ribavirin in patients who are immunocompromised.
### Organ Transplant Recipients
The safety and efficacy of peginterferon alfa-2a and ribavirin treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on peginterferon alfa-2a, alone or in combination with ribavirin
# Administration and Monitoring
### Administration
There is limited information regarding Ribavirin Administration in the drug label.
### Monitoring
Before beginning peginterferon alfa-2a/ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have preexisting cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/ribavirin.
After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.
The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:
- Platelet count ≥ 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV patients with cirrhosis or 70,000 cells/mm3 in patients with CHC and HIV)
- Absolute neutrophil count (ANC) ≥ 1500 cells/mm3
- TSH and T4 within normal limits or adequately controlled thyroid function
- CD4+ cell count ≥ 200 cells/μL or CD4+ cell count ≥ 100 cells/μL but < 200 cells/μL and HIV-1 RNA < 5000 copies/mL in patients coinfected with HIV
- Hemoglobin ≥ 12 g/dL for women and ≥ 13 g/dL for men in CHC monoinfected patients
- Hemoglobin ≥ 11 g/dL for women and ≥ 12 g/dL for men in patients with CHC and HIV
# IV Compatibility
There is limited information regarding the compatibility of Ribavirin and IV administrations.
# Overdosage
No cases of overdose with ribavirin have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.
# Pharmacology
## Mechanism of Action
There is limited information regarding Ribavirin Mechanism of Action in the drug label.
## Structure
Ribavirin is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1 H-1,2,4-triazole-3-carboxamide and has the following structural formula:
## Pharmacodynamics
There is limited information regarding Ribavirin Pharmacodynamics in the drug label.
## Pharmacokinetics
Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean ± SD (n = 39; body weight > 75 kg) AUC0-12hr was 25,361 ± 7110 nghr/mL and Cmax was 2748 ± 818 ng/mL. The average time to reach Cmax was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662 ± 545 ng/mL in HCV infected patients who received 800 mg/day (n = 89), and 2112 ± 810 ng/mL in patients who received 1200 mg/day (n = 75; body weight > 75 kg).
The terminal half-life of ribavirin following administration of a single oral dose of ribavirin is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose.
Bioavailability of a single oral dose of ribavirin was increased by coadministration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when ribavirin was taken with a high-fat meal compared with fasting conditions .
The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
In a p53 (+/-) mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2 year carcinogenicity study at doses up to the maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin, respectively.
Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. However, potential carcinogenic risk to humans cannot be excluded.
In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended daily human dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles.
Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months post therapy (i.e., 15 half-lives of clearance for ribavirin).
No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with ribavirin. However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.
### Animal Toxicology and/or Pharmacology
In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of ribavirin).
Long-term studies in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum daily human dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.
# Clinical Studies
### Chronic Hepatitis C Patients
- The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies.
- In Study NV15801, patients were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly with an oral placebo, peginterferon alfa-2a 180 mcg once weekly with ribavirin 1000 mg by mouth (body weight < 75 kg) or 1200 mg by mouth (body weight ≥ 75 kg) or interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (< 50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with ribavirin resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and ribavirin (Table 5). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alfa-2a in combination with ribavirin compared to patients with other viral genotypes.
- Difference in overall treatment response (peginterferon alfa-2a/ribavirin – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3). In Study NV15942, all patients received peginterferon alfa-2a 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a ribavirin dose of either 800 mg or 1000 mg/1200 mg (for body weight 2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.
- HCV 1 and 4- Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of ribavirin resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24 week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg ribavirin.
- HCV 2 and 3- Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin (see TABLE 6).
- The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.
### Treatment Response Predictors
- Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.
- In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or > 2 log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR
### Chronic Hepatitis C/HIV Coinfected Patients
- In Study NR15961, patients with CHC/HIV were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly plus an oral placebo, peginterferon alfa-2a 180 mcg once weekly plus ribavirin 800 mg by mouth daily or interferon alfa-2a, 3 MIU subcutaneous three times a week plus ribavirin 800 mg by mouth daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded in the peginterferon alfa-2a treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count ≥ 200 cells/mcL or CD4+ cell count ≥ 100 cells/mcL but < 200 cells/mcL and HIV-1 RNA < 5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 7.
- Treatment response rates were lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA > 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy.
- Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and ribavirin combination therapy, 2% (2/85) achieved an SVR.
- In CHC patients with HIV coinfection who received 48 weeks of peginterferon alfa-2a alone or in combination with ribavirin treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post treatment.
# How Supplied
Ribavirin tablets, 200 mg for oral administration are available as follows: Each tablet contains 200 mg of ribavirin and is light-pink to pink, round standard normal convex, coated tablet, debossed with “93” on one side and “7232” on the other side in bottles of 168.
Ribavirin for Inhalation Solution is supplied in four packs containing 100 mL glass vials with 6 grams of Sterile, lyophilized drug (NDC 0187-0007-14) which is to be reconstituted with 300 mL Sterile Water for Injection or Sterile Water for Inhalation (no preservatives added) and administered only by a small particle aerosol generator (SPAG-2)
## Storage
Store at 20° to 25°C (68° to 77°F). Keep bottle tightly closed. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Vials containing the lyophilized drug powder should be stored in a dry place at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Reconstituted solutions may be stored, under sterile conditions, at room temperature (20-30°C, 68-86°F) for 24 hours. Solutions which have been placed in the SPAG-2 unit should be discarded at least every 24 hours.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ribavirin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Ribavirin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Copegus
- Pegetron
- Rebetol
- Rebetron
- Ribasphere
- Virazole
# Look-Alike Drug Names
There is limited information regarding Ribavirin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ribavirin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
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# Black Box Warning
# Overview
Ribavirin is a nucleoside analogue that is FDA approved for the treatment of chronic hepatitis C (CHC) virus infection in combination with peginterferon alfa-2a in adults with compensated liver disease not previously treated with interferon alpha, and in CHC patients coinfected with HIV-1. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reaction, pruritus, weight decrease, diarrhea, gastrointestinal symptoms, loss of appetite, nausea, vomiting, neutropenia, asthenia, dizziness, excluding vertigo, headache, insomnia, fatigue and influenza-like illness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: 800-1200 mg/day, administered in two divided doses, for 24-48 week. Administer with food. Exact dose depends on the genotype of the Hepatitis C Virus (HCV) and weight of the patients.
- Dosage: peg-interferon alfa-2a 180 mcg subcutaneous once weekly and ribavirin tablets, 800 mg PO daily for a total duration of 48 weeks, regardless of HCV genotype. Ribavirin tablets should be taken with food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Ribavirin 15 mg/kg orally three times daily for 4 days, then 8 mg/kg three times daily for up to 10 days[1].
### Non–Guideline-Supported Use
- Dosage: 400 mg 4 times a day for 3 days followed by 400 mg twice a day for 5 days[2].
- Dosage: 6 g/day in 3 divided doses for 5 to 7 days (Aerosol RIbavirin)[3].
- Dosage: 1200 as initial dose, repeated at 1 and 2 hours; maintaining doses of 1200 mg were given every 12 hours during 2 days. In total, 8.4g in 2 days[4].
- Dosage:
Loading dose: 30 mg/kg IV once (maximum 2 g)
Maintenance
First Stage: 6 mg/kg IV (maximum 1 g/dose) every 6 hours for 4 days.
- Loading dose: 30 mg/kg IV once (maximum 2 g)
- Maintenance
First Stage: 6 mg/kg IV (maximum 1 g/dose) every 6 hours for 4 days.
- First Stage: 6 mg/kg IV (maximum 1 g/dose) every 6 hours for 4 days.
Second Stage: 8 mg/kg IV (maximum 500 mg/dose) every 8 hours for 6 days[5].
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosage: The recommended treatment regimen is 20 mg/mL RIbavirin as the starting solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration for 12-18 hours per day for 3 to 7 days. Using the recommended drug concentration of 20 mg/mL the average aerosol concentration for a 12 hour delivery period would be 190 micrograms/liter of air. Aerosolized Ribavirin should not be administered in a mixture for combined aerosolization or simultaneously with other aerosolized medications.
- Dosage: 2 g 3 PO times daily[6].
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Ribavirin 15 mg/kg orally three times daily for 4 days, then 8 mg/kg three times daily for up to 10 days[7].
Hepatitis C virus treatment is indicated for all children with HIV/HCV co-infection 3 years or older.
- Dosage
Regardless of HCV Genotype
Peginterferon-2-alfa 180 micrograms/1.73 m2 (Max 180 micrograms) or (peginterferon-2-beta 60 micrograms/m2 body surface area) subcutaneous once weekly
Oral ribavirin 7.5 mg/kg twice daily for 48 weeks [8]
- Regardless of HCV Genotype
Peginterferon-2-alfa 180 micrograms/1.73 m2 (Max 180 micrograms) or (peginterferon-2-beta 60 micrograms/m2 body surface area) subcutaneous once weekly
Oral ribavirin 7.5 mg/kg twice daily for 48 weeks [8]
- Peginterferon-2-alfa 180 micrograms/1.73 m2 (Max 180 micrograms) or (peginterferon-2-beta 60 micrograms/m2 body surface area) subcutaneous once weekly
- Oral ribavirin 7.5 mg/kg twice daily for 48 weeks [8]
### Non–Guideline-Supported Use
- Dosage: 400 mg 4 times a day for 3 days followed by 400 mg twice a day for 5 days[2].
- Dosage: 25 mg/kg/day orally [9].
# Contraindications
Ribavirin tablets are contraindicated in:
- Women who are pregnant. Ribavirin tablets may cause fetal harm when administered to a pregnant woman. *Ribavirin tablets are contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Men whose female partners are pregnant.
- Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
- In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.
Ribavirin tablets and peginterferon alfa-2a combination therapy is contraindicated in patients with:
- Autoimmune hepatitis.
- Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment
- Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment
Ribavirin is contraindicated in individuals who have shown hypersensitivity to the drug or its components, and in women who are or may become pregnant during exposure to the drug. Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted (rodents and rabbits). Therefore, although clinical studies have not been performed, it should be assumed that ribavirin may cause fetal harm in humans. Studies in which the drug has been administered systemically demonstrate that ribavirin is concentrated in the red blood cells and persists for the life of the erythrocyte.
# Warnings
- Ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin.
- Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Patients should be instructed to use at least two forms of effective contraception during treatment and for 6 months after treatment has been stopped. Pregnancy testing should occur monthly during ribavirin therapy and for 6 months after therapy has stopped.
- The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin/peginterferon alfa-2a-treated subjects in clinical trials. Anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding)
- Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with preexisting cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin
- Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961, among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with ribavirin/peginterferon alfa-2a should be discontinued immediately in patients with hepatic decompensation.
- Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and ribavirin should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy.
- Ribavirin should not be used in patients with creatinine clearance < 50 mL/min.
- Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with ribavirin and interferon. Occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, patients should be closely monitored and, if appropriate, combination ribavirin/peginterferon alfa-2a treatment should be discontinued.
- Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n = 8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Peginterferon alfa-2a, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine.
- Ribavirin and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.
- Before beginning peginterferon alfa-2a/ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have preexisting cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/ribavirin.
- After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.
The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:
- Platelet count ≥ 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV patients with cirrhosis or 70,000 cells/mm3 in patients with CHC and HIV)
- Absolute neutrophil count (ANC) ≥ 1500 cells/mm3
- TSH and T4 within normal limits or adequately controlled thyroid function
- CD4+ cell count ≥ 200 cells/μL or CD4+ cell count ≥ 100 cells/μL but < 200 cells/μL and HIV-1 RNA < 5000 copies/mL in patients coinfected with HIV
- Hemoglobin ≥ 12 g/dL for women and ≥ 13 g/dL for men in CHC monoinfected patients
- Hemoglobin ≥ 11 g/dL for women and ≥ 12 g/dL for men in patients with CHC and HIV
# Adverse Reactions
## Clinical Trials Experience
- Injection Site Reaction
- Hypothyroidism
- Fatigue/Asthenia
- Pyrexia
- Rigors
- Pain
- Nausea/Vomiting
- Diarrhea
- Abdominal pain
- Dry Mouth
- Dyspepsia
- Lymphopenia
- Anemia
- Neutropenia
- Thrombocytopenia
- Anorexia
- Weight decrease
- Myalgia
- Arthralgia
- Back pain
- Headache
- Dizziness (excluding vertigo)
- Memory impairment
- Irritability/Anxiety/Nervousness
- Insomnia
- Depression
- Concentration impairment
- Mood alteration
- Dyspnea
- Cough
- Dyspnea exertional
- Alopecia
- Pruritus
- Dermatitis
- Dry Skin
- Rash
- Sweating increased
- Eczema
- Vision Blurred
## Postmarketing Experience
- Pure red cell aplasia
- Hearing impairment
- Hearing loss
- Serous retinal detachment
- Renal graft rejection
- Liver graft rejection
- Dehydration
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
# Drug Interactions
Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin.
In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HCV/HIV coinfected patients. In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed.
Patients receiving peginterferon alfa-2a/ribavirin and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a, ribavirin or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh ≥ 6).
Coadministration of ribavirin and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) concentrations are increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.
In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin developed severe neutropenia (ANC < 500) and severe anemia (hemoglobin < 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.
In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.
The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Ribavirin produced significant embryocidal and/or teratogenic effects in all animal species in which adequate studies have been conducted. Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced.
In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended daily human dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended daily human dose of ribavirin).
Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.
Ribavirin should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post therapy.
A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ribavirin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ribavirin during labor and delivery.
### Nursing Mothers
It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with ribavirin, based on the importance of the therapy to the mother.
### Pediatric Use
- Pharmacokinetic evaluations in pediatric patients have not been performed.
- Safety and effectiveness of ribavirin have not been established in patients below the age of 18.
### Geriatic Use
Clinical studies of ribavirin and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. Ribavirin should not be administered to patients with creatinine clearance < 50 mL/min.
### Gender
No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects.
Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.
### Race
A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n = 14), Hispanic (n = 13) and Caucasian (n = 15) subjects.
### Renal Impairment
The pharmacokinetics of ribavirin following administration of ribavirin have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin in patients with creatinine clearance < 50 mL/min. Therefore, patients with creatinine clearance < 50 mL/min should not be treated with ribavirin.
### Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child-Pugh class A disease.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ribavirin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ribavirin in patients who are immunocompromised.
### Organ Transplant Recipients
The safety and efficacy of peginterferon alfa-2a and ribavirin treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on peginterferon alfa-2a, alone or in combination with ribavirin
# Administration and Monitoring
### Administration
There is limited information regarding Ribavirin Administration in the drug label.
### Monitoring
Before beginning peginterferon alfa-2a/ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have preexisting cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/ribavirin.
After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.
The entrance criteria used for the clinical studies of ribavirin and peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:
- Platelet count ≥ 90,000 cells/mm3 (as low as 75,000 cells/mm3 in HCV patients with cirrhosis or 70,000 cells/mm3 in patients with CHC and HIV)
- Absolute neutrophil count (ANC) ≥ 1500 cells/mm3
- TSH and T4 within normal limits or adequately controlled thyroid function
- CD4+ cell count ≥ 200 cells/μL or CD4+ cell count ≥ 100 cells/μL but < 200 cells/μL and HIV-1 RNA < 5000 copies/mL in patients coinfected with HIV
- Hemoglobin ≥ 12 g/dL for women and ≥ 13 g/dL for men in CHC monoinfected patients
- Hemoglobin ≥ 11 g/dL for women and ≥ 12 g/dL for men in patients with CHC and HIV
# IV Compatibility
There is limited information regarding the compatibility of Ribavirin and IV administrations.
# Overdosage
No cases of overdose with ribavirin have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.
# Pharmacology
## Mechanism of Action
There is limited information regarding Ribavirin Mechanism of Action in the drug label.
## Structure
Ribavirin is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1 H-1,2,4-triazole-3-carboxamide and has the following structural formula:
## Pharmacodynamics
There is limited information regarding Ribavirin Pharmacodynamics in the drug label.
## Pharmacokinetics
Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean ± SD (n = 39; body weight > 75 kg) AUC0-12hr was 25,361 ± 7110 ng•hr/mL and Cmax was 2748 ± 818 ng/mL. The average time to reach Cmax was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662 ± 545 ng/mL in HCV infected patients who received 800 mg/day (n = 89), and 2112 ± 810 ng/mL in patients who received 1200 mg/day (n = 75; body weight > 75 kg).
The terminal half-life of ribavirin following administration of a single oral dose of ribavirin is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose.
Bioavailability of a single oral dose of ribavirin was increased by coadministration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when ribavirin was taken with a high-fat meal compared with fasting conditions [see Dosage and Administration (2.1) and Patient Counseling Information (17)].
The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
In a p53 (+/-) mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2 year carcinogenicity study at doses up to the maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin, respectively.
Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. However, potential carcinogenic risk to humans cannot be excluded.
In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended daily human dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles.
Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months post therapy (i.e., 15 half-lives of clearance for ribavirin).
No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with ribavirin. However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.
### Animal Toxicology and/or Pharmacology
In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of ribavirin).
Long-term studies in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum daily human dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.
# Clinical Studies
### Chronic Hepatitis C Patients
- The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies.
- In Study NV15801, patients were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly with an oral placebo, peginterferon alfa-2a 180 mcg once weekly with ribavirin 1000 mg by mouth (body weight < 75 kg) or 1200 mg by mouth (body weight ≥ 75 kg) or interferon alfa-2b 3 MIU subcutaneous three times a week plus ribavirin 1000 mg or 1200 mg by mouth. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (< 50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with ribavirin resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and ribavirin (Table 5). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alfa-2a in combination with ribavirin compared to patients with other viral genotypes.
- Difference in overall treatment response (peginterferon alfa-2a/ribavirin – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3). In Study NV15942, all patients received peginterferon alfa-2a 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a ribavirin dose of either 800 mg or 1000 mg/1200 mg (for body weight < 75 kg/≥ 75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as > 2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.
- HCV 1 and 4- Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of ribavirin resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24 week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg ribavirin.
- HCV 2 and 3- Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin (see TABLE 6).
- The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.
### Treatment Response Predictors
- Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.
- In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or > 2 log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR
### Chronic Hepatitis C/HIV Coinfected Patients
- In Study NR15961, patients with CHC/HIV were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly plus an oral placebo, peginterferon alfa-2a 180 mcg once weekly plus ribavirin 800 mg by mouth daily or interferon alfa-2a, 3 MIU subcutaneous three times a week plus ribavirin 800 mg by mouth daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. Ribavirin or placebo treatment assignment was blinded in the peginterferon alfa-2a treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count ≥ 200 cells/mcL or CD4+ cell count ≥ 100 cells/mcL but < 200 cells/mcL and HIV-1 RNA < 5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 7.
- Treatment response rates were lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA > 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy.
- Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2 log10 reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and ribavirin combination therapy, 2% (2/85) achieved an SVR.
- In CHC patients with HIV coinfection who received 48 weeks of peginterferon alfa-2a alone or in combination with ribavirin treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post treatment.
# How Supplied
Ribavirin tablets, 200 mg for oral administration are available as follows: Each tablet contains 200 mg of ribavirin and is light-pink to pink, round standard normal convex, coated tablet, debossed with “93” on one side and “7232” on the other side in bottles of 168.
Ribavirin for Inhalation Solution is supplied in four packs containing 100 mL glass vials with 6 grams of Sterile, lyophilized drug (NDC 0187-0007-14) which is to be reconstituted with 300 mL Sterile Water for Injection or Sterile Water for Inhalation (no preservatives added) and administered only by a small particle aerosol generator (SPAG-2)
## Storage
Store at 20° to 25°C (68° to 77°F). Keep bottle tightly closed. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Vials containing the lyophilized drug powder should be stored in a dry place at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Reconstituted solutions may be stored, under sterile conditions, at room temperature (20-30°C, 68-86°F) for 24 hours. Solutions which have been placed in the SPAG-2 unit should be discarded at least every 24 hours.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ribavirin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Ribavirin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Copegus
- Pegetron
- Rebetol
- Rebetron
- Ribasphere
- Virazole
# Look-Alike Drug Names
There is limited information regarding Ribavirin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Copegus | |
d59554e13b6cff025ccd91d5da43d7e9d8e761e5 | wikidoc | Duvelisib | Duvelisib
# Disclaimer
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# Black Box Warning
# Overview
Duvelisib is a kinase inhibitor that is FDA approved for the treatment of adult patients with:
- Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies.
- Relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
- Duvelisib is indicated for the treatment of adult patients with relapsed or refractory CLL or SLL after at least two prior therapies.
Follicular Lymphoma (FL)
- Duvelisib is indicated for the treatment of adult patients with relapsed or refractory FL after at least two prior systemic therapies.
- This indication is approved under accelerated approval based on overall response rate (ORR); continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- 25 mg orally, twice daily. Modify dosage for toxicity.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of duvelisib have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- Serious, including fatal (18/442; 4%), infections occurred in 31% of patients receiving duvelisib 25 mg BID (N = 442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months.
- Treat infections prior to initiation of duvelisib. Advise patients to report any new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold duvelisib until infection has resolved. Resume duvelisib at the same or reduced dose.
- Serious, including fatal, ‘’Pneumocystis jirovecii’’ pneumonia (PJP) occurred in 1% of patients taking duvelisib. Provide prophylaxis for PJP during treatment with duvelisib. Following completion of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/µL. Withhold duvelisib in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed.
- CMV reactivation/infection occurred in 1% of patients taking duvelisib. Consider prophylactic antivirals during duvelisib treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia, withhold duvelisib until infection or viremia resolves. If duvelisib is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.
- Serious, including fatal (1/442; <1%), diarrhea or colitis occurred in 18% of patients receiving duvelisib 25 mg BID (N = 442). The median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75th percentile: 1 month).
- Advise patients to report any new or worsening diarrhea. For non-infectious diarrhea or colitis, follow the guidelines below:
- For patients presenting with mild or moderate diarrhea (Grade 1-2) (i.e. up to 6 stools per day over baseline) or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents as appropriate, continue duvelisib at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold duvelisib and initiate supportive therapy with enteric acting steroids (e.g. budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting duvelisib at a reduced dose.
- For patients presenting with abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, or with severe diarrhea (Grade 3) (i.e. > 6 stools per day over baseline) withhold duvelisib and initiate supportive therapy with enteric acting steroids (e.g. budesonide) or systemic steroids. A diagnostic work-up to determine etiology, including colonoscopy, should be performed. Monitor at least weekly. Upon resolution of the diarrhea or colitis, restart duvelisib at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue duvelisib. Discontinue duvelisib for life-threatening diarrhea or colitis.
- Serious, including fatal (2/442; < 1%), cutaneous reactions occurred in 5% of patients receiving duvelisib 25 mg BID (N = 442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months), with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months).
- Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report any new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue duvelisib at the current dose, initiate supportive care with emollients, anti-histamines (for pruritus), or topical steroids, and monitor the patient closely. Withhold duvelisib for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or anti-histamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event, restart duvelisib at a reduced dose. Discontinue duvelisib if severe cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue duvelisib. In patients with SJS, TEN, or DRESS of any grade, discontinue duvelisib.
- Serious, including fatal (1/442; < 1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving duvelisib 25 mg BID (N = 442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months). The median event duration was 1 month, with 75% of cases resolving by 2 months.
- Withhold duvelisib in patients who present with new or progressive pulmonary signs and symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation and evaluate for etiology. If the pneumonitis is infectious, patients may be restarted on duvelisib at the previous dose once the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), treat with systemic corticosteroids, and resume duvelisib at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy, discontinue duvelisib. For severe or life-threatening non-infectious pneumonitis, discontinue duvelisib and treat with systemic steroids.
- Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, in patients receiving duvelisib 25 mg BID (N = 442). Two percent of patients had both an ALT or AST greater than 3 x ULN and total bilirubin greater than 2 x ULN. Median time to onset of any grade transaminase elevation was 2 months (range: 3 days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months).
- Monitor hepatic function during treatment with duvelisib. For Grade 2 ALT/AST elevation (greater than 3 to 5 × ULN), maintain duvelisib dose and monitor at least weekly until return to less than 3 × ULN. For Grade 3 ALT/AST elevation (greater than 5 to 20 × ULN), withhold duvelisib and monitor at least weekly until return to less than 3 × ULN. Resume duvelisib at the same dose (first occurrence) or at a reduced dose for subsequent occurrence. For grade 4 ALT/AST elevation (greater than 20 × ULN) discontinue duvelisib.
- Grade 3 or 4 neutropenia occurred in 42% of patients receiving duvelisib 25 mg BID (N = 442), with Grade 4 neutropenia occurring in 24% of all patients. The median time to onset of Grade ≥ 3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 months.
- Monitor neutrophil counts at least every 2 weeks for the first 2 months of duvelisib therapy, and at least weekly in patients with neutrophil counts 0.5 Gi/L, resume duvelisib at same dose for the first occurrence or a reduced dose for subsequent occurrence.
- Based on findings in animals and its mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses approximately 10 times and 39 times the maximum recommended human dose (MRHD) of 25 mg BID in rats and rabbits, respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in practice.
Summary of Clinical Trial Experience in B-cell Malignancies
- The data described below reflect exposure to duvelisib in two single-arm, open-label clinical trials, one open-label extension clinical trial, and one randomized, open-label, actively controlled clinical trial totaling 442 patients with previously treated hematologic malignancies primarily including CLL/SLL (69%) and FL (22%). Patients were treated with duvelisib 25 mg BID until unacceptable toxicity or progressive disease. The median duration of exposure was 9 months (range: 0.1 to 53 months), with 36% (160/442) of patients having at least 12 months of exposure.
- For the 442 patients, the median age was 67 years (range: 30 to 90 years), 65% were male, 92% were White, and 93% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patients had a median of 2 prior therapies. The trials required hepatic transaminases at least ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 1.5 times ULN. Patients were excluded for prior exposure to a PI3K inhibitor within 4 weeks.
- Fatal adverse reactions within 30 days of the last dose occurred in 36 patients (8%) treated with duvelisib 25 mg BID.
- Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%).
- Adverse reactions resulted in treatment discontinuation in 156 patients (35%), most often due to diarrhea or colitis, infection, and rash. Duvelisib was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and transaminase elevation. The median time to first dose modification or discontinuation was 4 months (range: 0.1 to 27 months), with 75% of patients having their first dose modification or discontinuation within 7 months.
Common Adverse Reactions
- TABLE 3 summarizes common adverse reactions in patients receiving duvelisib 25 mg BID, and TABLE 4 summarizes the treatment-emergent laboratory abnormalities. The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.
- Grade 4 adverse reactions occurring in ≥ 2% of recipients of duvelisib included neutropenia (18%), thrombocytopenia (6%), sepsis (3%), hypokalemia and increased lipase (2% each), and pneumonia and pneumonitis (2% each).
- Grade 4 laboratory abnormalities developing in ≥ 2% of patients included neutropenia (24%), thrombocytopenia (7%), lipase increase (4%), lymphocytopenia (3%), and leukopenia (2%).
Summary of Clinical Trial Experience in CLL/SLL
Study 1
- The safety data below reflects exposure in a randomized, open-label, actively controlled clinical trial for adult patients with CLL or SLL who received at least one prior therapy. Of 313 patients treated, 158 received duvelisib monotherapy and 155 received ofatumumab. The 442-patient safety analysis above includes patients from Study 1.
- Duvelisib was administered at 25 mg BID in 28-day treatment cycles until unacceptable toxicity or progressive disease. The comparator group received 12 doses of ofatumumab with an initial dose of 300 mg intravenous (IV) on Day 1 followed a week later by 7 weekly doses of 2000 mg IV, followed 4 weeks later by 2000 mg IV every 4 weeks for 4 doses.
- In the total study population, the median age was 69 years (range: 39 to 90 years), 60% were male, 92% were White, and 91% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior therapies, with 61% of patients having received 2 or more prior therapies. The trial required a hemoglobin ≥ 8 g/dL and platelets ≥ 10,000 µL with or without transfusion support, hepatic transaminases ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 2 times ULN. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a PI3K inhibitor or a Bruton’s tyrosine kinase (BTK) inhibitor, and uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
- During randomized treatment, the median duration of exposure to duvelisib was 11.6 months with 72% (114/158) exposed for ≥ 6 months and 49% (77/158) exposed for ≥ 1 year. The median duration of exposure to ofatumumab was 5.3 months, with 77% (120/155) receiving at least 10 of 12 doses.
- Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with duvelisib and in 4% (7/155) of patients treated with ofatumumab.
- Serious adverse reactions were reported in 73% (115/158) of patients treated with duvelisib and most often involved infection (38% of patients; 60/158) and diarrhea or colitis (23% of patients; 36/158).
- Duvelisib was discontinued in 57 patients (36%), most often due to diarrhea or colitis, infection, and rash. Duvelisib was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash.
Common Adverse Reactions
- TABLE 5 summarizes selected adverse reactions in Study 1, and TABLE 6 summarizes treatment-emergent laboratory abnormalities. The most common adverse reactions with duvelisib (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.
- Grade 4 laboratory abnormalities that developed in ≥ 2% of duvelisib treated patients included neutropenia (32%), thrombocytopenia (6%), lymphopenia (3%), and hypokalemia (2%).
- The data above are not an adequate basis for comparison of rates between the study drug and the active control.
Summary of Clinical Trial Experience in FL
- The data described below reflect the exposure to duvelisib 25 mg BID in 96 patients with relapsed or refractory FL. These patients were included in the 442-patient safety analysis presented above. The median duration of treatment was 24 weeks, with 46% of patients exposed for ≥ 6 months and 19% exposed for ≥ 1 year.
- The median age was 64 years (range: 30 to 82 years), and 93% had an ECOG performance status of 0 to 1. Patients had a median of 3 prior systemic therapies.
- Serious adverse reactions were reported in 58% and most often involved diarrhea or colitis, pneumonia, renal insufficiency, rash, and sepsis. The most common adverse reactions (≥ 20% of patients) were diarrhea or colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.
- Adverse reactions resulted in duvelisib discontinuation in 29% of patients, most often due to diarrhea or colitis and rash. Duvelisib was dose reduced in 23% due to adverse reactions, most often due to transaminase elevation, diarrhea or colitis, lipase increased, and infection.
## Postmarketing Experience
There is limited information regarding Duvelisib Postmarketing Experience in the drug label.
# Drug Interactions
CYP3A Inducers
- Co-administration with a strong CYP3A inducer decreases duvelisib area under the curve (AUC), which may reduce duvelisib efficacy. Avoid co-administration of duvelisib with strong CYP3A4 inducers.
CYP3A Inhibitors
- Co-administration with a strong CYP3A inhibitor increases duvelisib AUC, which may increase the risk of duvelisib toxicities. Reduce duvelisib dose to 15 mg BID when co-administered with a strong CYP3A4 inhibitor.
CYP3A Substrates
- Co-administration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the co-administered sensitive CYP3A substrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Based on findings from animal studies and the mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman.
- There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses 10 times and 39 times the MRHD of 25 mg BID in rats and rabbits, respectively.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Animal Data
- In an embryo-fetal development study in rats, pregnant animals received daily oral doses of duvelisib of 0, 10, 50, 150 and 275 mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 50 mg/kg/day resulted in adverse developmental outcomes including reduced fetal weights and external abnormalities (bent tail and fetal anasarca), and doses ≥ 150 mg/kg/day resulted in maternal toxicity including mortality and no live fetuses (100% resorption) in surviving dams. In another study in pregnant rats receiving oral doses of duvelisib up to 35 mg/kg/day during the period of organogenesis, no maternal or embryo-fetal effects were observed. The dose of 50 mg/kg/day in rats is approximately 10 times the MRHD of 25 mg BID.
- In an embryo-fetal development study in rabbits, pregnant animals received daily oral doses of duvelisib of 0, 25, 100, and 200 mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 100 mg/kg/day resulted in maternal toxicity (body weight losses or lower mean body weights and increased mortality) and adverse developmental outcomes (increased resorptions and post-implantation loss, abortion, and decreased numbers of viable fetuses). In another study in pregnant rabbits receiving oral doses of duvelisib up to 75 mg/kg/day, no maternal or embryo-fetal effects were observed. The dose of 100 mg/kg/day in rabbits is approximately 39 times the MRHD of 25 mg BID.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Duvelisib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Duvelisib during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of duvelisib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from duvelisib in a breastfed child, advise lactating women not to breastfeed while taking duvelisib and for at least 1 month after the last dose.
### Pediatric Use
- Safety and effectiveness of duvelisib have not been established in pediatric patients. Pediatric studies have not been conducted.
### Geriatic Use
- Clinical trials of duvelisib included 270 patients (61%) that were 65 years of age and older and 104 (24%) that were 75 years of age and older. No major differences in efficacy or safety were observed between patients less than 65 years of age and patients 65 years of age and older.
### Gender
There is no FDA guidance on the use of Duvelisib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Duvelisib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Duvelisib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Duvelisib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Pregnancy Testing
- Duvelisib can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing before initiation of duvelisib treatment.
Contraception
Females
- Based on animal studies, duvelisib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Males
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Infertility
- Based on testicular findings in animals, male fertility may be impaired by treatment with duvelisib. There are no data on the effect of duvelisib on human fertility.
### Immunocompromised Patients
There is no FDA guidance one the use of Duvelisib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dose of duvelisib is 25 mg administered as oral capsules twice daily (BID) with or without food. A cycle consists of 28 days. The capsules should be swallowed whole. Advise patients not to open, break, or chew the capsules.
- Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.
- Provide prophylaxis for ‘’Pneumocystis jirovecii’’ (PJP) during treatment with duvelisib. Following completion of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/µL.
- Withhold duvelisib in patients with suspected PJP of any grade, and discontinue if PJP is confirmed.
- Consider prophylactic antivirals during duvelisib treatment to prevent cytomegalovirus (CMV) infection including CMV reactivation.
- Manage toxicities per TABLE 1 with dose reduction, treatment hold, or discontinuation of duvelisib.
- Recommended dose modification levels for duvelisib are presented in TABLE 2.
- Reduce duvelisib dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole).
### Monitoring
There is limited information regarding Duvelisib Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Duvelisib and IV administrations.
# Overdosage
There is limited information regarding Duvelisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Duvelisib is an inhibitor of PI3K with inhibitory activity predominantly against PI3K-δ and PI3K-γ isoforms expressed in normal and malignant B-cells. Duvelisib induced growth inhibition and reduced viability in cell lines derived from malignant B-cells and in primary CLL tumor cells. Duvelisib inhibits several key cell-signaling pathways, including B-cell receptor signaling and CXCR12-mediated chemotaxis of malignant B-cells. Additionally, duvelisib inhibits CXCL12-induced T cell migration and M-CSF and IL-4 driven M2 polarization of macrophages.
## Structure
- Duvelisib is a white-to-off-white crystalline solid with the empirical formula C22H17ClN6OH2O and a molecular weight of 434.88 g/mol.
## Pharmacodynamics
- At the recommended dose of 25 mg BID, reductions in levels of phosphorylated AKT (a downstream marker for PI3K inhibition) were observed in patients treated with duvelisib.
Cardiac Electrophysiology
- The effect of multiple doses of duvelisib 25 and 75 mg BID on the QTc interval was evaluated in patients with previously treated hematologic malignancies. Increases of > 20 ms in the QTc interval were not observed.
## Pharmacokinetics
- Duvelisib exposure increased in a dose-proportional manner over a dose range of 8 mg to 75 mg twice daily (0.3 to 3 times the recommended dosage).
- At steady state following 25 mg BID administration of duvelisib in patients, the geometric mean (CV%) maximum concentration (Cmax) was 1.5 (64%) µg/mL and AUC was 7.9 (77%) µgh/mL.
Absorption
- The absolute bioavailability of 25 mg duvelisib after a single oral dose in healthy volunteers was 42%. The median time to peak concentration (Tmax) was observed at 1 to 2 hours in patients.
Effect of Food
- Duvelisib may be administered without regard to food. The administration of a single dose of duvelisib with a high-fat meal (fat accounted for approximately 50% of the total caloric content of the meal) decreased Cmax by approximately 37% and decreased the AUC by approximately 6%, relative to fasting conditions.
Distribution
- Protein binding of duvelisib is greater than 98% with no concentration dependence. The mean blood-to-plasma ratio was 0.5. The geometric mean (CV%) apparent volume of distribution at steady state (Vss/F) is 28.5 L (62%). Duvelisib is a substrate of P-glycoprotein (P-gp) and BCRP in vitro.
Elimination
- The geometric mean (CV%) apparent systemic clearance at steady-state is 4.2 L/hr (56%) in patients with lymphoma or leukemia. The geometric mean (CV%) terminal elimination half-life of duvelisib is 4.7 hours (57%).
Metabolism
- Duvelisib is primarily metabolized by cytochrome P450 CYP3A4.
Excretion
- Following a single 25 mg oral dose of radiolabeled duvelisib, 79% of the radioactivity was excreted in feces (11% unchanged) and 14% was excreted in the urine (< 1% unchanged).
Specific Populations
- Age (18 to 90 years), sex, race, renal impairment (creatinine clearance 23 to 80 mL/ min), hepatic impairment (Child Pugh Class A, B, and C) and body weight (40 to 154 kg) had no clinically significant effect on the exposure of duvelisib.
Drug Interaction Studies
Strong and Moderate CYP3A Inhibitors
- Co-administration of strong CYP3A inhibitor ketoconazole (at 200 mg BID for 5 days), a strong inhibitor of CYP3A4, with a single oral 10 mg dose of duvelisib in healthy adults (n= 16) increased duvelisib Cmax by 1.7-fold and AUC by 4-fold. Based on physiologically-based pharmacokinetic (PBPK) modeling and simulation, the increase in exposure to duvelisib is estimated to be ~2-fold at steady state when concomitantly used with strong CYP3A4 inhibitors such as ketoconazole. PBPK modeling and simulation estimated no effect on duvelisib exposures from concomitantly used mild or moderate CYP3A4 inhibitors.
Strong and Moderate CYP3A4 Inducers
- Co-administration of 600 mg once daily rifampin, a strong CYP3A inducer, for 7 days with a single oral 25 mg duvelisib dose in healthy adults (N = 13) decreased duvelisib Cmax by 66% and AUC by 82%.
- The effect of moderate CYP3A4 induction has not been studied.
CYP3A4 Substrates
- Co-administration of multiple doses of duvelisib 25 mg BID for 5 days with single oral 2 mg midazolam, a sensitive CYP3A4 substrate, in healthy adults (N = 14), increased in the midazolam AUC by 4.3-fold and Cmax by 2.2-fold.
In Vitro Studies
- Duvelisib is a substrate of P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP).
- Duvelisib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BCRP, or P-gp.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with duvelisib.
- Duvelisib did not cause genetic damage in in vitro or in vivo assays.
- Fertility studies with duvelisib were not conducted. Histological findings in male and female rats were observed in the repeat dose toxicity studies and included testis (seminiferous epithelial atrophy, decreased weight, soft testes), and epididymis (small size, oligo/aspermia) in males and ovary (decreased weight) and uterus (atrophy) in females.
# Clinical Studies
Study 1
- A randomized, multicenter, open-label trial (Study 1; NCT02004522) compared duvelisib versus ofatumumab in 319 adult patients with CLL (N = 312) or SLL (N = 7) after at least one prior therapy. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a PI3K inhibitor or a Bruton’s tyrosine kinase (BTK) inhibitor. The trial required hepatic transaminases ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 2 times ULN.
- The study randomized patients with a 1:1 ratio to receive either duvelisib 25 mg BID until disease progression or unacceptable toxicity or ofatumumab for 7 cycles. Ofatumumab was administered intravenously at an initial dose of 300 mg, followed one week later by 2000 mg once weekly for 7 doses, and then 2000 mg once every 4 weeks for 4 additional doses.
- The approval of duvelisib was based on efficacy and safety analysis of patients with at least 2 prior lines of therapy, where the benefit:risk appeared greater in this more heavily pretreated population compared to the overall trial population.
- In this subset (95 randomized to duvelisib, 101 to ofatumumab), the median patient age was 69 years (range: 40 to 90 years), 59% were male, and 88% had an ECOG performance status of 0 or 1. Forty-six percent received 2 prior lines of therapy, and 54% received 3 or more prior lines. At baseline, 52% of patients had at least one tumor ≥ 5 cm, and 22% of patients had a documented 17p deletion.
- During randomized treatment, the median duration of exposure to duvelisib was 13 months (range: 0.2 to 37), with 80% of patients receiving at least 6 months and 52% receiving at least 12 months of duvelisib. The median duration of exposure to ofatumumab was 5 months (range: < 0.1 to 6).
- Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). Other efficacy measures included overall response rate. Efficacy of duvelisib compared to ofatumumab specifically in patients treated with at least two prior therapies is presented in TABLE 8 and FIGURE 1.
Study 2
- Efficacy of duvelisib in patients with previously treated FL is based on a single-arm, multicenter trial (Study 2; NCT02204982). In this study, duvelisib 25 mg BID was administered in patients with FL (N = 83) who were refractory to rituximab and to either chemotherapy or radioimmunotherapy. Refractory disease was defined as less than a partial remission or relapse within 6 months after the last dose. The trial excluded patients with Grade 3b FL, large cell transformation, prior allogeneic transplant, and prior exposure to a PI3K inhibitor or to a Bruton’s tyrosine kinase inhibitor.
- The median age was 64 years (range: 30 to 82 years), 68% were male, and 37% had bulky disease assessed at baseline (target lesion ≥ 5 cm). Patients had a median of 3 prior lines of therapy (range: 1 to 10), with 94% being refractory to their last therapy and 81% being refractory to 2 or more prior lines of therapy. Most patients (93%) had an ECOG performance status of 0 or 1.
- The median duration of exposure to duvelisib was 5 months (range: 0.4 to 24), with 41% of patients receiving at least 6 months and 10% receiving at least 12 months of duvelisib.
- Efficacy was based on overall response rate and duration of response as assessed by an IRC (TABLE 9).
# How Supplied
- Duvelisib capsules are supplied as follows:
## Storage
- Store at 20° to 25°C (68° to 77°F), with excursions permitted at 15° to 30°C (59° to 86°F) . Retain in original package until dispensing. Dispense blister packs in original container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
- Physicians and healthcare professionals are advised to discuss the following with patients prior to treatment with duvelisib:
Infections
- Advise patients that duvelisib can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection (e.g. fever, chills).
Diarrhea or Colitis
- Advise patients that duvelisib can cause serious diarrhea or colitis (inflammation of the gut) that may be fatal, and to notify their healthcare provider immediately about any new or worsening diarrhea, stool with mucus or blood, or abdominal pain.
Cutaneous Reactions
- Advise patients that duvelisib can cause a serious skin rash that may be fatal, and to notify their healthcare provider immediately if they develop a new or worsening skin rash.
Pneumonitis
- Advise patients that duvelisib may cause pneumonitis (inflammation of the lungs) that may be fatal, and to report any new or worsening respiratory symptoms including cough or difficulty breathing.
Hepatotoxicity
- Advise patients that duvelisib may cause significant elevations in liver enzymes, and that monitoring of liver tests is needed. Advise patients to report symptoms of liver dysfunction including jaundice (yellow eyes or yellow skin), abdominal pain, bruising, or bleeding.
Neutropenia
- Advise patients of the need for periodic monitoring of blood counts. Advise patients to notify their healthcare provider immediately if they develop a fever or any sign of infection.
Embryo-Fetal Toxicity
- Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus.
- Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of duvelisib.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Lactation
- Advise lactating women not to breastfeed during treatment with duvelisib and for at least 1 month after the last dose.
- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products, before and during treatment with duvelisib.
Instructions for Taking Duvelisib
- Advise patients to take duvelisib exactly as prescribed. Duvelisib may be taken with or without food; the capsules should be swallowed whole.
- Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.
# Precautions with Alcohol
Alcohol-Duvelisib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Copiktra
# Look-Alike Drug Names
There is limited information regarding Duvelisib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Duvelisib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]
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# Black Box Warning
# Overview
Duvelisib is a kinase inhibitor that is FDA approved for the treatment of adult patients with:
- Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies.
- Relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
- Duvelisib is indicated for the treatment of adult patients with relapsed or refractory CLL or SLL after at least two prior therapies.
Follicular Lymphoma (FL)
- Duvelisib is indicated for the treatment of adult patients with relapsed or refractory FL after at least two prior systemic therapies.
- This indication is approved under accelerated approval based on overall response rate (ORR); continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- 25 mg orally, twice daily. Modify dosage for toxicity.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of duvelisib have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- Serious, including fatal (18/442; 4%), infections occurred in 31% of patients receiving duvelisib 25 mg BID (N = 442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months.
- Treat infections prior to initiation of duvelisib. Advise patients to report any new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold duvelisib until infection has resolved. Resume duvelisib at the same or reduced dose.
- Serious, including fatal, ‘’Pneumocystis jirovecii’’ pneumonia (PJP) occurred in 1% of patients taking duvelisib. Provide prophylaxis for PJP during treatment with duvelisib. Following completion of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/µL. Withhold duvelisib in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed.
- CMV reactivation/infection occurred in 1% of patients taking duvelisib. Consider prophylactic antivirals during duvelisib treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia, withhold duvelisib until infection or viremia resolves. If duvelisib is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.
- Serious, including fatal (1/442; <1%), diarrhea or colitis occurred in 18% of patients receiving duvelisib 25 mg BID (N = 442). The median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75th percentile: 1 month).
- Advise patients to report any new or worsening diarrhea. For non-infectious diarrhea or colitis, follow the guidelines below:
- For patients presenting with mild or moderate diarrhea (Grade 1-2) (i.e. up to 6 stools per day over baseline) or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents as appropriate, continue duvelisib at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold duvelisib and initiate supportive therapy with enteric acting steroids (e.g. budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting duvelisib at a reduced dose.
- For patients presenting with abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, or with severe diarrhea (Grade 3) (i.e. > 6 stools per day over baseline) withhold duvelisib and initiate supportive therapy with enteric acting steroids (e.g. budesonide) or systemic steroids. A diagnostic work-up to determine etiology, including colonoscopy, should be performed. Monitor at least weekly. Upon resolution of the diarrhea or colitis, restart duvelisib at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue duvelisib. Discontinue duvelisib for life-threatening diarrhea or colitis.
- Serious, including fatal (2/442; < 1%), cutaneous reactions occurred in 5% of patients receiving duvelisib 25 mg BID (N = 442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months), with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months).
- Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report any new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue duvelisib at the current dose, initiate supportive care with emollients, anti-histamines (for pruritus), or topical steroids, and monitor the patient closely. Withhold duvelisib for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or anti-histamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event, restart duvelisib at a reduced dose. Discontinue duvelisib if severe cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue duvelisib. In patients with SJS, TEN, or DRESS of any grade, discontinue duvelisib.
- Serious, including fatal (1/442; < 1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving duvelisib 25 mg BID (N = 442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months). The median event duration was 1 month, with 75% of cases resolving by 2 months.
- Withhold duvelisib in patients who present with new or progressive pulmonary signs and symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation and evaluate for etiology. If the pneumonitis is infectious, patients may be restarted on duvelisib at the previous dose once the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), treat with systemic corticosteroids, and resume duvelisib at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy, discontinue duvelisib. For severe or life-threatening non-infectious pneumonitis, discontinue duvelisib and treat with systemic steroids.
- Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, in patients receiving duvelisib 25 mg BID (N = 442). Two percent of patients had both an ALT or AST greater than 3 x ULN and total bilirubin greater than 2 x ULN. Median time to onset of any grade transaminase elevation was 2 months (range: 3 days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months).
- Monitor hepatic function during treatment with duvelisib. For Grade 2 ALT/AST elevation (greater than 3 to 5 × ULN), maintain duvelisib dose and monitor at least weekly until return to less than 3 × ULN. For Grade 3 ALT/AST elevation (greater than 5 to 20 × ULN), withhold duvelisib and monitor at least weekly until return to less than 3 × ULN. Resume duvelisib at the same dose (first occurrence) or at a reduced dose for subsequent occurrence. For grade 4 ALT/AST elevation (greater than 20 × ULN) discontinue duvelisib.
- Grade 3 or 4 neutropenia occurred in 42% of patients receiving duvelisib 25 mg BID (N = 442), with Grade 4 neutropenia occurring in 24% of all patients. The median time to onset of Grade ≥ 3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 months.
- Monitor neutrophil counts at least every 2 weeks for the first 2 months of duvelisib therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold duvelisib in patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4). Monitor until ANC is > 0.5 Gi/L, resume duvelisib at same dose for the first occurrence or a reduced dose for subsequent occurrence.
- Based on findings in animals and its mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses approximately 10 times and 39 times the maximum recommended human dose (MRHD) of 25 mg BID in rats and rabbits, respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in practice.
Summary of Clinical Trial Experience in B-cell Malignancies
- The data described below reflect exposure to duvelisib in two single-arm, open-label clinical trials, one open-label extension clinical trial, and one randomized, open-label, actively controlled clinical trial totaling 442 patients with previously treated hematologic malignancies primarily including CLL/SLL (69%) and FL (22%). Patients were treated with duvelisib 25 mg BID until unacceptable toxicity or progressive disease. The median duration of exposure was 9 months (range: 0.1 to 53 months), with 36% (160/442) of patients having at least 12 months of exposure.
- For the 442 patients, the median age was 67 years (range: 30 to 90 years), 65% were male, 92% were White, and 93% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patients had a median of 2 prior therapies. The trials required hepatic transaminases at least ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 1.5 times ULN. Patients were excluded for prior exposure to a PI3K inhibitor within 4 weeks.
- Fatal adverse reactions within 30 days of the last dose occurred in 36 patients (8%) treated with duvelisib 25 mg BID.
- Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%).
- Adverse reactions resulted in treatment discontinuation in 156 patients (35%), most often due to diarrhea or colitis, infection, and rash. Duvelisib was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and transaminase elevation. The median time to first dose modification or discontinuation was 4 months (range: 0.1 to 27 months), with 75% of patients having their first dose modification or discontinuation within 7 months.
Common Adverse Reactions
- TABLE 3 summarizes common adverse reactions in patients receiving duvelisib 25 mg BID, and TABLE 4 summarizes the treatment-emergent laboratory abnormalities. The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.
- Grade 4 adverse reactions occurring in ≥ 2% of recipients of duvelisib included neutropenia (18%), thrombocytopenia (6%), sepsis (3%), hypokalemia and increased lipase (2% each), and pneumonia and pneumonitis (2% each).
- Grade 4 laboratory abnormalities developing in ≥ 2% of patients included neutropenia (24%), thrombocytopenia (7%), lipase increase (4%), lymphocytopenia (3%), and leukopenia (2%).
Summary of Clinical Trial Experience in CLL/SLL
Study 1
- The safety data below reflects exposure in a randomized, open-label, actively controlled clinical trial for adult patients with CLL or SLL who received at least one prior therapy. Of 313 patients treated, 158 received duvelisib monotherapy and 155 received ofatumumab. The 442-patient safety analysis above includes patients from Study 1.
- Duvelisib was administered at 25 mg BID in 28-day treatment cycles until unacceptable toxicity or progressive disease. The comparator group received 12 doses of ofatumumab with an initial dose of 300 mg intravenous (IV) on Day 1 followed a week later by 7 weekly doses of 2000 mg IV, followed 4 weeks later by 2000 mg IV every 4 weeks for 4 doses.
- In the total study population, the median age was 69 years (range: 39 to 90 years), 60% were male, 92% were White, and 91% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior therapies, with 61% of patients having received 2 or more prior therapies. The trial required a hemoglobin ≥ 8 g/dL and platelets ≥ 10,000 µL with or without transfusion support, hepatic transaminases ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 2 times ULN. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a PI3K inhibitor or a Bruton’s tyrosine kinase (BTK) inhibitor, and uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
- During randomized treatment, the median duration of exposure to duvelisib was 11.6 months with 72% (114/158) exposed for ≥ 6 months and 49% (77/158) exposed for ≥ 1 year. The median duration of exposure to ofatumumab was 5.3 months, with 77% (120/155) receiving at least 10 of 12 doses.
- Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with duvelisib and in 4% (7/155) of patients treated with ofatumumab.
- Serious adverse reactions were reported in 73% (115/158) of patients treated with duvelisib and most often involved infection (38% of patients; 60/158) and diarrhea or colitis (23% of patients; 36/158).
- Duvelisib was discontinued in 57 patients (36%), most often due to diarrhea or colitis, infection, and rash. Duvelisib was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash.
Common Adverse Reactions
- TABLE 5 summarizes selected adverse reactions in Study 1, and TABLE 6 summarizes treatment-emergent laboratory abnormalities. The most common adverse reactions with duvelisib (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.
- Grade 4 laboratory abnormalities that developed in ≥ 2% of duvelisib treated patients included neutropenia (32%), thrombocytopenia (6%), lymphopenia (3%), and hypokalemia (2%).
- The data above are not an adequate basis for comparison of rates between the study drug and the active control.
Summary of Clinical Trial Experience in FL
- The data described below reflect the exposure to duvelisib 25 mg BID in 96 patients with relapsed or refractory FL. These patients were included in the 442-patient safety analysis presented above. The median duration of treatment was 24 weeks, with 46% of patients exposed for ≥ 6 months and 19% exposed for ≥ 1 year.
- The median age was 64 years (range: 30 to 82 years), and 93% had an ECOG performance status of 0 to 1. Patients had a median of 3 prior systemic therapies.
- Serious adverse reactions were reported in 58% and most often involved diarrhea or colitis, pneumonia, renal insufficiency, rash, and sepsis. The most common adverse reactions (≥ 20% of patients) were diarrhea or colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.
- Adverse reactions resulted in duvelisib discontinuation in 29% of patients, most often due to diarrhea or colitis and rash. Duvelisib was dose reduced in 23% due to adverse reactions, most often due to transaminase elevation, diarrhea or colitis, lipase increased, and infection.
## Postmarketing Experience
There is limited information regarding Duvelisib Postmarketing Experience in the drug label.
# Drug Interactions
CYP3A Inducers
- Co-administration with a strong CYP3A inducer decreases duvelisib area under the curve (AUC), which may reduce duvelisib efficacy. Avoid co-administration of duvelisib with strong CYP3A4 inducers.
CYP3A Inhibitors
- Co-administration with a strong CYP3A inhibitor increases duvelisib AUC, which may increase the risk of duvelisib toxicities. Reduce duvelisib dose to 15 mg BID when co-administered with a strong CYP3A4 inhibitor.
CYP3A Substrates
- Co-administration with duvelisib increases AUC of a sensitive CYP3A4 substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the co-administered sensitive CYP3A substrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Based on findings from animal studies and the mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman.
- There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses 10 times and 39 times the MRHD of 25 mg BID in rats and rabbits, respectively.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Animal Data
- In an embryo-fetal development study in rats, pregnant animals received daily oral doses of duvelisib of 0, 10, 50, 150 and 275 mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 50 mg/kg/day resulted in adverse developmental outcomes including reduced fetal weights and external abnormalities (bent tail and fetal anasarca), and doses ≥ 150 mg/kg/day resulted in maternal toxicity including mortality and no live fetuses (100% resorption) in surviving dams. In another study in pregnant rats receiving oral doses of duvelisib up to 35 mg/kg/day during the period of organogenesis, no maternal or embryo-fetal effects were observed. The dose of 50 mg/kg/day in rats is approximately 10 times the MRHD of 25 mg BID.
- In an embryo-fetal development study in rabbits, pregnant animals received daily oral doses of duvelisib of 0, 25, 100, and 200 mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 100 mg/kg/day resulted in maternal toxicity (body weight losses or lower mean body weights and increased mortality) and adverse developmental outcomes (increased resorptions and post-implantation loss, abortion, and decreased numbers of viable fetuses). In another study in pregnant rabbits receiving oral doses of duvelisib up to 75 mg/kg/day, no maternal or embryo-fetal effects were observed. The dose of 100 mg/kg/day in rabbits is approximately 39 times the MRHD of 25 mg BID.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Duvelisib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Duvelisib during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of duvelisib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from duvelisib in a breastfed child, advise lactating women not to breastfeed while taking duvelisib and for at least 1 month after the last dose.
### Pediatric Use
- Safety and effectiveness of duvelisib have not been established in pediatric patients. Pediatric studies have not been conducted.
### Geriatic Use
- Clinical trials of duvelisib included 270 patients (61%) that were 65 years of age and older and 104 (24%) that were 75 years of age and older. No major differences in efficacy or safety were observed between patients less than 65 years of age and patients 65 years of age and older.
### Gender
There is no FDA guidance on the use of Duvelisib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Duvelisib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Duvelisib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Duvelisib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Pregnancy Testing
- Duvelisib can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing before initiation of duvelisib treatment.
Contraception
Females
- Based on animal studies, duvelisib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Males
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Infertility
- Based on testicular findings in animals, male fertility may be impaired by treatment with duvelisib. There are no data on the effect of duvelisib on human fertility.
### Immunocompromised Patients
There is no FDA guidance one the use of Duvelisib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dose of duvelisib is 25 mg administered as oral capsules twice daily (BID) with or without food. A cycle consists of 28 days. The capsules should be swallowed whole. Advise patients not to open, break, or chew the capsules.
- Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.
- Provide prophylaxis for ‘’Pneumocystis jirovecii’’ (PJP) during treatment with duvelisib. Following completion of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/µL.
- Withhold duvelisib in patients with suspected PJP of any grade, and discontinue if PJP is confirmed.
- Consider prophylactic antivirals during duvelisib treatment to prevent cytomegalovirus (CMV) infection including CMV reactivation.
- Manage toxicities per TABLE 1 with dose reduction, treatment hold, or discontinuation of duvelisib.
- Recommended dose modification levels for duvelisib are presented in TABLE 2.
- Reduce duvelisib dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole).
### Monitoring
There is limited information regarding Duvelisib Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Duvelisib and IV administrations.
# Overdosage
There is limited information regarding Duvelisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Duvelisib is an inhibitor of PI3K with inhibitory activity predominantly against PI3K-δ and PI3K-γ isoforms expressed in normal and malignant B-cells. Duvelisib induced growth inhibition and reduced viability in cell lines derived from malignant B-cells and in primary CLL tumor cells. Duvelisib inhibits several key cell-signaling pathways, including B-cell receptor signaling and CXCR12-mediated chemotaxis of malignant B-cells. Additionally, duvelisib inhibits CXCL12-induced T cell migration and M-CSF and IL-4 driven M2 polarization of macrophages.
## Structure
- Duvelisib is a white-to-off-white crystalline solid with the empirical formula C22H17ClN6O•H2O and a molecular weight of 434.88 g/mol.
## Pharmacodynamics
- At the recommended dose of 25 mg BID, reductions in levels of phosphorylated AKT (a downstream marker for PI3K inhibition) were observed in patients treated with duvelisib.
Cardiac Electrophysiology
- The effect of multiple doses of duvelisib 25 and 75 mg BID on the QTc interval was evaluated in patients with previously treated hematologic malignancies. Increases of > 20 ms in the QTc interval were not observed.
## Pharmacokinetics
- Duvelisib exposure increased in a dose-proportional manner over a dose range of 8 mg to 75 mg twice daily (0.3 to 3 times the recommended dosage).
- At steady state following 25 mg BID administration of duvelisib in patients, the geometric mean (CV%) maximum concentration (Cmax) was 1.5 (64%) µg/mL and AUC was 7.9 (77%) µg•h/mL.
Absorption
- The absolute bioavailability of 25 mg duvelisib after a single oral dose in healthy volunteers was 42%. The median time to peak concentration (Tmax) was observed at 1 to 2 hours in patients.
Effect of Food
- Duvelisib may be administered without regard to food. The administration of a single dose of duvelisib with a high-fat meal (fat accounted for approximately 50% of the total caloric content of the meal) decreased Cmax by approximately 37% and decreased the AUC by approximately 6%, relative to fasting conditions.
Distribution
- Protein binding of duvelisib is greater than 98% with no concentration dependence. The mean blood-to-plasma ratio was 0.5. The geometric mean (CV%) apparent volume of distribution at steady state (Vss/F) is 28.5 L (62%). Duvelisib is a substrate of P-glycoprotein (P-gp) and BCRP in vitro.
Elimination
- The geometric mean (CV%) apparent systemic clearance at steady-state is 4.2 L/hr (56%) in patients with lymphoma or leukemia. The geometric mean (CV%) terminal elimination half-life of duvelisib is 4.7 hours (57%).
Metabolism
- Duvelisib is primarily metabolized by cytochrome P450 CYP3A4.
Excretion
- Following a single 25 mg oral dose of radiolabeled duvelisib, 79% of the radioactivity was excreted in feces (11% unchanged) and 14% was excreted in the urine (< 1% unchanged).
Specific Populations
- Age (18 to 90 years), sex, race, renal impairment (creatinine clearance 23 to 80 mL/ min), hepatic impairment (Child Pugh Class A, B, and C) and body weight (40 to 154 kg) had no clinically significant effect on the exposure of duvelisib.
Drug Interaction Studies
Strong and Moderate CYP3A Inhibitors
- Co-administration of strong CYP3A inhibitor ketoconazole (at 200 mg BID for 5 days), a strong inhibitor of CYP3A4, with a single oral 10 mg dose of duvelisib in healthy adults (n= 16) increased duvelisib Cmax by 1.7-fold and AUC by 4-fold. Based on physiologically-based pharmacokinetic (PBPK) modeling and simulation, the increase in exposure to duvelisib is estimated to be ~2-fold at steady state when concomitantly used with strong CYP3A4 inhibitors such as ketoconazole. PBPK modeling and simulation estimated no effect on duvelisib exposures from concomitantly used mild or moderate CYP3A4 inhibitors.
Strong and Moderate CYP3A4 Inducers
- Co-administration of 600 mg once daily rifampin, a strong CYP3A inducer, for 7 days with a single oral 25 mg duvelisib dose in healthy adults (N = 13) decreased duvelisib Cmax by 66% and AUC by 82%.
- The effect of moderate CYP3A4 induction has not been studied.
CYP3A4 Substrates
- Co-administration of multiple doses of duvelisib 25 mg BID for 5 days with single oral 2 mg midazolam, a sensitive CYP3A4 substrate, in healthy adults (N = 14), increased in the midazolam AUC by 4.3-fold and Cmax by 2.2-fold.
In Vitro Studies
- Duvelisib is a substrate of P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP).
- Duvelisib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BCRP, or P-gp.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with duvelisib.
- Duvelisib did not cause genetic damage in in vitro or in vivo assays.
- Fertility studies with duvelisib were not conducted. Histological findings in male and female rats were observed in the repeat dose toxicity studies and included testis (seminiferous epithelial atrophy, decreased weight, soft testes), and epididymis (small size, oligo/aspermia) in males and ovary (decreased weight) and uterus (atrophy) in females.
# Clinical Studies
Study 1
- A randomized, multicenter, open-label trial (Study 1; NCT02004522) compared duvelisib versus ofatumumab in 319 adult patients with CLL (N = 312) or SLL (N = 7) after at least one prior therapy. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a PI3K inhibitor or a Bruton’s tyrosine kinase (BTK) inhibitor. The trial required hepatic transaminases ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 2 times ULN.
- The study randomized patients with a 1:1 ratio to receive either duvelisib 25 mg BID until disease progression or unacceptable toxicity or ofatumumab for 7 cycles. Ofatumumab was administered intravenously at an initial dose of 300 mg, followed one week later by 2000 mg once weekly for 7 doses, and then 2000 mg once every 4 weeks for 4 additional doses.
- The approval of duvelisib was based on efficacy and safety analysis of patients with at least 2 prior lines of therapy, where the benefit:risk appeared greater in this more heavily pretreated population compared to the overall trial population.
- In this subset (95 randomized to duvelisib, 101 to ofatumumab), the median patient age was 69 years (range: 40 to 90 years), 59% were male, and 88% had an ECOG performance status of 0 or 1. Forty-six percent received 2 prior lines of therapy, and 54% received 3 or more prior lines. At baseline, 52% of patients had at least one tumor ≥ 5 cm, and 22% of patients had a documented 17p deletion.
- During randomized treatment, the median duration of exposure to duvelisib was 13 months (range: 0.2 to 37), with 80% of patients receiving at least 6 months and 52% receiving at least 12 months of duvelisib. The median duration of exposure to ofatumumab was 5 months (range: < 0.1 to 6).
- Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). Other efficacy measures included overall response rate. Efficacy of duvelisib compared to ofatumumab specifically in patients treated with at least two prior therapies is presented in TABLE 8 and FIGURE 1.
Study 2
- Efficacy of duvelisib in patients with previously treated FL is based on a single-arm, multicenter trial (Study 2; NCT02204982). In this study, duvelisib 25 mg BID was administered in patients with FL (N = 83) who were refractory to rituximab and to either chemotherapy or radioimmunotherapy. Refractory disease was defined as less than a partial remission or relapse within 6 months after the last dose. The trial excluded patients with Grade 3b FL, large cell transformation, prior allogeneic transplant, and prior exposure to a PI3K inhibitor or to a Bruton’s tyrosine kinase inhibitor.
- The median age was 64 years (range: 30 to 82 years), 68% were male, and 37% had bulky disease assessed at baseline (target lesion ≥ 5 cm). Patients had a median of 3 prior lines of therapy (range: 1 to 10), with 94% being refractory to their last therapy and 81% being refractory to 2 or more prior lines of therapy. Most patients (93%) had an ECOG performance status of 0 or 1.
- The median duration of exposure to duvelisib was 5 months (range: 0.4 to 24), with 41% of patients receiving at least 6 months and 10% receiving at least 12 months of duvelisib.
- Efficacy was based on overall response rate and duration of response as assessed by an IRC (TABLE 9).
# How Supplied
- Duvelisib capsules are supplied as follows:
## Storage
- Store at 20° to 25°C (68° to 77°F), with excursions permitted at 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Retain in original package until dispensing. Dispense blister packs in original container.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
- Physicians and healthcare professionals are advised to discuss the following with patients prior to treatment with duvelisib:
Infections
- Advise patients that duvelisib can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection (e.g. fever, chills).
Diarrhea or Colitis
- Advise patients that duvelisib can cause serious diarrhea or colitis (inflammation of the gut) that may be fatal, and to notify their healthcare provider immediately about any new or worsening diarrhea, stool with mucus or blood, or abdominal pain.
Cutaneous Reactions
- Advise patients that duvelisib can cause a serious skin rash that may be fatal, and to notify their healthcare provider immediately if they develop a new or worsening skin rash.
Pneumonitis
- Advise patients that duvelisib may cause pneumonitis (inflammation of the lungs) that may be fatal, and to report any new or worsening respiratory symptoms including cough or difficulty breathing.
Hepatotoxicity
- Advise patients that duvelisib may cause significant elevations in liver enzymes, and that monitoring of liver tests is needed. Advise patients to report symptoms of liver dysfunction including jaundice (yellow eyes or yellow skin), abdominal pain, bruising, or bleeding.
Neutropenia
- Advise patients of the need for periodic monitoring of blood counts. Advise patients to notify their healthcare provider immediately if they develop a fever or any sign of infection.
Embryo-Fetal Toxicity
- Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus.
- Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of duvelisib.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Lactation
- Advise lactating women not to breastfeed during treatment with duvelisib and for at least 1 month after the last dose.
- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products, before and during treatment with duvelisib.
Instructions for Taking Duvelisib
- Advise patients to take duvelisib exactly as prescribed. Duvelisib may be taken with or without food; the capsules should be swallowed whole.
- Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.
# Precautions with Alcohol
Alcohol-Duvelisib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Copiktra
# Look-Alike Drug Names
There is limited information regarding Duvelisib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Copiktra | |
98815c599e8ecf3061ea92665d3754198fdae3a9 | wikidoc | Copyright | Copyright
Copyright – symbolized "©" – is a legal concept enacted by most national governments, that gives the creator of an original work exclusive rights to it, usually for a limited period of time. At its most general, it is literally "the right to copy", but also gives the copyright holder the right to be credited for the work, to determine who (if anyone) may adapt the work to other forms, to determine who may perform the work, to benefit financially from the work, and other related rights. It is one form of intellectual property (distinct from patents, trademarks, and trade secrets), and applies to any particular expression of an idea or information, which is substantial and self-contained in a fixed form.
Although initially conceived as a way for the government to restrict printing, the intent of modern copyright is to promote the creation of new works by giving authors the ability to control them and to profit from them for a limited time. These rights have become standardized internationally, in most jurisdictions lasting 50-100 years after the death of the creator, or a fixed number of years for anonymous or corporate creations. Although some jurisdictions have required formalities to establish copyright, most now recognize copyright in any completed work, without registration. Copyright is generally enforced by the creator as a civil matter, though some jurisdictions also apply criminal sanctions.
Most jurisdictions recognize some limitations to copyright, allowing "fair" exceptions to the creator's exclusivity and giving certain rights to consumers. The development of digital media and networking technologies have prompted reinterpretation of these exceptions, introduced new difficulties in enforcing copyright, and inspired additional challenges to the philosophical basis for the law. Simultaneously, businesses with substantial economic dependence on copyright have advocated for the extension and expansion of their rights, and sought additional legal and technological means to enforce them.
# Scope
Copyright may apply to a wide range of creative, intellectual, or artistic forms, or "works". Specifics vary by jurisdiction, but these can include poems, theses, plays, other literary works, movies, dances, musical compositions, audio recordings, paintings, drawings, sculptures, photographs, software, radio and television broadcasts, and industrial designs. Graphic designs and industrial designs may have separate or overlapping laws applied to them in some jurisdictions.
Copyright does not cover ideas and information themselves, only the form or manner in which they are expressed. For example, the copyright to a Mickey Mouse cartoon restricts others from making copies of the cartoon or creating derivative works based on Disney's particular anthropomorphic mouse, but doesn't prohibit the creation of other works about anthropomorphic mice in general, so long as they're different enough to not be judged copies of Disney's. In many jurisdictions, copyright law makes exceptions to these restrictions when the work is copied for the purpose of commentary or other related uses (See Fair Use, Fair Dealing). Meanwhile, other laws may impose additional restrictions that copyright does not - such as trademarks and patents.
Copyright laws are standardized somewhat through international conventions such as the Berne Convention and Universal Copyright Convention. These multilateral treaties have been ratified by nearly all countries, and international organizations such as the European Union or World Trade Organization require their member states to comply with them.
# Theoretical basis
Copyright law as it is known today was originally established by legislative acts which cited two fundamental justifications for it: 1) to benefit society by promoting the creation of new works, and 2) to protect the moral rights of the creators of these works.
For example, the Copyright Clause of the United States Constitution (1787) authorized copyright legislation: "To promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries." That is, by guaranteeing them a period of time in which they alone could profit from their works, they would be enabled and encouraged to invest the time required to create them, and this would be good for society as a whole. A right to profit from the work has been the philosophical underpinning for much legislation extending the duration of copyright, to the life of the creator and beyond, to his heirs.
The earlier Statute of Anne (1709) further alluded to individual moral rights, beginning: "Whereas Printers, Booksellers, and other Persons, have of late frequently taken the Liberty of Printing... Books, and other Writings, without the Consent of the Authors... to their very great Detriment, and too often to the Ruin of them and their Families:..." A right to benefit financially from the work is articulated, and court rulings and legislation have recgonized a right to control the work, such as ensuring that the integrity of it is preserved. An irrevocable right to be recognized as the work's creator appears in some countries' copyright laws.
# History
Copyright was invented after the advent of the printing press and with wider public literacy. As a legal concept, its origins in Britain were from a reaction to printers' monopolies at the beginning of the eighteenth century. Charles II of England was concerned by the unregulated copying of books and used the royal prerogative to pass the Licensing Act of 1662, which established a register of licensed books and required a copy to be deposited with the Stationers Company, essentially continuing the licensing of material that had long been in effect.
The Statute of Anne was the first real copyright act, and gave the publishers rights for a fixed period, after which the copyright expired. Copyright has grown from a legal concept regulating copying rights in the publishing of books and maps to one with a significant effect on nearly every modern industry, covering such items as sound recordings, films, photographs, software, and architectural works.
The 1886 Berne Convention first established recognition of copyrights among sovereign nations, rather than merely bilaterally. Under the Berne Convention, copyrights for creative works do not have to be asserted or declared, as they are automatically in force at creation: an author need not "register" or "apply for" a copyright in countries adhering to the Berne Convention. As soon as a work is "fixed", that is, written or recorded on some physical medium, its author is automatically entitled to all copyrights in the work, and to any derivative works unless and until the author explicitly disclaims them, or until the copyright expires. The Berne Convention also resulted in foreign authors being treated equivalently to domestic authors, in any country signed onto the Convention. The UK signed the Berne Convention in 1887 but did not implement large parts of it until 100 years later with the passage of the Copyright, Designs and Patents Act of 1988. The USA did not sign the Berne Convention until 1989.
The United States and most Latin American countries instead entered into the Buenos Aires Convention in 1910, which required a copyright notice (such as "all rights reserved") on the work, and permitted signatory nations to limit the duration of copyrights to shorter and renewable terms. The Universal Copyright Convention was drafted in 1952 as another less demanding alternative to the Berne Convention, and ratified by nations such as the Soviet Union and developing nations.
The regulations of the Berne Convention are incorporated into the World Trade Organization's TRIPS agreement (1995), thus giving the Berne Convention effectively near-global application. The 2002 WIPO Copyright Treaty enacted greater restrictions on the use of technology to copy works in the nations that ratified it.
# Obtaining and enforcing copyright
Typically, a work must meet minimal standards of originality in order to qualify for copyright, and the copyright expires after a set period of time (some jurisdictions may allow this to be extended). Different countries impose different tests, although generally the requirements are low; in the United Kingdom there has to be some 'skill, labour and judgment' that has gone into it. In Australia and the United Kingdom it has been held that a single word is insufficient to comprise a copyright work. However, single words or a short string of words can sometimes be registered as a trademark instead.
Copyright law recognises the right of an author based on whether the work actually is an original creation, rather than based on whether it is unique; two authors may own copyright on two substantially identical works, if it is determined that the duplication was coincidental, and neither was copied from the other.
In all countries where the Berne Convention standards apply, copyright is automatic, and need not be obtained through official registration with any government office. Once an idea has been reduced to tangible form, for example by securing it in a fixed medium (such as a drawing, sheet music, photograph, a videotape, or a computer file), the copyright holder is entitled to enforce his or her exclusive rights. However, while registration isn't needed to exercise copyright, in jurisdictions where the laws provide for registration, it serves as prima facie evidence of a valid copyright and enables the copyright holder to seek statutory damages and attorney's fees. (In the USA, registering after an infringement only enables one to receive actual damages and lost profits.)
The original holder of the copyright may be the employer of the author rather than the author himself, if the work is a "work for hire". For example, in English law the Copyright Designs and Patents Act 1988 provides that if a copyrighted work is made by an employee in the course of that employment, the copyright is automatically owned by the employer which would be a "Work for Hire."
Copyrights are generally enforced by the holder in a civil law court, but there are also criminal infringement statutes in some jurisdictions. While central registries are kept in some countries which aid in proving claims of ownership, registering does not necessarily prove ownership, nor does the fact of copying (even without permission) necessarily proof that copyright was infringed. Criminal sanctions are generally aimed at serious counterfeiting activity, but are now becoming more commonplace as copyright collectives such as the RIAA are increasingly targeting the file sharing home Internet user. Thus far, however, most such cases against file sharers have been settled out of court. (See: File sharing and the law)
## Copyright notices in the U.S.
Prior to 1989, use of a copyright notice — consisting of the copyright symbol (Template:Unicode, the letter C inside a circle), the abbreviation "Copr.", or the word "Copyright", followed by the year of the first publication of the work and the name of the copyright holder — was part of United States statutory requirements. Several years may be noted if the work has gone through substantial revisions. The proper copyright notice for sound recordings of musical or other audio works is a sound recording copyright symbol (Template:Unicode, the letter P inside a circle), which indicates a sound recording copyright. Similarly, the phrase All rights reserved was once required to assert copyright.
In 1989, the U.S. enacted the Berne Convention Implementation Act, amending the 1976 Copyright Act to conform to most of the provisions of the Berne Convention. As a result, the use of copyright notices has become optional to claim copyright, because the Berne Convention makes copyright automatic. However, notice of copyright using these marks may have consequences in terms of reduced damages in an infringement lawsuit.
## "Poor man's copyright"
A widely circulated strategy to avoid the cost of copyright registration is referred to as the "poor man's copyright". It proposes that the creator send the work to himself in a sealed envelope by registered mail, using the postmark to establish the date. This technique has not been recognized by any United States court, and is dismissed as meaningless by the United States Copyright Office. However, the UK Patent Office suggests it as one method of proving the originality of a work as of the postmark date.
# Exclusive rights
Several exclusive rights typically attach to the holder of a copyright:
- to produce copies or reproductions of the work and to sell those copies (including, typically, electronic copies)
- to import or export the work
- to create derivative works (works that adapt the original work)
- to perform or display the work publicly
- to sell or assign these rights to others
- to transmit or display by radio or video
The phrase "exclusive right" means that only the copyright holder is free to exercise those rights, and others are prohibited from using the work without his permission. Copyright is sometimes called a "negative right", as it serves to prohibit certain people (e.g., readers, viewers, or listeners, and primarily publishers and would be publishers) from doing something they would otherwise be able to do, rather than permitting people (e.g., authors) to do something they would otherwise be unable to do. In this way it is similar to the unregistered design right in English law and European law. The rights of the copyright holder also permit him/her to not use or exploit their copyright, for some or all of the term.
There is, however, a critique which rejects this assertion as being based on a philosophical interpretation of copyright law that is not universally shared. There is also debate on whether copyright should be considered a property right or a moral right. Many argue that copyright does not exist merely to restrict third parties from publishing ideas and information, and that defining copyright purely as a negative right is incompatible with the public policy objective of encouraging authors to create new works and enrich the public domain.
The right to adapt a work means to transform the way in which the work is expressed. Examples include developing a stage play or film script from a novel, translating a short story, and making a new arrangement of a musical work.
# Limits and exceptions to copyright
## Idea-expression dichotomy and the merger doctrine
Immanuel Kant in his 1785 essay Von der Unrechtmäßigkeit des Büchernachdrucks distinguishes the physical from the ideational, the thought involved from the book. This distinction is of critical importance to the near constant wrangling between publishers, other intermediaries, and the original, creative authors.
Copyright usually protects the expression of an idea, not the idea itself — in US jurisprudence this is called the idea/expression or fact/expression dichotomy. For example, if a writer has a general concept or idea for a television program, the law of copyright does not prohibit other writers from copying that general idea. However, if the writer develops the idea so that it constitutes a detailed storyline or plot, then that may be protected by copyright, notwithstanding that it is "idea" rather than "expression". Similarly, the translation of a literary work will constitute an infringement of copyright, notwithstanding that no element of the "expression" is directly copied.
Another example could be if a book is written describing a new way to organize books in a library, a copyright does not prohibit a reader from freely using and describing that concept to others; it is only the particular expression of that process as originally described that is covered by copyright. One might be able to obtain a patent for the method, but that is a different area of law. Compilations of facts or data may also be copyrighted, but such a copyright is thin; it only applies to the particular selection and arrangement of the included items, not to the particular items themselves. In some jurisdictions the contents of databases are expressly covered by statute.
In some cases, ideas may be capable of intelligible expression in only one or a limited number of ways. Therefore even the expression in these circumstances is not covered. In the United States this is known as the merger doctrine, because the expression is considered to be inextricably merged with the idea. Merger is often pleaded as an affirmative defense to charges of infringement. That doctrine is not necessarily accepted in other jurisdictions.
## The first-sale doctrine and exhaustion of rights
Copyright law does not restrict the owner of a copy from reselling legitimately obtained copies of copyrighted works, provided that those copies were originally produced by or with the permission of the copyright holder. It is therefore legal, for example, to resell a copyrighted book or CD. In the United States this is known as the first-sale doctrine, and was established by the courts to clarify the legality of reselling books in second-hand bookstores. Some countries may have parallel importation restrictions that allow the copyright holder to control the aftermarket. This may mean for example that a copy of a book that does not infringe copyright in the country where it was printed does infringe copyright in a country into which it is imported for retailing. The first-sale doctrine is known as exhaustion of rights in other countries and is a principle which also applies, though somewhat differently, to patent and trademark rights. It is important to note that the first-sale doctrine permits the transfer of the particular legitimate copy involved. It does not permit making or distributing additional copies.
In addition, copyright, in most cases, does not prohibit one from acts such as modifying, defacing, or destroying his or her own legitimately obtained copy of a copyrighted work, so long as duplication is not involved. However, in countries that implement moral rights, a copyright holder can in some cases successfully prevent the mutilation or destruction of a work that is publicly visible.
## Fair use and fair dealing
Copyright does not prohibit all copying or replication. In the United States, the fair use doctrine, codified by the Copyright Act of 1976 as 17 U.S.C. Section 107, permits some copying and distribution without permission of the copyright holder or payment to same. The statute does not clearly define fair use, but instead gives four non-exclusive factors to consider in a fair use analysis. Those factors are:
- the purpose and character of your use
- the nature of the copyrighted work
- what amount and proportion of the whole work was taken, and
- the effect of the use upon the potential market for or value of the copyrighted work.
In the United Kingdom and many other Commonwealth countries, a similar notion of fair dealing was established by the courts or through legislation. The concept is sometimes not well defined; however in Canada, private copying for personal use has been expressly permitted by statute since 1999. In Australia, the fair dealing exceptions under the Copyright Act 1968 (Cth) are a limited set of circumstances under which copyrighted material can be legally copied or adapted without the copyright holder's consent. Fair dealing uses are research and study; review and critique; news reportage and the giving of professional advice (ie legal advice). Under current Australian law it is still a breach of copyright to copy, reproduce or adapt copyright material for personal or private use without permission from the copyright owner. Other technical exemptions from infringement may also apply, such as the temporary reproduction of a work in machine readable form for a computer.
In the United States the AHRA (Audio Home Recording Act Codified in Section 10, 1992) prohibits action against consumers making noncommercial recordings of music, in return for royalties on both media and devices plus mandatory copy-control mechanisms on recorders.
Later acts amended US Copyright law so that for certain purposes making 10 copies or more is construed to be commercial, but there is no general rule permitting such copying. Indeed making one complete copy of a work, or in many cases using a portion of it, for commercial purposes will not be considered fair use. The Digital Millennium Copyright Act prohibits the manufacture, importation, or distribution of devices whose intended use, or only significant commercial use, is to bypass an access or copy control put in place by a copyright owner. An appellate court has held that fair use is not a defense to engaging in such distribution.
## Transfer and licensing
A copyright, or aspects of it, may be assigned or transferred from one party to another. For example, a musician who records an album will often sign an agreement with a record company in which the musician agrees to transfer all copyright in the recordings in exchange for royalties and other considerations. The creator (and original copyright holder) benefits, or expects to, from production and marketing capabilities far beyond those of the author. In the digital age of music, music may be copied and distributed at minimal cost through the Internet, however the record industry attempts to provide promotion and marketing for the artist and his or her work so it can reach a much larger audience. A copyright holder need not transfer all rights completely, though many publishers will insist. Some of the rights may be transferred, or else the copyright holder may grant another party a non-exclusive license to copy and/or distribute the work in a particular region or for a specified period of time. A transfer or licence may have to meet particular formal requirements in order to be effective; see section 239 of the Australia Copyright Act 1968 (Cth). Under Australian law, it is not enough to pay for a work to be created in order to also own the copyright. The copyright itself must be expressly transferred in writing.
Under the U.S. Copyright Act, a transfer of ownership in copyright must be memorialized in a writing signed by the transferor. For that purpose, ownership in copyright includes exclusive licenses of rights. Thus exclusive licenses, to be effective, must be granted in a written instrument signed by the grantor. No special form of transfer or grant is required. A simple document that identifies the work involved and the rights being granted is sufficient. Non-exclusive grants (often called non-exclusive licenses) need not be in writing under U.S. law. They can be oral or even implied by the behavior of the parties. Transfers of copyright ownership, including exclusive licenses, may and should be recorded in the U.S. Copyright Office. (Information on recording transfers is available on the Office's web site.) While recording is not required to make the grant effective, it offers important benefits, much like those obtained by recording a deed in a real estate transaction.
Copyright may also be licensed. Some jurisdictions may provide that certain classes of copyrighted works be made available under a prescribed statutory license (e.g. musical works in the United States used for radio broadcast or performance). This is also called a compulsory license, because under this scheme, anyone who wishes to copy a covered work does not need the permission of the copyright holder, but instead merely files the proper notice and pays a set fee established by statute (or by an agency decision under statutory guidance) for every copy made. Failure to follow the proper procedures would place the copier at risk of an infringement suit. Because of the difficulty of following every individual work, copyright collectives or collecting societies and performing rights organizations (such as ASCAP, BMI, and SESAC have been formed to collect royalties for hundreds (thousands and more) works at once. Though this market solution bypasses the statutory license, the availability of the statutory fee still helps dictate the price per work collective rights organizations charge, driving it down to what avoidance of procedural hassle would justify.
## Similar legal rights
Copyright law covers the creative or artistic expression of an idea. Patent law covers inventions. Trademark law covers distinctive signs which are used in relation to products or services as indicators of origin, as does (in a similar fashion), Trade dress. Registered designs law covers the look or appearance of a manufactured or functional article. Trade secret law covers secret or sensitive knowledge or information.
Although copyright and trademark laws are theoretically distinct, more than one type of them may cover the same item or subject matter. For example, in the case of the Mickey Mouse cartoon, the image and name of Mickey Mouse would be the subject of trademark legislation, while the cartoon itself would be subject to copyright. Titles and character names from books or movies may also be trademarked while the works from which they are drawn may qualify for copyright.
Another point of distinction is that a copyright (and a patent) is generally subject to a statutorily-determined term, whereas a trademark registration may remain in force indefinitely if the trademark is periodically used and renewal fees continue to be duly paid to the relevant jurisdiction's trade marks office or registry. Once the term of a copyright has expired, the formerly copyrighted work enters the public domain and may be freely used or exploited by anyone. Courts in the United States and the United Kingdom have rejected the doctrine of a common law copyright. Public domain works should not be confused with works that are publicly available. Works posted in the internet for example, are publicly available, but are not generally in the public domain. Copying such works may therefore violate the author's copyright.
## Useful articles
If a pictorial, graphic or sculptural work is a useful article, it is copyrighted only if its aesthetic features are separable from its utilitarian features. A useful article is an article having an intrinsic utilitarian function that is not merely to portray the appearance of the article or to convey information. The must be separable from the functional aspect to be copyrighted.
There are two primary approaches to the separability issue: physical separability and conceptual separability. Physical separability is the ability to take the aesthetic thing away from the functional thing. Conceptual separability can be found in several different ways. It may be present if the useful article is also shown to be appreciated for its aesthetic appeal or by the design approach, which is the idea that separability is only available if the designer is able to make the aesthetic choices that are unaffected by the functional considerations. A question may also be asked of whether an individual would think of the aesthetic aspects of the work being separate from the functional aspects.
There are several different tests available for conceptual separability. The first, the Primary Use test, asks how is the thing primarily used: art or function? The second, the Marketable as Art test, asks can the article be sold as art, whether functional or not. This test does not have much backing, as almost anything can be sold as art. The third test, Temporal Displacement, asks could an individual conceptualize the article as art without conceptualizing functionality at the same time. Finally, the Denicola test says that copyrightability should ultimately depend on the extent to which the work reflects the artistic expression inhibited by functional consideration. If something came to have a pleasing shape because there were functional considerations, the artistic aspect was constrained by those concerns.
## Duration
Copyright subsists for a variety of lengths in different jurisdictions. The length of the term can depend on several factors, including the type of work (e.g. musical composition, novel), whether the work has been published or not, and whether the work was created by an individual or a corporation. In most of the world, the default length of copyright is the life of the author plus either 50 or 70 years. In the United States, the term for most existing works is a fixed number of years after the date of creation or publication. Under most countries' laws, copyrights expire at the end of the calendar year in question.
The length and requirements for copyright duration are subject to change by legislation, and since the early 20th century there have been a number of adjustments made in various countries, which can make determining the duration of a given copyright somewhat difficult. For example, the United States used to require copyrights to be renewed after 28 years to stay in force, and formerly required a copyright notice upon first publication to gain coverage. In Italy and France, there were post-wartime extensions that could increase the term by approximately 6 years in Italy and up to about 14 in France. Many countries have extended the length of their copyright terms (sometimes retroactively). International treaties establish minimum terms for copyrights, but individual countries may enforce longer terms than those.
In the United States, all books and other works published before 1923 have expired copyrights and are in the public domain. In addition, works published before 1964 that did not have their copyrights renewed 28 years after first publication year also are in the public domain, except that books originally published outside the US by non-Americans are exempt from this requirement, if they are still under copyright in their home country (see How Can I Tell Whether a Copyright Was Renewed for more details).
But if the intended exploitation of the work includes publication (or distribution of derivative work, such as a film based on a book protected by copyright) outside the U.S., the terms of copyright around the world must be considered. If the author has been dead more than 70 years, the work is in the public domain in most, but not all, countries. Some works are covered by copyright in Spain for 80 years after the author's death.
In 1998 the length of a copyright in the United States was increased by 20 years under the The Copyright Term Extension Act. This legislation was strongly promoted by corporations which had valuable copyrights which would otherwise would have expired, and has been the subject of substantial criticism on this point.
As a curiosity, the famous work Peter Pan, or The Boy Who Wouldn't Grow Up has a complex – and disputed – story of copyright expiry.
## Typefaces
In the United States, the Copyright Office maintains that typeface designs are not covered by copyright, and it will not accept applications for their registration. See 37. C.F.R. § 202.1(e). However, if a design is novel and "non-obvious," it may be covered by design patent. See, for example, U.S. Des. Patent No. 289,773, May 12, 1987), Charles A. Bigelow and Kris A. Holmes, inventors. Germany (in 1981) passed a special extension (Schriftzeichengesetz) to the design patent law (Geschmacksmustergesetz) for protecting them. This permits typefaces being registered as designs in Germany, too.
The United Kingdom (in 1989) has passed a law making typeface designs copyrightable. The British law also applies to designs produced before 1989.
## Accessible Copies
It is legal in several countries including Great Britain and the USA to produce alternative versions (for example, in large print or braille) of a copyrighted work to provide improved access to a work for blind and visually impaired persons without permission from the copyright holder. | Copyright
Copyright – symbolized "©" – is a legal concept enacted by most national governments, that gives the creator of an original work exclusive rights to it, usually for a limited period of time. At its most general, it is literally "the right to copy", but also gives the copyright holder the right to be credited for the work, to determine who (if anyone) may adapt the work to other forms, to determine who may perform the work, to benefit financially from the work, and other related rights. It is one form of intellectual property (distinct from patents, trademarks, and trade secrets), and applies to any particular expression of an idea or information, which is substantial and self-contained in a fixed form.
Although initially conceived as a way for the government to restrict printing, the intent of modern copyright is to promote the creation of new works by giving authors the ability to control them and to profit from them for a limited time. These rights have become standardized internationally, in most jurisdictions lasting 50-100 years after the death of the creator, or a fixed number of years for anonymous or corporate creations. Although some jurisdictions have required formalities to establish copyright, most now recognize copyright in any completed work, without registration. Copyright is generally enforced by the creator as a civil matter, though some jurisdictions also apply criminal sanctions.
Most jurisdictions recognize some limitations to copyright, allowing "fair" exceptions to the creator's exclusivity and giving certain rights to consumers. The development of digital media and networking technologies have prompted reinterpretation of these exceptions, introduced new difficulties in enforcing copyright, and inspired additional challenges to the philosophical basis for the law. Simultaneously, businesses with substantial economic dependence on copyright have advocated for the extension and expansion of their rights, and sought additional legal and technological means to enforce them.
# Scope
Copyright may apply to a wide range of creative, intellectual, or artistic forms, or "works". Specifics vary by jurisdiction, but these can include poems, theses, plays, other literary works, movies, dances, musical compositions, audio recordings, paintings, drawings, sculptures, photographs, software, radio and television broadcasts, and industrial designs. Graphic designs and industrial designs may have separate or overlapping laws applied to them in some jurisdictions.
Copyright does not cover ideas and information themselves, only the form or manner in which they are expressed. For example, the copyright to a Mickey Mouse cartoon restricts others from making copies of the cartoon or creating derivative works based on Disney's particular anthropomorphic mouse, but doesn't prohibit the creation of other works about anthropomorphic mice in general, so long as they're different enough to not be judged copies of Disney's. In many jurisdictions, copyright law makes exceptions to these restrictions when the work is copied for the purpose of commentary or other related uses (See Fair Use, Fair Dealing). Meanwhile, other laws may impose additional restrictions that copyright does not - such as trademarks and patents.
Copyright laws are standardized somewhat through international conventions such as the Berne Convention and Universal Copyright Convention. These multilateral treaties have been ratified by nearly all countries, and international organizations such as the European Union or World Trade Organization require their member states to comply with them.
# Theoretical basis
Copyright law as it is known today was originally established by legislative acts which cited two fundamental justifications for it: 1) to benefit society by promoting the creation of new works, and 2) to protect the moral rights of the creators of these works.
For example, the Copyright Clause of the United States Constitution (1787) authorized copyright legislation: "To promote the Progress of Science and useful Arts, by securing for limited Times to Authors and Inventors the exclusive Right to their respective Writings and Discoveries." That is, by guaranteeing them a period of time in which they alone could profit from their works, they would be enabled and encouraged to invest the time required to create them, and this would be good for society as a whole. A right to profit from the work has been the philosophical underpinning for much legislation extending the duration of copyright, to the life of the creator and beyond, to his heirs.
The earlier Statute of Anne (1709) further alluded to individual moral rights, beginning: "Whereas Printers, Booksellers, and other Persons, have of late frequently taken the Liberty of Printing... Books, and other Writings, without the Consent of the Authors... to their very great Detriment, and too often to the Ruin of them and their Families:..."[1] A right to benefit financially from the work is articulated, and court rulings and legislation have recgonized a right to control the work, such as ensuring that the integrity of it is preserved. An irrevocable right to be recognized as the work's creator appears in some countries' copyright laws.
# History
Copyright was invented after the advent of the printing press and with wider public literacy. As a legal concept, its origins in Britain were from a reaction to printers' monopolies at the beginning of the eighteenth century. Charles II of England was concerned by the unregulated copying of books and used the royal prerogative to pass the Licensing Act of 1662, which established a register of licensed books and required a copy to be deposited with the Stationers Company, essentially continuing the licensing of material that had long been in effect.
The Statute of Anne was the first real copyright act, and gave the publishers rights for a fixed period, after which the copyright expired. Copyright has grown from a legal concept regulating copying rights in the publishing of books and maps to one with a significant effect on nearly every modern industry, covering such items as sound recordings, films, photographs, software, and architectural works.
The 1886 Berne Convention first established recognition of copyrights among sovereign nations, rather than merely bilaterally. Under the Berne Convention, copyrights for creative works do not have to be asserted or declared, as they are automatically in force at creation: an author need not "register" or "apply for" a copyright in countries adhering to the Berne Convention. As soon as a work is "fixed", that is, written or recorded on some physical medium, its author is automatically entitled to all copyrights in the work, and to any derivative works unless and until the author explicitly disclaims them, or until the copyright expires. The Berne Convention also resulted in foreign authors being treated equivalently to domestic authors, in any country signed onto the Convention. The UK signed the Berne Convention in 1887 but did not implement large parts of it until 100 years later with the passage of the Copyright, Designs and Patents Act of 1988. The USA did not sign the Berne Convention until 1989.
The United States and most Latin American countries instead entered into the Buenos Aires Convention in 1910, which required a copyright notice (such as "all rights reserved") on the work, and permitted signatory nations to limit the duration of copyrights to shorter and renewable terms. The Universal Copyright Convention was drafted in 1952 as another less demanding alternative to the Berne Convention, and ratified by nations such as the Soviet Union and developing nations.
The regulations of the Berne Convention are incorporated into the World Trade Organization's TRIPS agreement (1995), thus giving the Berne Convention effectively near-global application. The 2002 WIPO Copyright Treaty enacted greater restrictions on the use of technology to copy works in the nations that ratified it.
# Obtaining and enforcing copyright
Typically, a work must meet minimal standards of originality in order to qualify for copyright, and the copyright expires after a set period of time (some jurisdictions may allow this to be extended). Different countries impose different tests, although generally the requirements are low; in the United Kingdom there has to be some 'skill, labour and judgment' that has gone into it.[2] In Australia and the United Kingdom it has been held that a single word is insufficient to comprise a copyright work. However, single words or a short string of words can sometimes be registered as a trademark instead.
Copyright law recognises the right of an author based on whether the work actually is an original creation, rather than based on whether it is unique; two authors may own copyright on two substantially identical works, if it is determined that the duplication was coincidental, and neither was copied from the other.
In all countries where the Berne Convention standards apply, copyright is automatic, and need not be obtained through official registration with any government office. Once an idea has been reduced to tangible form, for example by securing it in a fixed medium (such as a drawing, sheet music, photograph, a videotape, or a computer file), the copyright holder is entitled to enforce his or her exclusive rights. However, while registration isn't needed to exercise copyright, in jurisdictions where the laws provide for registration, it serves as prima facie evidence of a valid copyright and enables the copyright holder to seek statutory damages and attorney's fees. (In the USA, registering after an infringement only enables one to receive actual damages and lost profits.)
The original holder of the copyright may be the employer of the author rather than the author himself, if the work is a "work for hire". For example, in English law the Copyright Designs and Patents Act 1988 provides that if a copyrighted work is made by an employee in the course of that employment, the copyright is automatically owned by the employer which would be a "Work for Hire."
Copyrights are generally enforced by the holder in a civil law court, but there are also criminal infringement statutes in some jurisdictions. While central registries are kept in some countries which aid in proving claims of ownership, registering does not necessarily prove ownership, nor does the fact of copying (even without permission) necessarily proof that copyright was infringed. Criminal sanctions are generally aimed at serious counterfeiting activity, but are now becoming more commonplace as copyright collectives such as the RIAA are increasingly targeting the file sharing home Internet user. Thus far, however, most such cases against file sharers have been settled out of court. (See: File sharing and the law)
## Copyright notices in the U.S.
Prior to 1989, use of a copyright notice — consisting of the copyright symbol (Template:Unicode, the letter C inside a circle), the abbreviation "Copr.", or the word "Copyright", followed by the year of the first publication of the work and the name of the copyright holder — was part of United States statutory requirements.[3][4] Several years may be noted if the work has gone through substantial revisions. The proper copyright notice for sound recordings of musical or other audio works is a sound recording copyright symbol (Template:Unicode, the letter P inside a circle), which indicates a sound recording copyright. Similarly, the phrase All rights reserved was once required to assert copyright.
In 1989, the U.S. enacted the Berne Convention Implementation Act, amending the 1976 Copyright Act to conform to most of the provisions of the Berne Convention. As a result, the use of copyright notices has become optional to claim copyright, because the Berne Convention makes copyright automatic.[5] However, notice of copyright using these marks may have consequences in terms of reduced damages in an infringement lawsuit.[6]
## "Poor man's copyright"
A widely circulated strategy to avoid the cost of copyright registration is referred to as the "poor man's copyright". It proposes that the creator send the work to himself in a sealed envelope by registered mail, using the postmark to establish the date. This technique has not been recognized by any United States court, and is dismissed as meaningless by the United States Copyright Office. However, the UK Patent Office suggests it as one method of proving the originality of a work as of the postmark date.[7]
# Exclusive rights
Several exclusive rights typically attach to the holder of a copyright:
- to produce copies or reproductions of the work and to sell those copies (including, typically, electronic copies)
- to import or export the work
- to create derivative works (works that adapt the original work)
- to perform or display the work publicly
- to sell or assign these rights to others
- to transmit or display by radio or video
The phrase "exclusive right" means that only the copyright holder is free to exercise those rights, and others are prohibited from using the work without his permission. Copyright is sometimes called a "negative right", as it serves to prohibit certain people (e.g., readers, viewers, or listeners, and primarily publishers and would be publishers) from doing something they would otherwise be able to do, rather than permitting people (e.g., authors) to do something they would otherwise be unable to do. In this way it is similar to the unregistered design right in English law and European law. The rights of the copyright holder also permit him/her to not use or exploit their copyright, for some or all of the term.
There is, however, a critique which rejects this assertion as being based on a philosophical interpretation of copyright law that is not universally shared. There is also debate on whether copyright should be considered a property right or a moral right. Many argue that copyright does not exist merely to restrict third parties from publishing ideas and information, and that defining copyright purely as a negative right is incompatible with the public policy objective of encouraging authors to create new works and enrich the public domain.
The right to adapt a work means to transform the way in which the work is expressed. Examples include developing a stage play or film script from a novel, translating a short story, and making a new arrangement of a musical work.
# Limits and exceptions to copyright
## Idea-expression dichotomy and the merger doctrine
Immanuel Kant in his 1785 essay Von der Unrechtmäßigkeit des Büchernachdrucks distinguishes the physical from the ideational, the thought involved from the book. This distinction is of critical importance to the near constant wrangling between publishers, other intermediaries, and the original, creative authors.
Copyright usually protects the expression of an idea, not the idea itself — in US jurisprudence this is called the idea/expression or fact/expression dichotomy. For example, if a writer has a general concept or idea for a television program, the law of copyright does not prohibit other writers from copying that general idea. However, if the writer develops the idea so that it constitutes a detailed storyline or plot, then that may be protected by copyright, notwithstanding that it is "idea" rather than "expression". Similarly, the translation of a literary work will constitute an infringement of copyright, notwithstanding that no element of the "expression" is directly copied.
Another example could be if a book is written describing a new way to organize books in a library, a copyright does not prohibit a reader from freely using and describing that concept to others; it is only the particular expression of that process as originally described that is covered by copyright. One might be able to obtain a patent for the method, but that is a different area of law. Compilations of facts or data may also be copyrighted, but such a copyright is thin; it only applies to the particular selection and arrangement of the included items, not to the particular items themselves. In some jurisdictions the contents of databases are expressly covered by statute.
In some cases, ideas may be capable of intelligible expression in only one or a limited number of ways. Therefore even the expression in these circumstances is not covered. In the United States this is known as the merger doctrine, because the expression is considered to be inextricably merged with the idea. Merger is often pleaded as an affirmative defense to charges of infringement. That doctrine is not necessarily accepted in other jurisdictions.
## The first-sale doctrine and exhaustion of rights
Copyright law does not restrict the owner of a copy from reselling legitimately obtained copies of copyrighted works, provided that those copies were originally produced by or with the permission of the copyright holder. It is therefore legal, for example, to resell a copyrighted book or CD. In the United States this is known as the first-sale doctrine, and was established by the courts to clarify the legality of reselling books in second-hand bookstores. Some countries may have parallel importation restrictions that allow the copyright holder to control the aftermarket. This may mean for example that a copy of a book that does not infringe copyright in the country where it was printed does infringe copyright in a country into which it is imported for retailing. The first-sale doctrine is known as exhaustion of rights in other countries and is a principle which also applies, though somewhat differently, to patent and trademark rights. It is important to note that the first-sale doctrine permits the transfer of the particular legitimate copy involved. It does not permit making or distributing additional copies.
In addition, copyright, in most cases, does not prohibit one from acts such as modifying, defacing, or destroying his or her own legitimately obtained copy of a copyrighted work, so long as duplication is not involved. However, in countries that implement moral rights, a copyright holder can in some cases successfully prevent the mutilation or destruction of a work that is publicly visible.
## Fair use and fair dealing
Copyright does not prohibit all copying or replication. In the United States, the fair use doctrine, codified by the Copyright Act of 1976 as 17 U.S.C. Section 107, permits some copying and distribution without permission of the copyright holder or payment to same. The statute does not clearly define fair use, but instead gives four non-exclusive factors to consider in a fair use analysis. Those factors are:
- the purpose and character of your use
- the nature of the copyrighted work
- what amount and proportion of the whole work was taken, and
- the effect of the use upon the potential market for or value of the copyrighted work.
In the United Kingdom and many other Commonwealth countries, a similar notion of fair dealing was established by the courts or through legislation. The concept is sometimes not well defined; however in Canada, private copying for personal use has been expressly permitted by statute since 1999. In Australia, the fair dealing exceptions under the Copyright Act 1968 (Cth) are a limited set of circumstances under which copyrighted material can be legally copied or adapted without the copyright holder's consent. Fair dealing uses are research and study; review and critique; news reportage and the giving of professional advice (ie legal advice). Under current Australian law it is still a breach of copyright to copy, reproduce or adapt copyright material for personal or private use without permission from the copyright owner. Other technical exemptions from infringement may also apply, such as the temporary reproduction of a work in machine readable form for a computer.
In the United States the AHRA (Audio Home Recording Act Codified in Section 10, 1992) prohibits action against consumers making noncommercial recordings of music, in return for royalties on both media and devices plus mandatory copy-control mechanisms on recorders.
Later acts amended US Copyright law so that for certain purposes making 10 copies or more is construed to be commercial, but there is no general rule permitting such copying. Indeed making one complete copy of a work, or in many cases using a portion of it, for commercial purposes will not be considered fair use. The Digital Millennium Copyright Act prohibits the manufacture, importation, or distribution of devices whose intended use, or only significant commercial use, is to bypass an access or copy control put in place by a copyright owner. An appellate court has held that fair use is not a defense to engaging in such distribution.
## Transfer and licensing
A copyright, or aspects of it, may be assigned or transferred from one party to another. For example, a musician who records an album will often sign an agreement with a record company in which the musician agrees to transfer all copyright in the recordings in exchange for royalties and other considerations. The creator (and original copyright holder) benefits, or expects to, from production and marketing capabilities far beyond those of the author. In the digital age of music, music may be copied and distributed at minimal cost through the Internet, however the record industry attempts to provide promotion and marketing for the artist and his or her work so it can reach a much larger audience. A copyright holder need not transfer all rights completely, though many publishers will insist. Some of the rights may be transferred, or else the copyright holder may grant another party a non-exclusive license to copy and/or distribute the work in a particular region or for a specified period of time. A transfer or licence may have to meet particular formal requirements in order to be effective; see section 239 of the Australia Copyright Act 1968 (Cth). Under Australian law, it is not enough to pay for a work to be created in order to also own the copyright. The copyright itself must be expressly transferred in writing.
Under the U.S. Copyright Act, a transfer of ownership in copyright must be memorialized in a writing signed by the transferor. For that purpose, ownership in copyright includes exclusive licenses of rights. Thus exclusive licenses, to be effective, must be granted in a written instrument signed by the grantor. No special form of transfer or grant is required. A simple document that identifies the work involved and the rights being granted is sufficient. Non-exclusive grants (often called non-exclusive licenses) need not be in writing under U.S. law. They can be oral or even implied by the behavior of the parties. Transfers of copyright ownership, including exclusive licenses, may and should be recorded in the U.S. Copyright Office. (Information on recording transfers is available on the Office's web site.) While recording is not required to make the grant effective, it offers important benefits, much like those obtained by recording a deed in a real estate transaction.
Copyright may also be licensed. Some jurisdictions may provide that certain classes of copyrighted works be made available under a prescribed statutory license (e.g. musical works in the United States used for radio broadcast or performance). This is also called a compulsory license, because under this scheme, anyone who wishes to copy a covered work does not need the permission of the copyright holder, but instead merely files the proper notice and pays a set fee established by statute (or by an agency decision under statutory guidance) for every copy made. Failure to follow the proper procedures would place the copier at risk of an infringement suit. Because of the difficulty of following every individual work, copyright collectives or collecting societies and performing rights organizations (such as ASCAP, BMI, and SESAC have been formed to collect royalties for hundreds (thousands and more) works at once. Though this market solution bypasses the statutory license, the availability of the statutory fee still helps dictate the price per work collective rights organizations charge, driving it down to what avoidance of procedural hassle would justify.
## Similar legal rights
Copyright law covers the creative or artistic expression of an idea. Patent law covers inventions. Trademark law covers distinctive signs which are used in relation to products or services as indicators of origin, as does (in a similar fashion), Trade dress. Registered designs law covers the look or appearance of a manufactured or functional article. Trade secret law covers secret or sensitive knowledge or information.
Although copyright and trademark laws are theoretically distinct, more than one type of them may cover the same item or subject matter. For example, in the case of the Mickey Mouse cartoon, the image and name of Mickey Mouse would be the subject of trademark legislation, while the cartoon itself would be subject to copyright. Titles and character names from books or movies may also be trademarked while the works from which they are drawn may qualify for copyright.
Another point of distinction is that a copyright (and a patent) is generally subject to a statutorily-determined term, whereas a trademark registration may remain in force indefinitely if the trademark is periodically used and renewal fees continue to be duly paid to the relevant jurisdiction's trade marks office or registry. Once the term of a copyright has expired, the formerly copyrighted work enters the public domain and may be freely used or exploited by anyone. Courts in the United States and the United Kingdom have rejected the doctrine of a common law copyright. Public domain works should not be confused with works that are publicly available. Works posted in the internet for example, are publicly available, but are not generally in the public domain. Copying such works may therefore violate the author's copyright.
## Useful articles
If a pictorial, graphic or sculptural work is a useful article, it is copyrighted only if its aesthetic features are separable from its utilitarian features. A useful article is an article having an intrinsic utilitarian function that is not merely to portray the appearance of the article or to convey information. The must be separable from the functional aspect to be copyrighted.
There are two primary approaches to the separability issue: physical separability and conceptual separability. Physical separability is the ability to take the aesthetic thing away from the functional thing. Conceptual separability can be found in several different ways. It may be present if the useful article is also shown to be appreciated for its aesthetic appeal or by the design approach, which is the idea that separability is only available if the designer is able to make the aesthetic choices that are unaffected by the functional considerations. A question may also be asked of whether an individual would think of the aesthetic aspects of the work being separate from the functional aspects.
There are several different tests available for conceptual separability. The first, the Primary Use test, asks how is the thing primarily used: art or function? The second, the Marketable as Art test, asks can the article be sold as art, whether functional or not. This test does not have much backing, as almost anything can be sold as art. The third test, Temporal Displacement, asks could an individual conceptualize the article as art without conceptualizing functionality at the same time. Finally, the Denicola test says that copyrightability should ultimately depend on the extent to which the work reflects the artistic expression inhibited by functional consideration. If something came to have a pleasing shape because there were functional considerations, the artistic aspect was constrained by those concerns.
## Duration
Copyright subsists for a variety of lengths in different jurisdictions. The length of the term can depend on several factors, including the type of work (e.g. musical composition, novel), whether the work has been published or not, and whether the work was created by an individual or a corporation. In most of the world, the default length of copyright is the life of the author plus either 50 or 70 years. In the United States, the term for most existing works is a fixed number of years after the date of creation or publication. Under most countries' laws, copyrights expire at the end of the calendar year in question.
The length and requirements for copyright duration are subject to change by legislation, and since the early 20th century there have been a number of adjustments made in various countries, which can make determining the duration of a given copyright somewhat difficult. For example, the United States used to require copyrights to be renewed after 28 years to stay in force, and formerly required a copyright notice upon first publication to gain coverage. In Italy and France, there were post-wartime extensions that could increase the term by approximately 6 years in Italy and up to about 14 in France. Many countries have extended the length of their copyright terms (sometimes retroactively). International treaties establish minimum terms for copyrights, but individual countries may enforce longer terms than those.
In the United States, all books and other works published before 1923 have expired copyrights and are in the public domain. In addition, works published before 1964 that did not have their copyrights renewed 28 years after first publication year also are in the public domain, except that books originally published outside the US by non-Americans are exempt from this requirement, if they are still under copyright in their home country (see How Can I Tell Whether a Copyright Was Renewed for more details).
But if the intended exploitation of the work includes publication (or distribution of derivative work, such as a film based on a book protected by copyright) outside the U.S., the terms of copyright around the world must be considered. If the author has been dead more than 70 years, the work is in the public domain in most, but not all, countries. Some works are covered by copyright in Spain for 80 years after the author's death.
In 1998 the length of a copyright in the United States was increased by 20 years under the The Copyright Term Extension Act. This legislation was strongly promoted by corporations which had valuable copyrights which would otherwise would have expired, and has been the subject of substantial criticism on this point.
As a curiosity, the famous work Peter Pan, or The Boy Who Wouldn't Grow Up has a complex – and disputed – story of copyright expiry.
## Typefaces
In the United States, the Copyright Office maintains that typeface designs are not covered by copyright, and it will not accept applications for their registration. See 37. C.F.R. § 202.1(e). However, if a design is novel and "non-obvious," it may be covered by design patent. See, for example, U.S. Des. Patent No. 289,773, May 12, 1987), Charles A. Bigelow and Kris A. Holmes, inventors. Germany (in 1981) passed a special extension (Schriftzeichengesetz) to the design patent law (Geschmacksmustergesetz) for protecting them. This permits typefaces being registered as designs in Germany, too.
The United Kingdom (in 1989) has passed a law making typeface designs copyrightable. The British law also applies to designs produced before 1989.
## Accessible Copies
It is legal in several countries including Great Britain and the USA to produce alternative versions (for example, in large print or braille) of a copyrighted work to provide improved access to a work for blind and visually impaired persons without permission from the copyright holder.[8][9] | https://www.wikidoc.org/index.php/Copyright | |
1c50f2d21e72644019fc1dd6ca299f04a3663bac | wikidoc | Coricidin | Coricidin
Coricidin, Coricidin 'D' (decongestant), or CoricidinHBP (for high blood pressure), is the name of a drug marketed by Schering-Plough that contains dextromethorphan (a cough suppressant) and chlorphenamine maleate (an antihistamine). Varieties of Coricidin may also contain acetaminophen (an analgesic/fever reducer) and guaifenesin (an expectorant). The drug is marketed as a remedy for the common cold, especially for people with hypertension, whose high blood pressure may worsen if they take other decongestants.
# Recreational use
Coricidin is sometimes used in high doses as a recreational drug because it contains the psychoactive drug dextromethorphan. In this context, Coricidin is referred to as C's, Corey (Cori), Red Devils (Red D's), Skittles (they are the same size and color of a red skittle) or Triple C's (the coricidin used for recreational activity has three c's on the front). Use of Coricidin for this purpose is dangerous because chlorphenamine has anticholinergic activity, which in high doses can cause serious reactions. Fatalities have resulted from overdoses of chlorphenamine. Some Coricidin products also contain acetaminophen, which is toxic to the liver in large doses.
# Use in popular music
In the 1960s, blues-rock guitarist Duane Allman (1946-1971) of The Allman Brothers Band began using an empty glass Coricidin bottle as a guitar slide, finding it to be just the right size and shape for this purpose. Other prominent slide guitarists, such as Derek Trucks, Rory Gallagher, and Gary Rossington of Lynyrd Skynyrd adopted the Coricidin bottle as well, but such bottles eventually went out of production in the early 1980s (although replicas have been produced since 1985). | Coricidin
Coricidin, Coricidin 'D' (decongestant), or CoricidinHBP (for high blood pressure), is the name of a drug marketed by Schering-Plough that contains dextromethorphan (a cough suppressant) and chlorphenamine maleate (an antihistamine). Varieties of Coricidin may also contain acetaminophen (an analgesic/fever reducer) and guaifenesin (an expectorant). The drug is marketed as a remedy for the common cold, especially for people with hypertension, whose high blood pressure may worsen if they take other decongestants.
# Recreational use
Coricidin is sometimes used in high doses as a recreational drug because it contains the psychoactive drug dextromethorphan. In this context, Coricidin is referred to as C's, Corey (Cori), Red Devils (Red D's), Skittles (they are the same size and color of a red skittle) or Triple C's (the coricidin used for recreational activity has three c's on the front). Use of Coricidin for this purpose is dangerous because chlorphenamine has anticholinergic activity, which in high doses can cause serious reactions. Fatalities have resulted from overdoses of chlorphenamine.[1] Some Coricidin products also contain acetaminophen, which is toxic to the liver in large doses.
# Use in popular music
In the 1960s, blues-rock guitarist Duane Allman (1946-1971) of The Allman Brothers Band began using an empty glass Coricidin bottle as a guitar slide, finding it to be just the right size and shape for this purpose. Other prominent slide guitarists, such as Derek Trucks, Rory Gallagher, and Gary Rossington of Lynyrd Skynyrd adopted the Coricidin bottle as well, but such bottles eventually went out of production in the early 1980s (although replicas have been produced since 1985).[2][3] | https://www.wikidoc.org/index.php/Coricidin | |
c80595f3f0c9d20dbda3c5169c73f97adf55a982 | wikidoc | Corn smut | Corn smut
Corn smut is a disease of maize caused by the pathogenic plant fungus Ustilago maydis. U. maydis causes smut disease on maize (Zea mays) and teosinte (Euchlena mexicana). Although it can infect any part of the plant it usually enters the ovaries and replaces the normal kernels of the cobs with large distorted tumors analogous to mushrooms. These tumors, or "galls", are made up of much-enlarged cells of the infected plant, fungal threads, and blue-black spores. The spores give the cob a burned, scorched appearance. In fact, the name Ustilago comes from the Latin word ustilare (to burn).
Considered a pest in most of the United States, smut feeds off the corn plant and decreases the yield. Usually smut-infected crops are destroyed. However, in Mexico corn smut is called huitlacoche (IPA Template:IPA, sometimes spelled cuitlacoche), an Aztec word reportedly meaning raven's excrement . It is considered a delicacy, even being preserved and sold for a higher price than corn. For culinary use, the galls are harvested while still immature — fully mature galls are dry and almost entirely spore-filled. The immature galls, gathered two to three weeks after an ear of corn is infected, still retain moisture and, when cooked, have a flavor described as mushroom-like, sweet, savory, woody, and earthy. Flavor compounds include sotolon and vanillin, as well as the sugar glucose.
The fungus has had difficulty entering into the American and European diets as most farmers see it as blight, despite attempts by government and high profile chefs. In the mid-1990s and due to demand created by high-end restaurants, Pennsylvania and Florida farms were allowed by the United States Department of Agriculture (USDA) to intentionally infect corn with huitlacoche. Most observers consider the program to have had little impact, although the initiative is still in progress. Regardless, the cursory show of interest is significant because the USDA has spent a considerable amount of time and money trying to eradicate huitlacoche in the United States. Moreover, in 1989 the James Beard Foundation held a high-profile huitlacoche dinner. This dinner famously tried to get Americans to eat more of it by renaming it the Mexican truffle.
Huitlacoche grows best during times of drought in a 78°F to 93°F (25°C–34°C) temperature range. Aztecs purposely inoculated corn with the spores by scratching their corn plants at the soil level with a knife—thereby allowing the water-borne spores easy entrance into the plant.
# Life cycle
When grown in the lab on very simple media, it behaves like baker's yeast, forming single cells going by the name sporidia. These cells multiply by budding off daughter cells. When two compatible sporidia meet on the surface of the plant, they switch to a different mode of growth. First, they send out conjugation tubes to find each other, after which they fuse and make a hypha to enter the maize plant. Hyphae growing in the plant are dikaryotic; they possess two haploid nuclei per hyphal compartment. In contrast to sporida, the dikaryotic phase of U. maydis requires infection of the plant in order to grow and differentiate and cannot be maintained in the laboratory.
Proliferation of the fungus inside the plant leads to disease symptoms as chlorosis, anthocyanin formation, reduced growth and the appearance of tumors harboring the developing teliospores (Banuett, 1995; Christensen, 1963).
Mature spores are released from the tumors and spread by rain and wind. Under appropriate conditions a probasidium is formed in which meiosis occurs. Resulting haploid nuclei migrate into elongated single cells. These cells detach from the probasidium; these are the sporidia, completing the life cycle.
# Uses
Native Americans of the American Southwest, including the Zuni tribe, have used corn smut to induce labor. It has similar medicinal effects to ergot, but weaker, due to the presence of the chemical ustilagine.
# Model system
The yeast-like growth is a big advantage for research, although its relevance in nature is unknown. The fungus is exceptionally well-suited for genetic modification. This allows researchers to study the interaction between fungus and host with relative ease. The availability of the entire genome is another advantage of this fungus as model system.
Ustilago maydis is not only used to study plant disease. It has also been used to study recombination, DNA repair and the role of the cytoskeleton in polarized growth as well. That the function of the breast-cancer gene BRCA2 is now known is largely due to work with Ustilago maydis.
# Availability
Huitlacoche can be bought as a canned good in some markets and over the net. Some farmers markets and organic growers are endeavoring to bring fresh huitlacoche to their customers and local food service trade. The Troy Community Farm of Madison, Wisconsin started a project in 2003 to grow corn and produce huitlacoche to make available in the Madison area and now sell it directly to the public from their farm stand once a week. | Corn smut
Corn smut is a disease of maize caused by the pathogenic plant fungus Ustilago maydis. U. maydis causes smut disease on maize (Zea mays) and teosinte (Euchlena mexicana). Although it can infect any part of the plant it usually enters the ovaries and replaces the normal kernels of the cobs with large distorted tumors analogous to mushrooms. These tumors, or "galls", are made up of much-enlarged cells of the infected plant, fungal threads, and blue-black spores. The spores give the cob a burned, scorched appearance. In fact, the name Ustilago comes from the Latin word ustilare (to burn).
Considered a pest in most of the United States, smut feeds off the corn plant and decreases the yield. Usually smut-infected crops are destroyed. However, in Mexico corn smut is called huitlacoche (IPA Template:IPA, sometimes spelled cuitlacoche), an Aztec word reportedly meaning raven's excrement [1]. It is considered a delicacy, even being preserved and sold for a higher price than corn. For culinary use, the galls are harvested while still immature — fully mature galls are dry and almost entirely spore-filled. The immature galls, gathered two to three weeks after an ear of corn is infected, still retain moisture and, when cooked, have a flavor described as mushroom-like, sweet, savory, woody, and earthy. Flavor compounds include sotolon and vanillin, as well as the sugar glucose.
The fungus has had difficulty entering into the American and European diets as most farmers see it as blight, despite attempts by government and high profile chefs. In the mid-1990s and due to demand created by high-end restaurants, Pennsylvania and Florida farms were allowed by the United States Department of Agriculture (USDA) to intentionally infect corn with huitlacoche. Most observers consider the program to have had little impact, although the initiative is still in progress. Regardless, the cursory show of interest is significant because the USDA has spent a considerable amount of time and money trying to eradicate huitlacoche in the United States. Moreover, in 1989 the James Beard Foundation held a high-profile huitlacoche dinner. This dinner famously tried to get Americans to eat more of it by renaming it the Mexican truffle.
Huitlacoche grows best during times of drought in a 78°F to 93°F (25°C–34°C) temperature range. Aztecs purposely inoculated corn with the spores by scratching their corn plants at the soil level with a knife—thereby allowing the water-borne spores easy entrance into the plant.
# Life cycle
When grown in the lab on very simple media, it behaves like baker's yeast, forming single cells going by the name sporidia. These cells multiply by budding off daughter cells. When two compatible sporidia meet on the surface of the plant, they switch to a different mode of growth. First, they send out conjugation tubes to find each other, after which they fuse and make a hypha to enter the maize plant. Hyphae growing in the plant are dikaryotic; they possess two haploid nuclei per hyphal compartment. In contrast to sporida, the dikaryotic phase of U. maydis requires infection of the plant in order to grow and differentiate and cannot be maintained in the laboratory.
Proliferation of the fungus inside the plant leads to disease symptoms as chlorosis, anthocyanin formation, reduced growth and the appearance of tumors harboring the developing teliospores (Banuett, 1995; Christensen, 1963).
Mature spores are released from the tumors and spread by rain and wind. Under appropriate conditions a probasidium is formed in which meiosis occurs. Resulting haploid nuclei migrate into elongated single cells. These cells detach from the probasidium; these are the sporidia, completing the life cycle.
# Uses
Native Americans of the American Southwest, including the Zuni tribe, have used corn smut to induce labor. It has similar medicinal effects to ergot, but weaker, due to the presence of the chemical ustilagine.[2]
# Model system
The yeast-like growth is a big advantage for research, although its relevance in nature is unknown. The fungus is exceptionally well-suited for genetic modification. This allows researchers to study the interaction between fungus and host with relative ease. The availability of the entire genome is another advantage of this fungus as model system.
Ustilago maydis is not only used to study plant disease. It has also been used to study recombination, DNA repair and the role of the cytoskeleton in polarized growth as well. That the function of the breast-cancer gene BRCA2 is now known is largely due to work with Ustilago maydis.
# Availability
Huitlacoche can be bought as a canned good in some markets and over the net. Some farmers markets and organic growers are endeavoring to bring fresh huitlacoche to their customers and local food service trade. The Troy Community Farm of Madison, Wisconsin started a project in 2003 to grow corn and produce huitlacoche to make available in the Madison area and now sell it directly to the public from their farm stand once a week.[3] | https://www.wikidoc.org/index.php/Corn_smut | |
27bb1ebd70950af262d80b6c3082a3d63fdbc875 | wikidoc | Cortactin | Cortactin
Cortactin (from "cortical actin binding protein") is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types. When activated, it will recruit Arp2/3 complex proteins to existing actin microfilaments, facilitating and stabilizing nucleation sites for actin branching. Cortactin is important in promoting lamellipodia formation, invadopodia formation, cell migration, and endocytosis.
# Gene
In humans, cortactin is encoded by the CTTN gene on chromosome 11.
# Structure
Cortactin is a thin, elongated monomer that consists of an amino-terminal acidic (NTA) region; 37-residue-long segments that are highly conserved among cortactin proteins of all species and repeated up to 6.5 times in tandem (“cortactin repeats”); a proline-rich region; and an SH3 domain. This basic structure is highly conserved among all species that express cortactin.
# Activation and binding
Cortactin is activated via phosphorylation, by tyrosine kinases or serine/threonine kinases, in response to extracellular signals like growth factors, adhesion sites, or pathogenic invasion of the epithelial layer.
The SH3 domain of certain tyrosine kinases, such as the oncogene Src kinase, binds to cortactin’s proline-rich region and phosphorylates it on Tyr421, Tyr466, and Tyr482. Once activated in this way, it can bind to filamentous actin (F-actin) with the fourth of its cortactin repeats. As the concentration of phosphorylated cortactin increases in specific regions within the cell, the monomers each begin to recruit an Arp2/3 complex to F-actin. It binds to Arp2/3 with an aspartic acid-aspartic acid-tryptophan (DDW) sequence in its NTA region, a motif that is often seen in other actin nucleation-promoting factors (NPFs).
Certain serine/threonine kinases, such as ERK, can phosphorylate cortactin on Ser405 and Ser418 in the SH3 domain. Activated like this, it still associates with Arp2/3 and F-actin, but will also allow other actin NPFs, most importantly N-WASp (Neuronal Wiskott-Aldrich syndrome protein), to bind to the complex as well; when phosphorylated by tyrosine kinases, other NPFs are excluded. The ability of these other NPFs to bind the Arp2/3 complex while cortactin is also bound could come from new interactions with cortactin’s SH3 domain, which is in a different conformation when phosphorylated by Ser/Thr kinases and thus may be more open to interactions with other NPFs. Having other NPFs bind to the Arp2/3 complex at the same time as cortactin may enhance nucleation site stability.
# Location and function in the cell
Inactive cortactin diffuses throughout the cytoplasm, but upon phosphorylation, the protein begins to target certain areas in the cell. Cortactin-assisted Arp2/3-nucleated actin branches are most prominent in the actin cortex, around the periphery of the cell. A phosphorylated cortactin monomer binds to, activates, and stabilizes an Arp2/3 complex on preexisting F-actin, which provides a nucleation site for a new actin branch to form from the “mother” filament. Branches formed from cortactin-assisted nucleation sites are very stable; cortactin has been shown to inhibit debranching. Thus, polymerization and branching of actin is promoted in areas of the cell where cortactin is localized.
Cortactin is very active in lamellipodia, protrusions of the cell membrane formed by actin polymerization and treadmilling that propel the cell along a surface as it migrates towards some target.
Cortactin acts as a link between extracellular signals and lamellipodial “steering.” When a receptor tyrosine kinase on the cell membrane binds to an adhesion site, for example, cortactin will be phosphorylated locally to the area of binding, activate and recruit Arp2/3 to the actin cortex in that region, and thus stimulate cortical actin polymerization and movement of the cell in that direction. Macrophages, highly motile immune cells that engulf cellular debris and pathogens, are propelled by lamellipodia and identify/migrate toward a target via chemotaxis; thus, cortactin must also be activated by receptor kinases that pick up a large variety of chemical signals.
Studies have implicated cortactin in both clathrin-mediated endocytosis and clathrin-independent endocytosis. In both kinds of endocytosis, it has long been known that actin localizes to sites of vesicle invagination and is a vital part of the endocytic pathway, but the actual mechanisms by which actin facilitates endocytosis are still unclear. Recently, however, it has been found that dynamin, the protein responsible for breaking the newly formed vesicular bud off the inside of the plasma membrane, can associate with the SH3 domain of cortactin. Since cortactin recruits the Arp2/3 complexes that lead to actin polymerization, this suggests that it may play an important part in linking vesicle formation to the as yet unknown functions actin has in endocytosis.
# Clinical significance
Amplification of the genes encoding cortactin—in humans, EMS1—has been found to occur in certain tumors. Overexpression of cortactin can lead to highly-active lamellipodia in tumor cells, dubbed “invadopodia.” These cells are especially invasive and migratory, making them very dangerous, for they can easily spread cancer across the body into other tissues.
# Interactions
Cortactin has been shown to interact with:
- ACTR3
- ARPC2,
- CTNND1,
- FER,
- KCNA2,
- SHANK2,
- WASL, and
- WIPF1. | Cortactin
Cortactin (from "cortical actin binding protein") is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery.[1][2] It is present in all cell types. When activated, it will recruit Arp2/3 complex proteins to existing actin microfilaments, facilitating and stabilizing nucleation sites for actin branching. Cortactin is important in promoting lamellipodia formation, invadopodia formation, cell migration, and endocytosis.
# Gene
In humans, cortactin is encoded by the CTTN gene on chromosome 11.[3]
# Structure
Cortactin is a thin, elongated monomer that consists of an amino-terminal acidic (NTA) region; 37-residue-long segments that are highly conserved among cortactin proteins of all species and repeated up to 6.5 times in tandem (“cortactin repeats”); a proline-rich region; and an SH3 domain. This basic structure is highly conserved among all species that express cortactin.[4]
# Activation and binding
Cortactin is activated via phosphorylation, by tyrosine kinases or serine/threonine kinases, in response to extracellular signals like growth factors, adhesion sites, or pathogenic invasion of the epithelial layer.
The SH3 domain of certain tyrosine kinases, such as the oncogene Src kinase, binds to cortactin’s proline-rich region and phosphorylates it on Tyr421, Tyr466, and Tyr482. Once activated in this way, it can bind to filamentous actin (F-actin) with the fourth of its cortactin repeats.[4] As the concentration of phosphorylated cortactin increases in specific regions within the cell, the monomers each begin to recruit an Arp2/3 complex to F-actin. It binds to Arp2/3 with an aspartic acid-aspartic acid-tryptophan (DDW) sequence in its NTA region, a motif that is often seen in other actin nucleation-promoting factors (NPFs).[5]
Certain serine/threonine kinases, such as ERK, can phosphorylate cortactin on Ser405 and Ser418 in the SH3 domain.[4] Activated like this, it still associates with Arp2/3 and F-actin, but will also allow other actin NPFs, most importantly N-WASp (Neuronal Wiskott-Aldrich syndrome protein), to bind to the complex as well; when phosphorylated by tyrosine kinases, other NPFs are excluded.[6] The ability of these other NPFs to bind the Arp2/3 complex while cortactin is also bound could come from new interactions with cortactin’s SH3 domain, which is in a different conformation when phosphorylated by Ser/Thr kinases and thus may be more open to interactions with other NPFs.[6] Having other NPFs bind to the Arp2/3 complex at the same time as cortactin may enhance nucleation site stability.[4]
# Location and function in the cell
Inactive cortactin diffuses throughout the cytoplasm, but upon phosphorylation, the protein begins to target certain areas in the cell. Cortactin-assisted Arp2/3-nucleated actin branches are most prominent in the actin cortex, around the periphery of the cell.[7] A phosphorylated cortactin monomer binds to, activates, and stabilizes an Arp2/3 complex on preexisting F-actin, which provides a nucleation site for a new actin branch to form from the “mother” filament. Branches formed from cortactin-assisted nucleation sites are very stable; cortactin has been shown to inhibit debranching.[7] Thus, polymerization and branching of actin is promoted in areas of the cell where cortactin is localized.
Cortactin is very active in lamellipodia, protrusions of the cell membrane formed by actin polymerization and treadmilling that propel the cell along a surface as it migrates towards some target.[8]
Cortactin acts as a link between extracellular signals and lamellipodial “steering.” When a receptor tyrosine kinase on the cell membrane binds to an adhesion site, for example, cortactin will be phosphorylated locally to the area of binding, activate and recruit Arp2/3 to the actin cortex in that region, and thus stimulate cortical actin polymerization and movement of the cell in that direction. Macrophages, highly motile immune cells that engulf cellular debris and pathogens, are propelled by lamellipodia and identify/migrate toward a target via chemotaxis; thus, cortactin must also be activated by receptor kinases that pick up a large variety of chemical signals.[8]
Studies have implicated cortactin in both clathrin-mediated endocytosis[9] and clathrin-independent endocytosis.[10] In both kinds of endocytosis, it has long been known that actin localizes to sites of vesicle invagination and is a vital part of the endocytic pathway, but the actual mechanisms by which actin facilitates endocytosis are still unclear. Recently, however, it has been found that dynamin, the protein responsible for breaking the newly formed vesicular bud off the inside of the plasma membrane, can associate with the SH3 domain of cortactin. Since cortactin recruits the Arp2/3 complexes that lead to actin polymerization, this suggests that it may play an important part in linking vesicle formation to the as yet unknown functions actin has in endocytosis.[11]
# Clinical significance
Amplification of the genes encoding cortactin—in humans, EMS1—has been found to occur in certain tumors. Overexpression of cortactin can lead to highly-active lamellipodia in tumor cells, dubbed “invadopodia.” These cells are especially invasive and migratory, making them very dangerous, for they can easily spread cancer across the body into other tissues.[12]
# Interactions
Cortactin has been shown to interact with:
- ACTR3[13][14]
- ARPC2,[13]
- CTNND1,[15]
- FER,[16]
- KCNA2,[17]
- SHANK2,[18]
- WASL,[19] and
- WIPF1.[20] | https://www.wikidoc.org/index.php/Cortactin | |
98b65d1c9a61da82621b6bf2ef5a9ba6d40329aa | wikidoc | Cortisone | Cortisone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Cortisone is a hormone that is FDA approved for the treatment of primary and secondary adrenocortical deficiency, rheumatic disorders, psoriasis, exfoliative dermatitis, bronchial asthma, allergic conjunctivitis, hemolytic anemia, enteritis, tuberculosis, trichnosis. Common adverse reactions include convulsions, increased intracranial pressure with papilledema, vertigo, headache, psychic disturbances, hirsuitism, glaucoma, exophthalmos.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance).
- Congenital adrenal hyperplasia
- Nonsuppurative thyroiditis
- Hypercalcemia associated with cancer
- As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in the following conditions
- Psoriatic arthritis
- Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
- Ankylosing spondylitis
- Acute and subacute bursitis
- Acute nonspecific tenosynovitis
- Acute gouty arthritis
- Post-traumatic osteoarthritis
- Synovitis of osteoarthritis
- Epicondylitis
- During an exacerbation or as maintenance therapy in selected cases of following conditions.
- Systemic lupus erythematosus
- Acute rheumatic carditis
- Systemic dermatomyositis (polymyositis)
- Dermatologic Diseases
- Pemphigus
- Bullous dermatitis herpetiformis
- Severe erythema multiforme (Stevens-Johnson syndrome)
- Exfoliative dermatitis
- Mycosis fungoides
- Severe psoriasis
- Severe seborrheic dermatitis
- Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment of following conditions.
- Seasonal or perennial allergic rhinitis
- Bronchial asthma
- Contact dermatitis
- Atopic dermatitis
- Serum sickness
- Drug hypersensitivity reactions
- Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, such as:
- Allergic conjunctivitis
- Keratitis
- Allergic corneal marginal ulcers
- Herpes zoster ophthalmicus
- Iritis and iridocyclitis
- Chorioretinitis
- Anterior segment inflammation
- Diffuse posterior uveitis and choroiditis
- Optic neuritis
- Sympathetic ophthalmia
- Respiratory Diseases
- Symptomatic sarcoidosis
- Loeffler's syndrome not manageable by other means
- Berylliosis
- Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculosis chemotherapy
- Aspiration pneumonitis
- Idiopathic thrombocytopenic purpura in adults
- Secondary thrombocytopenia in adults
- Acquired (autoimmune) hemolytic anemia
- Erythroblastopenia (RBC anemia)
- Congenital (erythroid) hypoplastic anemia
- For palliative management of following conditions.
- Leukemias and lymphomas in adults
- Acute leukemia of childhood
- Edematous States
- To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus
- To tide the patient over a critical period of the disease in the follwoing conditions.
- Ulcerative colitis
- Regional enteritis
- Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy
- Trichinosis with neurologic or myocardial involvement.
### For Oral Administration=
- DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.
- The initial dosage varies from 25 to 300 mg a day depending on the disease being treated. In less severe diseases doses lower than 25 mg may suffice, while in severe diseases doses higher than 300 mg may be required. The initial dosage should be maintained or adjusted until the patient's response is satisfactory. If satisfactory clinical response does not occur after a reasonable period of time, discontinue cortisone acetate tablets and transfer the patient to other therapy.
- After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.
- Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma). During stress it may be necessary to increase dosage temporarily.
- If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cortisone in adult patients.
### Non–Guideline-Supported Use
- Carcinoma of breast
- Carcinoma of prostate
- Fever, due tomalignancy; treatment adjunct
- Intracranial tumor
- Multiple myeloma
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cortisone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cortisone in pediatric patients.
### Non–Guideline-Supported Use
- Adrenal insufficiency: 0.5-0.75 mg/kg/day or 20-25 mg/m(2)/day ORALLY divided every 8 hr
- Adrenal insufficiency: 0.25-0.35 mg/kg/day or 12.5 mg/m(2)/day IM
# Contraindications
- Systemic fungal infections
- Hypersensitivity to this product
# Warnings
- In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.
- Drug-induced secondary adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage.
- This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.
- If the patient is receiving steroids already, dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.
- Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.
- Moreover, corticosteroids may affect the nitroblue-tetrazolium test for bacterial infection and produce false negative results.
- In cerebral malaria, a double-blind trial has shown that the use of corticosteroids is associated with prolongation of coma and a higher incidence of pneumonia and gastrointestinal bleeding.
- Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has time in the tropics or any patient with unexplained diarrhea.
- Prolonged use of corticosteroids may produce posterior subsapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
- Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses.
- Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
- Administration of live virus vaccines, including smallpox, is contraindicated in individuals receiving immunosuppressive doses of corticosteroids. If inactivated viral or bacterial vaccines are administered to individuals receiving immunosuppressive doses of corticosteroids, the expected serum antibody response may not be obtained.
- However, immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.
- Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have more serious or even fatal course in non-immune children or adults on corticosteroids.
- In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.
- If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information). If chickenpox develops, treatment with antiviral agents may be considered.
- The use of cortisone acetate tablets in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.
- If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
- Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Cortisone in the drug label.
## Postmarketing Experience
- Sodium retention
- Fluid retention
- Congestive heart failure in susceptible patients
- Potassium loss
- Hypokalemic alkalosis
- Hypertension
- Muscle weakness
- Steroid myopathy
- Loss of muscle mass
- Osteoporosis
- Vertebral compression fractures
- Aseptic necrosis of femoral and humeral heads
- Pathologic fracture of long bones
- Tendon rupture
- Peptic ulcer with possible perforation and hemorrhage
- Perforation of the small and large bowel, particularly in patients with inflammatory bowel disease
- Pancreatitis
- Abdominal distention
- Ulcerative esophagitis
- Impaired wound healing
- Thin fragile skin
- Petechiae and ecchymoses
- Erythema
- Increased sweating
- May suppress reactions to skin tests
- Other cutaneous reactions, such as allergic dermatitis, urticaria, angioneurotic edema
- Convulsions
- Increased intracranial pressure with papilledema (pseudotumor cerbri) usually after treatment
- Vertigo
- Headache
- Psychic disturbances
- Menstrual irregularities
- Development of cushingoid state
- Suppression of growth in children
- Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness
- Decreased carbohydrate tolerance
- Manifestations of latent diabetes mellitus
- Increased requirements for insulin or oral hypoglycemic agents in diabetics
- Hirsutism
- Posterior subcapsular cataracts
- Increased intraocular pressure
- Glaucoma
- Exophthalmos
- Negative nitrogen balance due to protein catabolism
- Myocardial rupture following recent myocardial infarctions
- Thromboembolism
- Weight gain
- Increased appetite
- Nausea
- Malaise
# Drug Interactions
There is limited information regarding Cortisone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy or in women of childbearing potential requires that the anticipated benefits be weighed against the possible hazards to the mother and embryo or fetus.
- Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.
- Corticosteroids appear in breast milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other unwanted effects. Mothers taking pharmacologic doses of corticosteroids should be advised not to nurse.
Pregnancy Category (AUS): A
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cortisone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cortisone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Cortisone with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Cortisone with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Cortisone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Cortisone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cortisone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cortisone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cortisone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cortisone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cortisone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Cortisone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cortisone in the drug label.
# Overdosage
- Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.
- The intraperitoneal LD50 of cortisone acetate in female mice was 1405 mg/kg.
# Pharmacology
## Mechanism of Action
- Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. They are also used for their potent anti-inflammatory effects in disorders of many organ systems.
- Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.
## Structure
- Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract.
- Cortisone acetate is a white or practically white, odorless, crystalline powder. It is stable in air. It is insoluble in water. The molecular weight is 402.49. It is designated chemically as 21-(acetyloxy)-17-hydroxypregn-4-ene-3,11,20-trione. The molecular formula is C23H30O6 and the structural formula is
- Cortisone Acetate tablets contain 25 mg of cortisone acetate in each tablet.
- Inactive ingredients are Anhydrous Lactose, Colloidal Silicon Dioxide, Magnesium Stearate, Microcrystalline Cellulose, Sodium Lauryl Sulfate, and Sodium Starch Glycolate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cortisone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Cortisone in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Cortisone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Cortisone in the drug label.
# How Supplied
- Cortisone Acetate Tablets USP 25 mg: White, Round, Scored Tablet; Imprinted "West-ward 202."
- Bottles of 100 tablets (NDC 60429-015-01).
## Storage
- Store at 20-25°C (68-77°F) . Protect from light and moisture.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Cortisone in the drug label.
# Precautions with Alcohol
- Alcohol-Cortisone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CORTISONE ACETATE ®
# Look-Alike Drug Names
There is limited information regarding Cortisone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cortisone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Cortisone is a hormone that is FDA approved for the treatment of primary and secondary adrenocortical deficiency, rheumatic disorders, psoriasis, exfoliative dermatitis, bronchial asthma, allergic conjunctivitis, hemolytic anemia, enteritis, tuberculosis, trichnosis. Common adverse reactions include convulsions, increased intracranial pressure with papilledema, vertigo, headache, psychic disturbances, hirsuitism, glaucoma, exophthalmos.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance).
- Congenital adrenal hyperplasia
- Nonsuppurative thyroiditis
- Hypercalcemia associated with cancer
- As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in the following conditions
- Psoriatic arthritis
- Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy)
- Ankylosing spondylitis
- Acute and subacute bursitis
- Acute nonspecific tenosynovitis
- Acute gouty arthritis
- Post-traumatic osteoarthritis
- Synovitis of osteoarthritis
- Epicondylitis
- During an exacerbation or as maintenance therapy in selected cases of following conditions.
- Systemic lupus erythematosus
- Acute rheumatic carditis
- Systemic dermatomyositis (polymyositis)
- Dermatologic Diseases
- Pemphigus
- Bullous dermatitis herpetiformis
- Severe erythema multiforme (Stevens-Johnson syndrome)
- Exfoliative dermatitis
- Mycosis fungoides
- Severe psoriasis
- Severe seborrheic dermatitis
- Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment of following conditions.
- Seasonal or perennial allergic rhinitis
- Bronchial asthma
- Contact dermatitis
- Atopic dermatitis
- Serum sickness
- Drug hypersensitivity reactions
- Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, such as:
- Allergic conjunctivitis
- Keratitis
- Allergic corneal marginal ulcers
- Herpes zoster ophthalmicus
- Iritis and iridocyclitis
- Chorioretinitis
- Anterior segment inflammation
- Diffuse posterior uveitis and choroiditis
- Optic neuritis
- Sympathetic ophthalmia
- Respiratory Diseases
- Symptomatic sarcoidosis
- Loeffler's syndrome not manageable by other means
- Berylliosis
- Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculosis chemotherapy
- Aspiration pneumonitis
- Idiopathic thrombocytopenic purpura in adults
- Secondary thrombocytopenia in adults
- Acquired (autoimmune) hemolytic anemia
- Erythroblastopenia (RBC anemia)
- Congenital (erythroid) hypoplastic anemia
- For palliative management of following conditions.
- Leukemias and lymphomas in adults
- Acute leukemia of childhood
- Edematous States
- To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus
- To tide the patient over a critical period of the disease in the follwoing conditions.
- Ulcerative colitis
- Regional enteritis
- Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy
- Trichinosis with neurologic or myocardial involvement.
### For Oral Administration=
- DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.
- The initial dosage varies from 25 to 300 mg a day depending on the disease being treated. In less severe diseases doses lower than 25 mg may suffice, while in severe diseases doses higher than 300 mg may be required. The initial dosage should be maintained or adjusted until the patient's response is satisfactory. If satisfactory clinical response does not occur after a reasonable period of time, discontinue cortisone acetate tablets and transfer the patient to other therapy.
- After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.
- Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma). During stress it may be necessary to increase dosage temporarily.
- If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cortisone in adult patients.
### Non–Guideline-Supported Use
- Carcinoma of breast
- Carcinoma of prostate
- Fever, due tomalignancy; treatment adjunct
- Intracranial tumor
- Multiple myeloma
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cortisone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cortisone in pediatric patients.
### Non–Guideline-Supported Use
- Adrenal insufficiency: 0.5-0.75 mg/kg/day or 20-25 mg/m(2)/day ORALLY divided every 8 hr
- Adrenal insufficiency: 0.25-0.35 mg/kg/day or 12.5 mg/m(2)/day IM
# Contraindications
- Systemic fungal infections
- Hypersensitivity to this product
# Warnings
- In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated.
- Drug-induced secondary adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage.
- This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.
- If the patient is receiving steroids already, dosage may have to be increased. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently.
- Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.
- Moreover, corticosteroids may affect the nitroblue-tetrazolium test for bacterial infection and produce false negative results.
- In cerebral malaria, a double-blind trial has shown that the use of corticosteroids is associated with prolongation of coma and a higher incidence of pneumonia and gastrointestinal bleeding.
- Corticosteroids may activate latent amebiasis. Therefore, it is recommended that latent or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has time in the tropics or any patient with unexplained diarrhea.
- Prolonged use of corticosteroids may produce posterior subsapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.
- Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses.
- Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.
- Administration of live virus vaccines, including smallpox, is contraindicated in individuals receiving immunosuppressive doses of corticosteroids. If inactivated viral or bacterial vaccines are administered to individuals receiving immunosuppressive doses of corticosteroids, the expected serum antibody response may not be obtained.
- However, immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.
- Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have more serious or even fatal course in non-immune children or adults on corticosteroids.
- In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.
- If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information). If chickenpox develops, treatment with antiviral agents may be considered.
- The use of cortisone acetate tablets in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.
- If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.
- Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Cortisone in the drug label.
## Postmarketing Experience
- Sodium retention
- Fluid retention
- Congestive heart failure in susceptible patients
- Potassium loss
- Hypokalemic alkalosis
- Hypertension
- Muscle weakness
- Steroid myopathy
- Loss of muscle mass
- Osteoporosis
- Vertebral compression fractures
- Aseptic necrosis of femoral and humeral heads
- Pathologic fracture of long bones
- Tendon rupture
- Peptic ulcer with possible perforation and hemorrhage
- Perforation of the small and large bowel, particularly in patients with inflammatory bowel disease
- Pancreatitis
- Abdominal distention
- Ulcerative esophagitis
- Impaired wound healing
- Thin fragile skin
- Petechiae and ecchymoses
- Erythema
- Increased sweating
- May suppress reactions to skin tests
- Other cutaneous reactions, such as allergic dermatitis, urticaria, angioneurotic edema
- Convulsions
- Increased intracranial pressure with papilledema (pseudotumor cerbri) usually after treatment
- Vertigo
- Headache
- Psychic disturbances
- Menstrual irregularities
- Development of cushingoid state
- Suppression of growth in children
- Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery, or illness
- Decreased carbohydrate tolerance
- Manifestations of latent diabetes mellitus
- Increased requirements for insulin or oral hypoglycemic agents in diabetics
- Hirsutism
- Posterior subcapsular cataracts
- Increased intraocular pressure
- Glaucoma
- Exophthalmos
- Negative nitrogen balance due to protein catabolism
- Myocardial rupture following recent myocardial infarctions
- Thromboembolism
- Weight gain
- Increased appetite
- Nausea
- Malaise
# Drug Interactions
There is limited information regarding Cortisone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Since adequate human reproduction studies have not been done with corticosteroids, use of these drugs in pregnancy or in women of childbearing potential requires that the anticipated benefits be weighed against the possible hazards to the mother and embryo or fetus.
- Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.
- Corticosteroids appear in breast milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other unwanted effects. Mothers taking pharmacologic doses of corticosteroids should be advised not to nurse.
Pregnancy Category (AUS): A
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cortisone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cortisone during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Cortisone with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Cortisone with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Cortisone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Cortisone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cortisone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cortisone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cortisone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cortisone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cortisone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Cortisone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cortisone in the drug label.
# Overdosage
- Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. In the event of overdosage, no specific antidote is available; treatment is supportive and symptomatic.
- The intraperitoneal LD50 of cortisone acetate in female mice was 1405 mg/kg.
# Pharmacology
## Mechanism of Action
- Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. They are also used for their potent anti-inflammatory effects in disorders of many organ systems.
- Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.
## Structure
- Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract.
- Cortisone acetate is a white or practically white, odorless, crystalline powder. It is stable in air. It is insoluble in water. The molecular weight is 402.49. It is designated chemically as 21-(acetyloxy)-17-hydroxypregn-4-ene-3,11,20-trione. The molecular formula is C23H30O6 and the structural formula is
- Cortisone Acetate tablets contain 25 mg of cortisone acetate in each tablet.
- Inactive ingredients are Anhydrous Lactose, Colloidal Silicon Dioxide, Magnesium Stearate, Microcrystalline Cellulose, Sodium Lauryl Sulfate, and Sodium Starch Glycolate.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cortisone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Cortisone in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Cortisone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Cortisone in the drug label.
# How Supplied
- Cortisone Acetate Tablets USP 25 mg: White, Round, Scored Tablet; Imprinted "West-ward 202."
- Bottles of 100 tablets (NDC 60429-015-01).
## Storage
- Store at 20-25°C (68-77°F) [See USP Controlled Room Temperature]. Protect from light and moisture.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Cortisone in the drug label.
# Precautions with Alcohol
- Alcohol-Cortisone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CORTISONE ACETATE ®[1]
# Look-Alike Drug Names
There is limited information regarding Cortisone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cortisone | |
afdd32a1deb0ff5f9492d68c313d9c877d085264 | wikidoc | Ibutilide | Ibutilide
CHOICE OF PATIENTS
Patients with chronic atrial fibrillation have a strong tendency to revert after conversion to sinus rhythm and treatments to maintain sinus rhythm carry risks. Patients to be treated with CORVERT, therefore, should be carefully selected such that the expected benefits of maintaining sinus rhythm outweigh the immediate risks of CORVERT, and the risks of maintenance therapy, and are likely to offer an advantage compared with alternative management.
# Atrial Fibrillation or Atrial Flutter
- Dosing information
- The recommended dose based on controlled trials is outlined in the Table below. Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in the event of sustained or nonsustained ventricular tachycardia, or marked QT prolongation or QTc.
- In a trial comparing ibutilide and sotalol, 2 mg ibutilide fumarate administered as a single infusion to patients weighing more than 60 kg was also effective in terminating atrial fibrillation or atrial flutter.
- In the post-cardiac surgery study, one or two intravenous infusions of 0.5 mg (0.005 mg/kg per dose for patients weighing less than 60 kg) was effective in terminating atrial fibrillation or atrial flutter.
- Patients should be observed with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. Longer monitoring is required if any arrhythmic activity is noted. Skilled personnel and proper equipment, Proarrhythmia), such as a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during administration of CORVERT and subsequent monitoring of the patient.
- CORVERT Injection may be administered undiluted or diluted in 50 mL of diluent. CORVERT may be added to 0.9% Sodium Chloride Injection or 5% Dextrose Injection before infusion. The contents of one 10 mL vial (0.1 mg/mL) may be added to a 50 mL infusion bag to form an admixture of approximately 0.017 mg/mL ibutilide fumarate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
# Wolff-Parkinson-White syndrome
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS)
- Class of Recommendation: Class I
- Level of Evidence: Level C
- Dosing Information
- 1 mg IV over 10 minutes; repeat 1 mg when needed
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS)
- Class of Recommendation: Class IIb
- Level of Evidence: Level B
- Dosing Information
- 1 mg IV over 10 minutes; repeat 1 mg when needed
- Dosing Information
- Loading dosage: 0.005-0.02 mg/kg
- Maintenance doses: 0.001-0.004 mg/kg.
- Like other antiarrhythmic agents, CORVERT Injection can induce or worsen ventricular arrhythmias in some patients. This may have potentially fatal consequences. Torsades de pointes, a polymorphic ventricular tachycardia that develops in the setting of a prolonged QT interval, may occur because of the effect CORVERT has on cardiac repolarization, but CORVERT can also cause polymorphic VT in the absence of excessive prolongation of the QT interval. In general, with drugs that prolong the QT interval, the risk of torsades de pointes is thought to increase progressively as the QT interval is prolonged and may be worsened with bradycardia, a varying heart rate, and hypokalemia. In clinical trials conducted in patients with atrial fibrillation and atrial flutter, those with QTc intervals >440 msec were not usually allowed to participate, and serum potassium had to be above 4.0 mEq/L. Although change in QTc was dose dependent for ibutilide, there was no clear relationship between risk of serious proarrhythmia and dose in clinical studies, possibly due to the small number of events. In clinical trials of intravenous ibutilide, patients with a history of congestive heart failure (CHF) or low left ventricular ejection fraction appeared to have a higher incidence of sustained polymorphic ventricular tachycardia (VT), than those without such underlying conditions; for sustained polymorphic VT the rate was 5.4% in patients with a history of CHF and 0.8% without it. There was also a suggestion that women had a higher risk of proarrhythmia, but the sex difference was not observed in all studies and was most prominent for nonsustained ventricular tachycardia. The incidence of sustained ventricular arrhythmias was similar in male (1.8%) and female (1.5%) patients, possibly due to the small number of events. CORVERT is not recommended in patients who have previously demonstrated polymorphic ventricular tachycardia (eg, torsades de pointes).
- During registration trials, 1.7% of patients with atrial flutter or atrial fibrillation treated with CORVERT developed sustained polymorphic ventricular tachycardia requiring cardioversion. In these clinical trials, many initial episodes of polymorphic ventricular tachycardia occurred after the infusion of CORVERT was stopped but generally not more than 40 minutes after the start of the first infusion. There were, however, instances of recurrent polymorphic VT that occurred about 3 hours after the initial infusion. In two cases, the VT degenerated into ventricular fibrillation, requiring immediate defibrillation. Other cases were managed with cardiac pacing and magnesium sulfate infusions. Nonsustained polymorphic ventricular tachycardia occurred in 2.7% of patients and nonsustained monomorphic ventricular tachycardias occurred in 4.9% of the patients.
- Proarrhythmic events must be anticipated. Skilled personnel and proper equipment, including cardiac monitoring equipment, intracardiac pacing facilities, a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during and after administration of CORVERT. Before treatment with CORVERT, hypokalemia and hypomagnesemia should be corrected to reduce the potential for proarrhythmia. Patients should be observed with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. Longer monitoring is required if any arrhythmic activity is noted. Management of polymorphic ventricular tachycardia includes discontinuation of ibutilide, correction of electrolyte abnormalities, especially potassium and magnesium, and overdrive cardiac pacing, electrical cardioversion, or defibrillation. Pharmacologic therapies include magnesium sulfate infusions. Treatment with antiarrhythmics should generally be avoided.
- Class Ia antiarrhythmic drugs (Vaughan Williams Classification), such as disopyramide, quinidine, and procainamide, and other class III drugs, such as amiodarone and sotalol, should not be given concomitantly with CORVERT Injection or within 4 hours postinfusion because of their potential to prolong refractoriness. In the clinical trials, class I or other class III antiarrhythmic agents were withheld for at least 5 half-lives prior to ibutilide infusion and for 4 hours after dosing, but thereafter were allowed at the physician's discretion.
- The potential for proarrhythmia may increase with the administration of CORVERT Injection to patients who are being treated with drugs that prolong the QT interval, such as phenothiazines, tricyclic antidepressants, tetracyclic antidepressants, and certain antihistamine drugs (H1 receptor antagonists).
- Of the nine (1.5%) ibutilide-treated patients with reports of reversible heart block, five had first degree, three had second degree, and one had complete heart block.
- Other clinically important adverse events with an uncertain relationship to CORVERT include the following (0.2% represents one patient): sustained monomorphic ventricular tachycardia (0.2%), nonsustained monomorphic ventricular tachycardia (4.9%), AV block (1.5%), bundle branch block (1.9%), ventricular extrasystoles (5.1%), supraventricular extrasystoles (0.9%), hypotension/postural hypotension (2.0%), bradycardia/sinus bradycardia (1.2%), nodal arrhythmia (0.7%), congestive heart failure (0.5%), tachycardia/sinus tachycardia/supraventricular tachycardia (2.7%), idioventricular rhythm (0.2%), syncope (0.3%), and renal failure (0.3%). The incidence of these events, except for syncope, was greater in the group treated with CORVERT than in the placebo group.
- Another adverse reaction that may be associated with the administration of CORVERT was nausea, which occurred with a frequency greater than 1% more in ibutilide-treated patients than those treated with placebo.
- The medical events reported for more than 1% of the placebo- and ibutilide-treated patients are shown in the following Table.
- In the post-cardiac surgery study, similar types of medical events were reported. In the 1 mg ibutilide fumarate treatment group (N=70), 2 patients (2.9%) developed sustained polymorphic ventricular tachycardia and 2 other patients (2.9%) developed nonsustained polymorphic ventricular tachycardia. Polymorphic ventricular tachycardia was not reported in the 73 patients in the 0.5 mg dose group or in the 75 patients in the 0.25 mg dose group.
- Digoxin
- Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range. Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials.
- Calcium channel blocking agents
- Coadministration of calcium channel blockers did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.
- Beta-adrenergic blocking agents
- Coadministration of beta-adrenergic blocking agents did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.
In 285 patients with atrial fibrillation or atrial flutter who were treated with CORVERT, the clearance of ibutilide was independent of renal function, as assessed by creatinine clearance (range 21 to 140 mL/min).
- 5% Dextrose Injection
- 0.9% Sodium Chloride Injection
- The following intravenous solution containers are compatible with admixtures of CORVERT Injection (0.1 mg/mL):
- polyvinyl chloride plastic bags
- polyolefin bags
- Admixtures of the product, with approved diluents, are chemically and physically stable for 24 hours at room temperature (15° to 30° C or 59° to 86° F) and for 48 hours at refrigerated temperatures (2° to 8°C or 36° to 46°F). Strict adherence to the use of aseptic technique during the preparation of the admixture is recommended in order to maintain sterility.
- Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m2 basis, at least 250 times the maximum recommended human dose.
- In the registration trials with CORVERT Injection, four patients were unintentionally overdosed. The largest dose was 3.4 mg administered over 15 minutes. One patient (0.025 mg/kg) developed increased ventricular ectopy and monomorphic ventricular tachycardia, another patient (0.032 mg/kg) developed AV block—3rd degree and nonsustained polymorphic VT, and two patients (0.038 and 0.020 mg/kg) had no medical event reports. Based on known pharmacology, the clinical effects of an overdosage with ibutilide could exaggerate the expected prolongation of repolarization seen at usual clinical doses. Medical events (eg, proarrhythmia, AV block) that occur after the overdosage should be treated with measures appropriate for that condition.
- CORVERT Injection is an isotonic, clear, colorless, sterile aqueous solution.
- Ibutilide fumarate has one chiral center, and exists as a racemate of the (+) and (−) enantiomers.
- The chemical name for ibutilide fumarate is Methanesulfonamide, N-{4-{4-(ethylheptylamino)-1-hydroxybutyl}phenyl}, (+) (−), (E)-2-butenedioate (1:0.5) (hemifumarate salt). Its molecular formula is C22H38N2O5S, and its molecular weight is 442.62.
- Ibutilide fumarate is a white to off-white powder with an aqueous solubility of over 100 mg/mL at pH 7 or lower.
- The structural formula is represented below:
- The pharmacokinetics of CORVERT Injection in patients with atrial flutter or atrial fibrillation are similar regardless of the type of arrhythmia, patient age, sex, or the concomitant use of digoxin, calcium channel blockers, or beta blockers.
- In healthy male volunteers, about 82% of a 0.01 mg/kg dose of ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered in the feces.
- Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by ω-oxidation followed by sequential β-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the ω-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model. The plasma concentrations of this active metabolite, however, are less than 10% of that of ibutilide.
- Treatment with intravenous ibutilide fumarate for acute termination of recent onset atrial flutter/fibrillation was evaluated in 466 patients participating in two randomized, double-blind, placebo-controlled clinical trials. Patients had had their arrhythmias for 3 hours to 90 days, were anticoagulated for at least 2 weeks if atrial fibrillation was present more than 3 days, had serum potassium of at least 4.0 mEq/L and QTc below 440 msec, and were monitored by telemetry for at least 24 hours. Patients could not be on class I or other class III antiarrhythmics (these had to be discontinued at least 5 half-lives prior to infusion) but could be on calcium channel blockers, beta blockers, or digoxin. In one trial, single 10-minute infusions of 0.005 to 0.025 mg/kg were tested in parallel groups (0.3 to 1.5 mg in a 60 kg person). In the second trial, up to two infusions of ibutilide fumarate were evaluated—the first 1.0 mg, the second given 10 minutes after completion of the first infusion, either 0.5 or 1.0 mg. In a third double-blind study, 319 patients with atrial fibrillation or atrial flutter of 3 hours to 45 days duration were randomized to receive single, 10-minute intravenous infusions of either sotalol (1.5 mg/kg) or CORVERT (1 mg or 2 mg). Among patients with atrial flutter, 53% receiving 1 mg ibutilide fumarate and 70% receiving 2 mg ibutilide fumarate converted, compared to 18% of those receiving sotalol. In patients with atrial fibrillation, 22% receiving 1 mg ibutilide fumarate and 43% receiving 2 mg ibutilide fumarate converted compared to 10% of patients receiving sotalol.
- Patients in registration trials were hemodynamically stable. Patients with specific cardiovascular conditions such as symptomatic heart failure, recent acute myocardial infarction, and angina were excluded. About two thirds had cardiovascular symptoms, and the majority of patients had left atrial enlargement, decreased left ventricular ejection fraction, a history of valvular disease, or previous history of atrial fibrillation or flutter. Electrical cardioversion was allowed 90 minutes after the infusion was complete. Patients could be given other antiarrhythmic drugs 4 hours postinfusion.
- Results of the first two studies are shown in the tables below. Conversion of atrial flutter/ fibrillation usually (70% of those who converted) occurred within 30 minutes of the start of infusion and was dose related. The latest conversion seen was at 90 minutes after the start of the infusion. Most converted patients remained in normal sinus rhythm for 24 hours. Overall responses in these patients, defined as termination of arrhythmias for any length of time during or within 1 hour following completed infusion of randomized dose, were in the range of 43% to 48% at doses above 0.0125 mg/kg (vs 2% for placebo). Twenty-four hour responses were similar. For these atrial arrhythmias, ibutilide was more effective in patients with flutter than fibrillation ( ≥ 48% vs ≤ 40%).
- The numbers of patients who remained in the converted rhythm at the end of 24 hours were slightly less than those patients who converted initially, but the difference between conversion rates for ibutilide compared to placebo was still statistically significant. In long-term follow-up, approximately 40 % of all patients remained recurrence free, usually with chronic prophylactic treatment, 400 to 500 days after acute treatment, regardless of the method of conversion.
- Patients with more recent onset of arrhythmia had a higher rate of conversion. Response rates were 42% and 50% for patients with onset of atrial fibrillation/flutter for less than 30 days in the two efficacy studies compared to 16% and 31% in those with more chronic arrhythmias.
- Ibutilide was equally effective in patients below and above 65 years of age and in men and women. Female patients constituted about 20% of patients in controlled studies.
- In a double-blind, parallel group study, 302 patients with atrial fibrillation (n=201) or atrial flutter (n=101) that occurred 1 to 7 days after coronary artery bypass graft or valvular surgery and lasted 1 hour to 3 days were randomized to receive two 10-minute infusions of placebo, or 0.25, 0.5 or 1 mg of ibutilide fumarate. Among patients with atrial flutter, conversion rates at 1.5 hours were: placebo, 4%; 0.25 mg ibutilide fumarate, 56%; 0.5 mg ibutilide fumarate, 61%; and 1 mg ibutilide fumarate, 78%. Among patients with atrial fibrillation, conversion rates at 1.5 hours were: placebo, 20%; 0.25 mg ibutilide fumarate, 28%; 0.5 mg ibutilide fumarate, 42%, and 1 mg ibutilide fumarate, 44%. The majority of patients (53% and 72% in the 0.5-mg and 1-mg dose groups, respectively) converted to sinus rhythm remained in sinus rhythm for 24 hours. Patients were not given other antiarrhythmic drugs within 24 hours of ibutilide fumarate infusion in this study.
- Single-dose 10 mL vial, 1 mg /10 mL (0.1 mg/mL) NDC 0009-3794-01
- ↑ Wood MA, Stambler BS, Ellenbogen KA, Gilligan DM, Perry KT, Wakefield LK et al. (1998) Suppression of inducible ventricular tachycardia by ibutilide in patients with coronary artery disease. Ibutilide Investigators. Am Heart J 135 (6 Pt 1):1048-54. PMID: 9630110 | Ibutilide
CHOICE OF PATIENTS
Patients with chronic atrial fibrillation have a strong tendency to revert after conversion to sinus rhythm and treatments to maintain sinus rhythm carry risks. Patients to be treated with CORVERT, therefore, should be carefully selected such that the expected benefits of maintaining sinus rhythm outweigh the immediate risks of CORVERT, and the risks of maintenance therapy, and are likely to offer an advantage compared with alternative management.
### Atrial Fibrillation or Atrial Flutter
- Dosing information
- The recommended dose based on controlled trials is outlined in the Table below. Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in the event of sustained or nonsustained ventricular tachycardia, or marked QT prolongation or QTc.
- In a trial comparing ibutilide and sotalol, 2 mg ibutilide fumarate administered as a single infusion to patients weighing more than 60 kg was also effective in terminating atrial fibrillation or atrial flutter.
- In the post-cardiac surgery study, one or two intravenous infusions of 0.5 mg (0.005 mg/kg per dose for patients weighing less than 60 kg) was effective in terminating atrial fibrillation or atrial flutter.
- Patients should be observed with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. Longer monitoring is required if any arrhythmic activity is noted. Skilled personnel and proper equipment, Proarrhythmia), such as a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during administration of CORVERT and subsequent monitoring of the patient.
- CORVERT Injection may be administered undiluted or diluted in 50 mL of diluent. CORVERT may be added to 0.9% Sodium Chloride Injection or 5% Dextrose Injection before infusion. The contents of one 10 mL vial (0.1 mg/mL) may be added to a 50 mL infusion bag to form an admixture of approximately 0.017 mg/mL ibutilide fumarate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
### Wolff-Parkinson-White syndrome
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS)
- Class of Recommendation: Class I
- Level of Evidence: Level C
- Dosing Information
- 1 mg IV over 10 minutes; repeat 1 mg when needed
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS)
- Class of Recommendation: Class IIb
- Level of Evidence: Level B
- Dosing Information
- 1 mg IV over 10 minutes; repeat 1 mg when needed
- Dosing Information
- Loading dosage: 0.005-0.02 mg/kg
- Maintenance doses: 0.001-0.004 mg/kg. [1]
- Like other antiarrhythmic agents, CORVERT Injection can induce or worsen ventricular arrhythmias in some patients. This may have potentially fatal consequences. Torsades de pointes, a polymorphic ventricular tachycardia that develops in the setting of a prolonged QT interval, may occur because of the effect CORVERT has on cardiac repolarization, but CORVERT can also cause polymorphic VT in the absence of excessive prolongation of the QT interval. In general, with drugs that prolong the QT interval, the risk of torsades de pointes is thought to increase progressively as the QT interval is prolonged and may be worsened with bradycardia, a varying heart rate, and hypokalemia. In clinical trials conducted in patients with atrial fibrillation and atrial flutter, those with QTc intervals >440 msec were not usually allowed to participate, and serum potassium had to be above 4.0 mEq/L. Although change in QTc was dose dependent for ibutilide, there was no clear relationship between risk of serious proarrhythmia and dose in clinical studies, possibly due to the small number of events. In clinical trials of intravenous ibutilide, patients with a history of congestive heart failure (CHF) or low left ventricular ejection fraction appeared to have a higher incidence of sustained polymorphic ventricular tachycardia (VT), than those without such underlying conditions; for sustained polymorphic VT the rate was 5.4% in patients with a history of CHF and 0.8% without it. There was also a suggestion that women had a higher risk of proarrhythmia, but the sex difference was not observed in all studies and was most prominent for nonsustained ventricular tachycardia. The incidence of sustained ventricular arrhythmias was similar in male (1.8%) and female (1.5%) patients, possibly due to the small number of events. CORVERT is not recommended in patients who have previously demonstrated polymorphic ventricular tachycardia (eg, torsades de pointes).
- During registration trials, 1.7% of patients with atrial flutter or atrial fibrillation treated with CORVERT developed sustained polymorphic ventricular tachycardia requiring cardioversion. In these clinical trials, many initial episodes of polymorphic ventricular tachycardia occurred after the infusion of CORVERT was stopped but generally not more than 40 minutes after the start of the first infusion. There were, however, instances of recurrent polymorphic VT that occurred about 3 hours after the initial infusion. In two cases, the VT degenerated into ventricular fibrillation, requiring immediate defibrillation. Other cases were managed with cardiac pacing and magnesium sulfate infusions. Nonsustained polymorphic ventricular tachycardia occurred in 2.7% of patients and nonsustained monomorphic ventricular tachycardias occurred in 4.9% of the patients.
- Proarrhythmic events must be anticipated. Skilled personnel and proper equipment, including cardiac monitoring equipment, intracardiac pacing facilities, a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during and after administration of CORVERT. Before treatment with CORVERT, hypokalemia and hypomagnesemia should be corrected to reduce the potential for proarrhythmia. Patients should be observed with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. Longer monitoring is required if any arrhythmic activity is noted. Management of polymorphic ventricular tachycardia includes discontinuation of ibutilide, correction of electrolyte abnormalities, especially potassium and magnesium, and overdrive cardiac pacing, electrical cardioversion, or defibrillation. Pharmacologic therapies include magnesium sulfate infusions. Treatment with antiarrhythmics should generally be avoided.
- Class Ia antiarrhythmic drugs (Vaughan Williams Classification), such as disopyramide, quinidine, and procainamide, and other class III drugs, such as amiodarone and sotalol, should not be given concomitantly with CORVERT Injection or within 4 hours postinfusion because of their potential to prolong refractoriness. In the clinical trials, class I or other class III antiarrhythmic agents were withheld for at least 5 half-lives prior to ibutilide infusion and for 4 hours after dosing, but thereafter were allowed at the physician's discretion.
- The potential for proarrhythmia may increase with the administration of CORVERT Injection to patients who are being treated with drugs that prolong the QT interval, such as phenothiazines, tricyclic antidepressants, tetracyclic antidepressants, and certain antihistamine drugs (H1 receptor antagonists).
- Of the nine (1.5%) ibutilide-treated patients with reports of reversible heart block, five had first degree, three had second degree, and one had complete heart block.
- Other clinically important adverse events with an uncertain relationship to CORVERT include the following (0.2% represents one patient): sustained monomorphic ventricular tachycardia (0.2%), nonsustained monomorphic ventricular tachycardia (4.9%), AV block (1.5%), bundle branch block (1.9%), ventricular extrasystoles (5.1%), supraventricular extrasystoles (0.9%), hypotension/postural hypotension (2.0%), bradycardia/sinus bradycardia (1.2%), nodal arrhythmia (0.7%), congestive heart failure (0.5%), tachycardia/sinus tachycardia/supraventricular tachycardia (2.7%), idioventricular rhythm (0.2%), syncope (0.3%), and renal failure (0.3%). The incidence of these events, except for syncope, was greater in the group treated with CORVERT than in the placebo group.
- Another adverse reaction that may be associated with the administration of CORVERT was nausea, which occurred with a frequency greater than 1% more in ibutilide-treated patients than those treated with placebo.
- The medical events reported for more than 1% of the placebo- and ibutilide-treated patients are shown in the following Table.
- In the post-cardiac surgery study, similar types of medical events were reported. In the 1 mg ibutilide fumarate treatment group (N=70), 2 patients (2.9%) developed sustained polymorphic ventricular tachycardia and 2 other patients (2.9%) developed nonsustained polymorphic ventricular tachycardia. Polymorphic ventricular tachycardia was not reported in the 73 patients in the 0.5 mg dose group or in the 75 patients in the 0.25 mg dose group.
- Digoxin
- Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range. Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials.
- Calcium channel blocking agents
- Coadministration of calcium channel blockers did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.
- Beta-adrenergic blocking agents
- Coadministration of beta-adrenergic blocking agents did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.
In 285 patients with atrial fibrillation or atrial flutter who were treated with CORVERT, the clearance of ibutilide was independent of renal function, as assessed by creatinine clearance (range 21 to 140 mL/min).
- 5% Dextrose Injection
- 0.9% Sodium Chloride Injection
- The following intravenous solution containers are compatible with admixtures of CORVERT Injection (0.1 mg/mL):
- polyvinyl chloride plastic bags
- polyolefin bags
- Admixtures of the product, with approved diluents, are chemically and physically stable for 24 hours at room temperature (15° to 30° C or 59° to 86° F) and for 48 hours at refrigerated temperatures (2° to 8°C or 36° to 46°F). Strict adherence to the use of aseptic technique during the preparation of the admixture is recommended in order to maintain sterility.
- Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m2 basis, at least 250 times the maximum recommended human dose.
- In the registration trials with CORVERT Injection, four patients were unintentionally overdosed. The largest dose was 3.4 mg administered over 15 minutes. One patient (0.025 mg/kg) developed increased ventricular ectopy and monomorphic ventricular tachycardia, another patient (0.032 mg/kg) developed AV block—3rd degree and nonsustained polymorphic VT, and two patients (0.038 and 0.020 mg/kg) had no medical event reports. Based on known pharmacology, the clinical effects of an overdosage with ibutilide could exaggerate the expected prolongation of repolarization seen at usual clinical doses. Medical events (eg, proarrhythmia, AV block) that occur after the overdosage should be treated with measures appropriate for that condition.
- CORVERT Injection is an isotonic, clear, colorless, sterile aqueous solution.
- Ibutilide fumarate has one chiral center, and exists as a racemate of the (+) and (−) enantiomers.
- The chemical name for ibutilide fumarate is Methanesulfonamide, N-{4-{4-(ethylheptylamino)-1-hydroxybutyl}phenyl}, (+) (−), (E)-2-butenedioate (1:0.5) (hemifumarate salt). Its molecular formula is C22H38N2O5S, and its molecular weight is 442.62.
- Ibutilide fumarate is a white to off-white powder with an aqueous solubility of over 100 mg/mL at pH 7 or lower.
- The structural formula is represented below:
- The pharmacokinetics of CORVERT Injection in patients with atrial flutter or atrial fibrillation are similar regardless of the type of arrhythmia, patient age, sex, or the concomitant use of digoxin, calcium channel blockers, or beta blockers.
- In healthy male volunteers, about 82% of a 0.01 mg/kg dose of [14C] ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered in the feces.
- Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by ω-oxidation followed by sequential β-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the ω-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model. The plasma concentrations of this active metabolite, however, are less than 10% of that of ibutilide.
- Treatment with intravenous ibutilide fumarate for acute termination of recent onset atrial flutter/fibrillation was evaluated in 466 patients participating in two randomized, double-blind, placebo-controlled clinical trials. Patients had had their arrhythmias for 3 hours to 90 days, were anticoagulated for at least 2 weeks if atrial fibrillation was present more than 3 days, had serum potassium of at least 4.0 mEq/L and QTc below 440 msec, and were monitored by telemetry for at least 24 hours. Patients could not be on class I or other class III antiarrhythmics (these had to be discontinued at least 5 half-lives prior to infusion) but could be on calcium channel blockers, beta blockers, or digoxin. In one trial, single 10-minute infusions of 0.005 to 0.025 mg/kg were tested in parallel groups (0.3 to 1.5 mg in a 60 kg person). In the second trial, up to two infusions of ibutilide fumarate were evaluated—the first 1.0 mg, the second given 10 minutes after completion of the first infusion, either 0.5 or 1.0 mg. In a third double-blind study, 319 patients with atrial fibrillation or atrial flutter of 3 hours to 45 days duration were randomized to receive single, 10-minute intravenous infusions of either sotalol (1.5 mg/kg) or CORVERT (1 mg or 2 mg). Among patients with atrial flutter, 53% receiving 1 mg ibutilide fumarate and 70% receiving 2 mg ibutilide fumarate converted, compared to 18% of those receiving sotalol. In patients with atrial fibrillation, 22% receiving 1 mg ibutilide fumarate and 43% receiving 2 mg ibutilide fumarate converted compared to 10% of patients receiving sotalol.
- Patients in registration trials were hemodynamically stable. Patients with specific cardiovascular conditions such as symptomatic heart failure, recent acute myocardial infarction, and angina were excluded. About two thirds had cardiovascular symptoms, and the majority of patients had left atrial enlargement, decreased left ventricular ejection fraction, a history of valvular disease, or previous history of atrial fibrillation or flutter. Electrical cardioversion was allowed 90 minutes after the infusion was complete. Patients could be given other antiarrhythmic drugs 4 hours postinfusion.
- Results of the first two studies are shown in the tables below. Conversion of atrial flutter/ fibrillation usually (70% of those who converted) occurred within 30 minutes of the start of infusion and was dose related. The latest conversion seen was at 90 minutes after the start of the infusion. Most converted patients remained in normal sinus rhythm for 24 hours. Overall responses in these patients, defined as termination of arrhythmias for any length of time during or within 1 hour following completed infusion of randomized dose, were in the range of 43% to 48% at doses above 0.0125 mg/kg (vs 2% for placebo). Twenty-four hour responses were similar. For these atrial arrhythmias, ibutilide was more effective in patients with flutter than fibrillation ( ≥ 48% vs ≤ 40%).
- The numbers of patients who remained in the converted rhythm at the end of 24 hours were slightly less than those patients who converted initially, but the difference between conversion rates for ibutilide compared to placebo was still statistically significant. In long-term follow-up, approximately 40 % of all patients remained recurrence free, usually with chronic prophylactic treatment, 400 to 500 days after acute treatment, regardless of the method of conversion.
- Patients with more recent onset of arrhythmia had a higher rate of conversion. Response rates were 42% and 50% for patients with onset of atrial fibrillation/flutter for less than 30 days in the two efficacy studies compared to 16% and 31% in those with more chronic arrhythmias.
- Ibutilide was equally effective in patients below and above 65 years of age and in men and women. Female patients constituted about 20% of patients in controlled studies.
- In a double-blind, parallel group study, 302 patients with atrial fibrillation (n=201) or atrial flutter (n=101) that occurred 1 to 7 days after coronary artery bypass graft or valvular surgery and lasted 1 hour to 3 days were randomized to receive two 10-minute infusions of placebo, or 0.25, 0.5 or 1 mg of ibutilide fumarate. Among patients with atrial flutter, conversion rates at 1.5 hours were: placebo, 4%; 0.25 mg ibutilide fumarate, 56%; 0.5 mg ibutilide fumarate, 61%; and 1 mg ibutilide fumarate, 78%. Among patients with atrial fibrillation, conversion rates at 1.5 hours were: placebo, 20%; 0.25 mg ibutilide fumarate, 28%; 0.5 mg ibutilide fumarate, 42%, and 1 mg ibutilide fumarate, 44%. The majority of patients (53% and 72% in the 0.5-mg and 1-mg dose groups, respectively) converted to sinus rhythm remained in sinus rhythm for 24 hours. Patients were not given other antiarrhythmic drugs within 24 hours of ibutilide fumarate infusion in this study.
- Single-dose 10 mL vial, 1 mg /10 mL (0.1 mg/mL) NDC 0009-3794-01
- ↑ Wood MA, Stambler BS, Ellenbogen KA, Gilligan DM, Perry KT, Wakefield LK et al. (1998) Suppression of inducible ventricular tachycardia by ibutilide in patients with coronary artery disease. Ibutilide Investigators. Am Heart J 135 (6 Pt 1):1048-54. PMID: 9630110 | https://www.wikidoc.org/index.php/Corvert | |
505f8bdc5d2175696277e284b9c9d8a88e826149 | wikidoc | Cosmogony | Cosmogony
Cosmogony is any scientific theory concerning the coming into existence, or origin, of the cosmos or universe, or about how what sentient beings perceive as "reality" came to be.
Usually, the philosophy of cause and effect needs a beginning, a first cause. Modal logic may only require a probability rather than a sequence of events. The concept of uncountable suggests an unknown somewhere between a finite number of likely rationales and an infinite number of possibilities.
From a sense of time as moving forward from yesterday to today and onward to tomorrow, there is again a suggestion of a prehistoric time before the first hominins.
The use of any system of thought or emotion to perceive reality suggests that some existences may precede others.
When more detail becomes available an existence may be transformed into something, an entity, a source, an object, a rocky object, or out of existence.
As a topic in astronomy, cosmogony deals with the origin of each astronomical entity.
Observation, for example, using radiation astronomy may provide some details.
Theoretical astronomy may provide some understanding, or at least some perspective.
# Astronomy
In astronomy, cosmogony refers to the study of the origin of particular astrophysical objects or systems, and is most commonly used in reference to the origin of the solar system.
# Cosmology
"Cosmology is the study of the structure and changes in the present universe, while the scientific field of cosmogony is concerned with the origin of the universe. Observations about our present universe may not only allow predictions to be made about the future, but they also provide clues to events that happened long ago when ... the cosmos began."
# Astrogony
The hominins of Earth may have observed and recorded a genealogy, or a begetting, of astronomical objects. Such a begetting may be called an astrogony.
Their astronomical observations may have suggested a genealogy, a progression from one astronomical object to another from the point of view of Earth. These objects may have been recorded and perhaps regarded based on what was observed.
# Sun-system astrogony
At least in the northern hemisphere of Earth, the local hominins may have observed, recorded, and regarded a progression of astronomical objects in the sky.
These objects have been remarkable enough that they have made their presence known to the locals of Earth. The time frame could be as short as 10,000 years or as long as a million.
From the current state of knowledge about astronomical objects around other stars, especially nearby, it may be possible to imagine similar objects in the solar system to account for these observations.
Since hominins are recording these phenomena, it is reasonable that these phenomena occurred during an oral history into a written history in some form.
## Watery abyss
The image at right is Chaos magno, a primordial or first Greek god.
For specific cosmogonic details the most important piece of Mesopotamian literature is the Babylonian epic story of creation, Enuma Elish (ibid., 60–72). Here, as in Genesis, the priority of water is taken for granted, i.e., the primeval chaos consisted of a watery abyss. The name for this watery abyss, part of which is personified by the goddess Tiamat, is the etymological equivalent of the Hebrew tehom (Gen. 1:2), a proper name that always appears in the Bible without the definite article. (It should be noted, however, that whereas "Tiamat" is the name of a primal generative force, tehom is merely a poetic term for a lifeless mass of water.) In both Genesis (1:6–7) and Enuma Elish (4:137–40) the creation of heaven and earth resulted from the separation of the waters by a firmament. The existence of day and night precedes the creation of the luminous bodies (Gen. 1:5, 8, 13, and 14ff.; Enuma Elish 1:38).
Neptune was the Roman god of water and the sea in Roman mythology and religion. He is the counterpart of the Greek god Poseidon. In the Greek-influenced tradition, Neptune was the brother of Jupiter. Italic Neptune has been securely identified as a god of freshwater sources as well as the sea.
The orbit of Neptune is the furthest from the Sun of the planets. Its orbit may be slowly increasing as it moves further away from the Sun.
## Skies
Uranus, Ouranos meaning "sky" or "heaven", was the primal Greek god personifying the sky. His equivalent in Roman mythology was Caelus. In Ancient Greek literature, Uranus or Father Sky was the son and husband of Gaia, Mother Earth. According to Hesiod's Theogony, Uranus was conceived by Gaia alone, but other sources cite Aether as his father.
The image at right is a painting by artist Giorgio Vasari (1511–1574). The main focus is on Cronus (Saturn) castrating Uranus (the Greek sky god). As both Uranus and Cronus are represented by men, this suggests that they were similar in nature. "he ancients’ religions and mythology speak for their knowledge of Uranus; the dynasty of gods had Uranus followed by Saturn, and the latter by Jupiter. ... It is quite possible that the planet Uranus is the very planet known by this name to the ancients. The age of Uranus preceded the age of Saturn; it came to an end with the “removal” of Uranus by Saturn. Saturn is said to have emasculated his father Uranus."
## Aphrodite
""Foam-born" Aphrodite is linked to the Moon through her epithet Pasiphaessa, the 'All-shinig One'. In Hesiod's Theogony, Aphrodite was conceived in the lap of the waves which were fertilized by semen from the severed genitals of Ouranos, Heaven, and was 'born in soft foam', as the Homeric Hymn to Aphrodite puts it.71"
"Democritus and Anaxagoras taught that there was a time when the Earth was without the Moon. Aristotle wrote that Arcadia in Greece, before being inhabited by the Hellenes, had a population of Pelasgians, and that these aborigines occupied the land already before there was a moon in the sky above the Earth; for this reason they were called Proselenes."
"Apollonius of Rhodes mentioned the time “when not all the orbs were yet in the heavens, before the Danai and Deukalion races came into existence, and only the Arcadians lived, of whom it is said that they dwelt on mountains and fed on acorns, before there was a moon.”"
"Plutarch wrote in The Roman Questions: “There were Arcadians of Evander’s following, the so-called pre-Lunar people.” Similarly wrote Ovid: “The Arcadians are said to have possessed their land before the birth of Jove, and the folk is older than the Moon.” Hippolytus refers to a legend that “Arcadia brought forth Pelasgus, of greater antiquity than the moon.” Lucian in his Astrology says that “the Arcadians affirm in their folly that they are older than the moon.”"
"Censorinus also alludes to the time in the past when there was no moon in the sky."
"he Moon’s formation took place away from the Earth,."
“The moon was formed independently of the earth and later captured, presumably by a three-body interaction, and these events were followed by the dissipation of the excess energy through tidal friction in a close encounter.”
"he Moon could not have been formed in orbit around the Earth".
"he planetary origin and capture of the Moon by the Earth becomes a strong dynamic possibility.”
## Golden age
"An, the oldest and highest of the Sumero-Babylonian gods, whose primordial age was "the year of abundance," signified Saturn, according to Jensen.6"
"There is one God, greatest among gods and men, neither in shape nor in thought like unto mortals ... He abides ever in the same place motionless, and it befits him not to wander hither and thither."
"The motif of Saturn handing over power to Jupiter derives, of course, from Hesiod's account of the succession of the gods in his Theogony, and his story of the five successive ages of men -- the first, or golden, age being under the reign of Kronos (Saturn) and the following ages being under the reign of Zeus (Jupiter) -- in his Works and Days (110ff.). These stories were often retold. Ovid, for example, combines in his Metamorphoses the stories in the Theogony and Works and Days, telling us how, "when Saturn was consigned to the darkness of Tartarus, and the world passed under the rule of Jove, the age of silver replaced that of gold."8"
Saturn is third furthest away from the Sun and its orbit may also be slowly getting further away from the Sun.
## Hermeneutes
Nabu (in Biblical Hebrew Nebo נבו) is the Assyrian and Babylonian god of wisdom and writing, worshipped by Babylonians as the son of Marduk and his consort, Sarpanitum, and as the grandson of Ea.
In Chaldean mythology, Nebo was a god whose worship was introduced into Assyria by Pul (Isa. 46:1; Jer. 48:1). The great temple at Birs Nimrud was dedicated to Nebo.
Hominins “lived without town or laws, speaking one tongue under the rule of Jove. But after Mercury explained the languages of men (whence he is called hermeneutes, ‘interpreter,’ for Mercury in Greek is called Hermes; he, too, divided the nations) then discord arose among mortals.”
“The meaning is clearly that Hermes invented one language for one people, another for another. The whole account reminds one of the Biblical Tower of Babel.”
"In my understanding Mercury was once a satellite of Jupiter, or possibly of Saturn. In the course of the events which followed Saturn’s interaction with Jupiter and its subsequent disruption, Mercury was pushed from its orbit and was directed to the sun by Jupiter. It could, however, have been a comet and the entwined snakes of the caduceus may memorialize the appearance it had when seen by the inhabitants of the Earth."
## Silver and iron ages
In the ancient Greek religion, Zeus (Ancient Greek is the "Father of Gods and men". He is the god of sky and thunder in Greek mythology. His Roman counterpart is Jupiter and Etruscan counterpart is Tinia. Zeus is the child of Cronus and Rhea, and the youngest of his siblings. In most traditions he is married to Hera, although, at the oracle of Dodona, his consort is Dione: according to the Iliad, he is the father of Aphrodite by Dione.
## Morning star
The Greeks thought of the two as separate stars, Phosphorus and Hesperus , until the time of Pythagoras in the sixth century BC.
The Romans designated the morning aspect of Venus as Lucifer, literally "Light-Bringer", and the evening aspect as Vesper.
"During a rare period of very low density solar outflow, the ionosphere of Venus was observed to become elongated downstream, rather like a long-tailed comet. ... Under normal conditions, the solar wind has a density of 5 - 10 particles per cubic cm at Earth's orbit, but occasionally the solar wind almost disappears, as happened in May 1999. ... A rare opportunity to examine what happens when a tenuous solar wind arrives at Venus came 3 - 4 August 2010, following a series of large coronal mass ejections on the Sun. NASA's STEREO-B spacecraft, orbiting downstream from Venus, observed that the solar wind density at Earth's orbit dropped to the remarkably low figure of 0.1 particles per cubic cm and persisted at this value for an entire day."
"The observations show that the night side ionosphere moved outward to at least 15 000 km from Venus' centre over a period of only a few hours," said Markus Fraenz, also from the Max Planck Institute for Solar System Research, who was the team leader and a co-author of the paper. "It may possibly have extended for millions of kilometres, like an enormous tail."
"Although we cannot determine the full length of the night-side ionosphere, since the orbit of Venus Express provides limited coverage, our results suggest that Venus' ionosphere resembled the teardrop-shaped ionosphere found around comets, rather than the more symmetrical, spherical shape which usually exists."
"The side of Venus' ionosphere that faces away from the sun can billow outward like the tail of a comet, while the side facing the star remains tightly compacted, researchers said. ... "As this significantly reduced solar wind hit Venus, Venus Express saw the planet’s ionosphere balloon outwards on the planet’s ‘downwind’ nightside, much like the shape of the ion tail seen streaming from a comet under similar conditions," ESA officials said in a statement today (Jan. 29). It only takes 30 to 60 minutes for the planet's comet-like tail to form after the solar wind dies down. Researchers observed the ionosphere stretch to at least 7,521 miles (12,104 kilometers) from the planet, said Yong Wei, a scientist at the Max Planck Institute in Katlenburg, Germany who worked on this research."
## The Children of Heracles
"Violent earthshocks and other perturbations of nature destroyed the Mycenaean citadels and left their defenders exposed to the assaults of migrant tribes, dislodged in the same upheavals, and calling themselves the Children of Heracles, or Mars."
"At the end of the eighth century and the beginning of the seventh century before the present era, when every fifteen years Mars was approaching dangerously close to the Earth, Isaiah prophesied “the day of the Lord’s vengeance,” in which day “the streams shall be turned into pitch, and the dust thereof into brimstone, and the land thereof shall become burning pitch.” (8) A curse upon man and his land was that “brimstone shall be scattered upon his habitation.” (9) “Upon the wicked he shall rain pitch, fire and brimstone, and a horrible tempest.” (10) This eschatological vision was alive with Ezekiel in the days of the Babylonian Exile. He spoke about “an overflowing rain, and great hailstones , fire and brimstone.” (11) "
# Sun
Apparently from about 2687 b2k forward in time the only major astronomical objects, that is, objects with a visible disk, as viewed from Earth are the Sun and the Moon. All others are lesser in spectacle and regard. Comets still occur.
# Planetary sciences
"An aspect of current cosmogonic models is reviewed which until a few years ago had received little consideration: the transformation by accretion of kilometer-size objects into bodies comparable in size to the earth."
# Colors
"We present a 9 million star color-magnitude diagram (9M CMD) of the Large Magellanic Cloud (LMC) bar. The 9M CMD is assembled from MACHO Project two-color instrumental photometry calibrated to the standard Kron-Cousins V and R system (Alcock et al. 1999)."
"It is important to study the stellar populations of nearby galaxies like the LMC in order to understand the processes of galaxy evolution. In particular, the formation of exponential disks is an outstanding problem in cosmogony (e.g. Freeman 1970, Fall & Efstathiou 1980, Dalcanton et al. 1997). By studying the low-mass RR Lyrae variables, we make inferences to the nature of the old and metal-poor LMC field population. This elusive LMC population probes the formation epoch of the LMC, with general implications for cosmogony."
"Juno is also carrying a colour camera, promising Earthlings "the first detailed glimpse of Jupiter's poles"."
"The Juno mission was launched on 05 August 2011 to study Jupiter from polar orbit for approximately one year beginning in 2016. The primary scientific objectives of the mission are to collect data to investigate: (1) the formation and origin of Jupiter's atmosphere and the potential migration of planets through the measurement of Jupiter's global abundance of oxygen (water) and nitrogen (ammonia); (2) variations in Jupiter's deep atmosphere related to meteorology, composition, temperature profiles, cloud opacity, and atmospheric dynamics; (3) the fine structure of Jupiter's magnetic field, providing information on its internal structure and the nature of the dynamo; (4) the gravity field and distribution of mass inside the planet; and (5) Jupiter's three-dimensional polar magnetosphere and aurorae. Juno carries eight experiments to achieve these objectives."
# Minerals
"A new cosmogony proposed by author bases on idea that formation of planets takes place on pre-solar stage of evolution of proto-stellar/proto-planetary nebula. The hypothesis predicts that all particles in one stream are of the same mineral composition and of the same density."
# Theoretical cosmogony
Def.
- the "study of the origin, and sometimes the development, of the universe or the solar system, in astrophysics, religion, and other fields",
- any "specific theory, model, , of the origin of the universe", or
- the "creation of the universe" is called a cosmogony.
Def. the "origin and development of the cosmos" is called a cosmogenesis.
Def.
- "the study of the physical universe, its structure, dynamics, origin and evolution, and fate",
- "a metaphysical study into the origin and nature of the universe", or
- a "particular view (cultural or religious) of the structure and origin of the universe", is called a cosmology.
## Cold dark matter cosmogony
Consider a universe "dominated by neutrinos and 'cold dark matter'".
"The evidence for unseen mass suggests that the cosmological density parameter Ω is at least 0.1-0.2 Einstein-de-Sitter 'flat' universe with Ω = 1 can only be reconciled with the data if the galaxies are more 'clumped' than the overall mass distribution, and are poor tracers of the unseen mass even on scales of several Mpc."
"Particle physicists have other particles ‘in reserve’ which could make a substantial (non-baryonic) contribution to Ω, but which differ from neutrinos in that their freestreaming velocity is negligible, so that small-scale adiabatic perturbations are not phase-mixed away. Such particles can be described as ‘cold dark matter’, in contrast to neutrinos whose free streaming velocity renders them ‘hot’."
"There is no shortage of ‘cold dark matter’ candidate particles—although each of them is highly speculative, to say the least. The motivation for nonetheless considering the hypothesis that the universe is dominated by cold dark matter is that it leads to a cosmogonic scheme that avoids the difficulties of the neutrino-dominated scheme and correctly predicts many of the observed properties of galaxies, including their range of masses, irrespective of the identity of the cold particle (Peebles 1984; Blumenthal et al. 1984)."
"In cosmogonic schemes involving cold dark matter, there is no equally obvious process that might inhibit galaxy formation in the incipient voids".
# Entities
"I shall introduce the themes with several quotations which are representative of a number of popular contemporary writings on cosmogony. ... First, they each personify an entity or concept-'the laws of physics', 'chance' and 'natural selection' respectively."
# Sources
"The amount of energy needed is not exorbitant; however there are physical problems of coupling it to the gas in a suitable way. For instance, the most obvious possibility is photoionization. The temperature attained depends on the mean energy of an ejected photoelectron, and in a typical HII region is never more than a few times 104 K. At first sight, one might suppose that a source spectrum peaking sharply at photon energies 100 eV (e.g. a blackbody spectrum with Τ 106 K) would yield a correspondingly hot HII region. But this is not so (except in the implausible case of very sudden ionization) because a photoelectron would then collisionally ionize several neutral atoms before they had a chance to be photoionized, the energy of each photoelectron consequently being shared among several electrons and ions (Bardeen 1984, personal communication)."
# Objects
Notation: let the symbol h, or h, "denotes the Hubble constant in units of 100 km s–1 Mpc–1".
"Most of the initial baryons might have been incorporated in a population of stars that were either pregalactic, or else formed during the initial collapse phase of a protogalaxy: these stars, or their remnants, could perhaps now have a high M/L and contribute to the unseen mass. Ideally, one would like to be able to calculate what happens when a cloud of 105–107 M⊙ condenses out from primordial material: does it form one (or a few) supermassive objects , or does fragmentation proceed efficiently down to low-mass stars?"
"An uncertainty in the evolution of massive or supermassive stars is the amount of loss during H-burning; however the hypothesis that most mass goes into very massive objects (VMOs) of greater than about 103 Μ⊙ is compatible with the nucleosynthesis constraints."
"Other possible ‘escape clauses’ can be invoked—for instance, there might be large-amplitude inhomogeneities in the initial baryon distribution, such that all the baryonic material we can now sample comes from underdense regions, the overdense regions having turned into dark population III objects (Rees 1983)."
# Strong forces
"Due to the very low energy of the colliding protons in the Sun, only states with no angular momentum (s-waves) contribute significantly. One can consider it as a head-on collision, so that angular momentum plays no role. Consequently, the total angular momentum is the sum of the spins, and the spins alone control the reaction. Because of Pauli's exclusion principle, the incoming protons must have opposite spins. On the other hand, in the only bound state of deuterium, the spins of the neutron and proton are aligned. Hence a spin flip must take place The strength of the nuclear force which holds the neutron and the proton together depends on the spin of the particles. The force between an aligned proton and neutron is sufficient to give a bound state, but the interaction between two protons does not yield a bound state under any circumstances. Deuterium has only one bound state."
The "force acting between the protons and the neutrons the strong force".
"A potential of 36 MeV is needed to get just one energy state."
The width of a bound proton and neutron is "2.02 x 10-13 cm".
# Electromagnetics
"The first systematic attempt to base a theory of the origin of the solar system on electromagnetic or hydromagnetic effects was made in Alfvén (1942). The reason for doing so was that a basic difficulty with the old Laplacian hypothesis: how can a central body (Sun or planet) transfer angular momentum to the secondary bodies (planets or satellites) orbiting around it? It was demonstrated that this could be done by electromagnetic effects. No other acceptable mechanism has yet been worked out. the electromagnetic transfer mechanism has been confirmed by observations, as described in the monograph Cosmic Plasma (Alfvén, 1981, pp. 28, 52, 53 0."
"If charged particles (electrons, ions or charged grains) move in a magnetic dipole field - strong enough to dominate their motion - under the action of gravitation and the centrifugal force, they will find an equilibrium in a circular orbit if their centrifugal force is 2/3 of the gravitational force The consequence of this is that if they become neutralized, so that electromagnetic forces disappear, the centrifugal force is too small to balance the gravitation. Their circular orbit changes to an elliptical orbit with the semi-major axis a = 3/4a0 and e = 1/3 (where a0 is the central distance where the neutralization takes place Collisional (viscous) interaction between the condensed particles will eventually change the orbit into a new circular orbit with a = 2/3a0 and e = 0."
"If there is plasma in the region matter in the 2/3-. matter in the region will produce a shadow in the region".
# Weak forces
"If Egrav is the gravitational energy of a star and Etherm is its total thermal energy, then the binding energy of the star is given by Ebind = Egrav + Etherm < 0, where Egrav is negative and Etherm is positive. The temperature of the cores of stars is determined by the balance between the gravitational attraction and the gas pressure. Since the gravitational energy determines the gravitational force and the thermal energy determines the gas pressure, it is obvious that there exists a relation between the two. If the gas in the star behaves like an ideal gas, then 2Etherm + Egrav = 0, a result which is known as the viral theorem.14 The theorem is extremely simple and can be derived in just 6 lines.15"
"14Poincaré, H., Lecons sur les hypothéses cosmogoniques, Librarie Scientifique, A. Hermann, 1811. This theorem is also the basis for the negative effective specific heat of stars. Only at this point do we need the Clausius connection between kinetic energy and temperature . The temperature is given by the kinetic energy divided by the Boltzmann constant. If the star loses energy L, it must contract, i.e., reduce its radius, and consequently lower its negative gravitational energy Egrav. The kinetic energy T is then more positive, so the temperature rises. In this way the star can lose energy and increases its temperature, in contrast to normal matter. This is one of Eddington's famous paradoxes about stars: they lose energy and heat up."
"15 See Jeans, Astronomy and Cosmogony, Cambridge University Press, 1929, p. 67."
"In 1937, Gamow and Teller36 postulated an extremely important addition to Fermi's β-decay theory. They realized that there are cases where the Fermi theory fails to explain the decays. Consequently, Gamow and Teller proposed an ad hoc solution to explain the discrepancy. the difference between the Fermi and Gamow-Teller interactions as they are expressed in the reaction relevant to stars, namely p + p → 2D + e+ + ν. In a Fermi interaction which converts a proton into a neutron and vice versa, the sum of all spins of the particles does not change. In a Gamow-Teller interaction, the total spin must change by one unit."
"What Gamow and Teller actually discovered was that the weak force, which is responsible for the β-decay, has two different components which behave and act differently and have different strengths. A good example is the electromagnetic force which can appear as a Coulomb force between electric charges or as a magnetic force acting on moving charges. The electric and magnetic components behave differently. Fierz37 generalized the theory by combining the Fermi and Gamow-Teller conditions into a unified theory of this complicated force."
"37Fierz, M., Zeit. für Phys. 194, 553 (1937)."
# Continua
"The problem of formation of generic structures in the Universe is addressed, whereby first the kinematics of inertial continua for coherent initial data is considered. The generalization to self-gravitating continua is outlined focused on the classification problem of singularities and metamorphoses arising in the density field."
# Emissions
"The prismoidal method provides a good approximation of the dust emission peak for cold sources , but probably overestimates the long-wavelength flux for warmer, flatter SED sources , resulting in a bias toward lower Tbol."
"In a binary formed via gravitational fragmentation, we would expect the separation to correspond to the local Jeans length (Jeans 1928):"
"where cs is the local sound speed, and μp = 2.33 and n are the mean molecular weight and mean particle density, respectively. A Jeans length of 4200 AU would require a relatively high density (n ~ 6 x 105 cm−3, assuming cs = 0.2 km s−1). The mean density of the Per-Bolo 102 core, measured within an aperture of 104 AU, is 4 x 105 cm−3, close to the required value."
# Absorptions
"Recent years have seen the emergence of a standard model for the growth of structure – the hierarchical clustering model – in which the gravitational effects of dark matter drive the evolution of structure from the near-uniform recombination epoch until the present day. Simple models for galaxy formation in the context of these CDM cosmogonies have been remarkably successful in reproducing the properties of the local galaxy population (Kauffmann, White, & Guiderdoni 1993; Cole et al. 1994) and have been extended to predict the sizes, surface densities and circular velocities of spiral galaxy disks (Dalcanton, Spergel, & Summers 1997; Mo, Mao, & White 1998)."
"For quenched galaxies, the Hα absorption trough is deep and can be traced through the nucleus and along the major axis. It extends to a radius at or beyond 2 Rd in all but three cases. This makes it possible to determine a velocity width from the optical spectrum as is done for emission line flux, with appropriate corrections between stellar and gas velocities (see discussion in Paper I, also Neistein, Maoz, Rix, & Tonry, 1999). In the few cases where a velocity width can also be measured from the H I data, it is found to be in good agreement with that taken from the Hα absorption line flux."
"The extent of the Hα absorption trough along the major axes of the quenched spirals is significantly more truncated than the distribution of the Hα emission line for H I deficient galaxies. The distribution of the old stellar population contributing to the Hαext absorption of the quenched spirals may be partly responsible for this extreme truncation, if disks are built up from the inside to the outside over time."
# Bands
"The hydromagnetic approach led to the discovery of two important observational regularities in the solar system: (1) the band structure , and (2) the cosmogonic shadow effect (the two-thirds fall down effect)."
# Backgrounds
"Although we cannot confidently predict what these so-called ‘population ΙΙI’ stars would be like (Kashlinsky & Rees 1983), there are several constraints which, in combination, imply that if there are enough of them to provide the unseen mass, the individual masses must either be less than 0.1 M⊙ or else in the range 103–106 Μ⊙. Masses above ~ 0.1 M⊙ would contribute too much background light unless they had all evolved and died, leaving dark remnants. But the remnants of ordinary massive stars of 10–100 M⊙ would produce too much material in the form of heavy elements."
# Meteors
Current "knowledge of the orbital structure of the outer solar system, mostly slanted towards that information which has been learned from the Canada-France-Ecliptic Plane
Survey (CFEPS: www.cfeps.net). Based on our current datasets (inside and outside CFEPS) outer solar system modeling is now entering the erra of precission cosmogony."
"Since the discovery of the first members of the Kuiper belt (Jewitt and Luu, 1993) the growth in knowledge of the outer solar system has been marked (perhaps driven) by the discovery of individual objects whose dynamics pointed at previously unknown reserviours; for example: 1993 RO and the plutinos, 1996 TL66 and the ‘scattering disk’, 2003 CR103 and the detectatch disk, 90377 Sedna and the Inner Oort Cloud."
The "‘main Kuiper belt’ is populated by dynamically ‘hot’ and ‘cold’ subcomponents
(Brown 2001), the dyncamically ‘cold’ component is further sub-divided into a ‘stirred’ and ‘kernel’ component (Petit et al., 2011). The plane of the Ecliptic does not match the ecliptic or invariable planes of the solar sytem (Elliot et al., 2005). Collisional families exists, Haumea (Brown et al., 2007)."
# Cosmic rays
"Violent activity and Supernovae generate cosmic ray (suprathermal) particles. The speeds of individual particles may be ~ c, and their energy density, if they diffused uniformly through the universe, could well exceed 100 eV per baryon. Subrelativistic particles would be slowed down, and would transmit their energy to the thermal component. However, the relativistic particles could themselves exert a pressure if they were coupled (e.g. via magnetic fields) so that they constituted, with the thermal gas, a composite fluid, to which they contributed most of the pressure. Although there is here even less problem in fulfilling the energy density requirement than there is for ultraviolet radiation, there is uncertainty about how uniformly it can spread. If the cosmic-ray energy remains concentrated around the sources, it is irrelevant in the present context ; at the other extreme, if the particles diffuse too freely, they do not couple well enough to protogalactic gas for their pressure gradients to oppose gravitational collapse."
# Neutrons
"Primordial nucleosynthesis depends on two things: the expansion timescale at 0.1–1 MeV and the baryon density at that same epoch (which is proportional to Ωbh2). The predicted 4He abundance is rather insensitive to the matter density: for Ωbh2 ≳ 10–2 the density of baryons is high enough to ensure that most of the neutrons that survive when the neutron-proton ratio ‘freezes out’ at kT ≃ 1 MeV get incorporated
in 4He."
# Protons
"It is fair to note, however, that almost all theories which invoke non-baryonic matter require some level of coincidence in order that the luminous and unseen mass contribute comparable densities (to within one or two powers often). For instance, in a neutrino-dominated universe, (mv/mproton) must be within a factor ~ 10 of nb/nγ. The only model that seems to evade this requirement is Witten’s (1984) idea that the quark-hadron phase transition may leave comparable amounts of material in ‘ordinary’ baryons and in ‘nuggets’ of exotic matter."
# Electrons
"Various gaps and density minima have been observed in the Saturnian ring system. Attempts have been made to attribute these observations to gravitational resonances with the inner satellites, thus causing the removal of particles from the dark regions of the ring system (Alexander 1953, 1962)."
"According to an alternative theory (Alfvén and Arrhenius, 1976) the observed dark regions are the result of a 'cosmogonic shadow effect' produced by the 'two-thirds fall-down mechanism'. The basis of this mechanism is the following: plasma contained in the magnetic dipole field of a central (celestial) body is brought up to a state of partial corotation. In the corotating frame of reference, the plasma experiences an outward centrifugal force which drives a current of density J.
The "charge on a dust particle changes with latitude, i.e., from the equator up to the '2/3' points. The electrostatic charging of dust particles in a plasma charging processes such as photo-emission, field emission thermo-ionic emission, and secondary emission can be neglected contributions to the total charging current come mainly from thermal fluxes of electrons and ions, i.e., I = I_i + I_e. A dust grain acquires its equilibrium charge -qe (q > 0) when"
"The electron and ion currents are given by (Mendis et al., 1984)"
"where y = -q(e2/kTC), C being the grain capacitance rg is the grain radius, n_e the average electron density, and n_p is the average ion (plasma) density."
# Positrons
"The two conversions of protons into neutrons are assumed to take place inside the nucleus, and the extra positive charge is emitted as a positron."
# Neutrinos
"If neutrinos have negligible rest mass, the present density expected for relic neutrinos from the big bang is nν = 110 (Tγ/2.7 K)3 cm–3 for each two-component species. This is of order the photon density nγ, differing just by a factor 3/11 (i.e. a factor 3/4 because neutrinos are fermions rather than bosons, multiplied by 4/11, the factor by which the neutrinos are diluted when e+–e– annihilation boosts the photon density). This conclusion holds for non-zero masses, provided that mvc2 is far below the thermal energy (~ 5 MeV) at which neutrinos decoupled from other species and that the neutrinos are stable for the Hubble time. Comparison with the baryon density, related to Ω via nb = 1.5 x 10–5 Ωb h2 cm–3, shows that neutrinos outnumber baryons by such a big factor that they can be dynamically dominant over baryons even if their masses are only a few electron volts. In fact, a single species of neutrino would yield a contribution to Ω of Ωv = 0.01 h–2 (mv)eV, so if h = 0.5, only 25 eV is sufficient to provide the critical density."
"Neutrinos of nonzero mass would be dynamically important not only for the expanding universe as a whole but also for large bound systems such as clusters of galaxies. This is because they would now be moving slowly: if the universe had cooled homogeneously, primordial neutrinos would now be moving at around 200 (mv)-1eV km s–1. They would be influenced even by the weak (~ 10–5 c2) gravitational potential fluctuations of galaxies and clusters. If the three (or more) types of neutrinos have different masses, then the heaviest will obviously be gravitationally dominant, since the numbers of each species should be the same."
# Gamma rays
"Over the last few years, the cold dark matter cosmogony has become a fiducial model for the formation of structure. The problem with detecting dark matter using annihilation radiation gamma rays has been that the expected signal is comparable to the background (Stecker 1988) and it would be difficult to separate a "cosmic-ray halo" from a dark halo."
"The flux of annihilation gamma rays is given by"
"where (\sigma V) is the cross section, D is the distance to the dSph's, m_\lambda is the WIMP's mass, X is the average number of gamma rays in excess of 100 MeV per annihilation and depends weakly on m_\lambda (Stecker 1988)."
In March 2010 it was announced that active galactic nuclei are not responsible for most gamma-ray background radiation. Though active galactic nuclei do produce some of the gamma-ray radiation detected here on Earth, less than 30% originates from these sources. The search now is to locate the sources for the remaining 70% or so of all gamma-rays detected. Possibilities include star forming galaxies, galactic mergers, and yet-to-be explained dark matter interactions.
# X-rays
"The X-rays from clusters of galaxies reveal that hot gas is present, with temperature such that the sound speed is similar to the virial velocity (Forman & Jones 1982). The amount of gas in the cores is not enough to satisfy the virial theorem—it is comparable with the amount in ‘luminous’ galactic material. However, gas could provide a bigger fraction of the mass in the outlying parts—because the X-ray emission per unit mass goes as n, diffuse gas is less conspicuous. (The X-ray spectrum shows that this gas has a temperature consistent with being gravitationally bound in a cluster potential whose depth is inferred from the velocity dispersions of the galaxies. This fact argues against ‘radical’ ideals, such as that the clusters are not virialized, or that the galactic redshifts are not true velocity indicators.)"
"Gas that gets heated to kT 10 keV would not be confined in cluster potential wells, but would constitute a roughly homogeneous intercluster medium. It has been suggested that such a gas is the prime contributor to the X-ray background at > 10 keV; even if it is not, the observed strength of this background constrains the density and thermal history of any such gas. More gas can be ‘hidden’ in intergalactic space if it is ultra-hot (~ 40 keV) rather than at a lower temperature. Indeed, there could be almost enough such gas to provide the critical density if it were heated up at a redshift z < 3. The difficulties with this idea stem from the very large energy input and special thermal history necessary to avoid conflict with various observational constraints (Fabian & Kembhavi 1982)."
# Ultraviolets
"What about radiation pressure? The microwave background is of course the dominant energy density. However, it is too weakly coupled (via Thomson scattering) to exert any effective damping on non-Hubble flows at epochs z ≲ 100. A somewhat more hopeful possibility is the pressure of Lyman line radiation. If the protogalactic gas is not completely ionized, most of the cosmic background emitted in the ultraviolet would have been transformed into Lyman alpha, whose energy density could exceed 100 eV per ion. The cross-section is certainly large enough to ensure that radiation has a short mean free path. However, in a collapsing (or expanding) medium, the photons would be shifted out of the line wings after the density has changed by a fraction (~ 3Δν/ν). Even though the line width may be as much as 50 Å, this means that the effectively trapped energy density at any instant would be only a tenth of the total radiation background density in the ultraviolet."
# Opticals
"For outside wave fields of the Moon and the Earth accept seismic and acoustic waves which characteristic frequencies first of all coincide with frequencies of orbital and own rotation of cosmogony objects (planets and their satellites, multiple star systems, pulsars)."
"Besides wave (acoustic) processes in the top Earth atmosphere and also those from that its are accompanied also by optical effects (polar lights) and strongly connected with gas dust streams acting ."
# Visuals
"Masses above ~ 0.1 M⊙ would contribute too much background light unless they had all evolved and died, leaving dark remnants."
# Violets
"The abundance ratios of stable isotopes of the light elements in comets may provide clues of cosmogonical significance."
"In 1997 we observed comet Hale-Bopp with the 2.6 m Nordic Optical Telescope on La Palma, Canary Islands, with a view to estimating the 12C/13C abundance ratio. About twenty high-resolution (λ /Δ λ ~ 70000) spectra of the strong CN Violet (0,0) band were secured with the SOFIN spectrograph from 7 to 13 April. The heliocentric and geocentric distances of the comet were then close to 0.9 AU and 1.4 AU, respectively. While the data do show the expected lines of the 13C14N isotopic molecule, we have been surprised to find in addition a number of very weak features, which are real and turn out to be positioned very near to the theoretical wavelengths of lines pertaining to the R branch of 12C15N."
# Blues
"Modern data on Coma and other clusters bear out the same trend : the overall mass-to-blue-light ratio M/L within the virialized parts of clusters is ~ 300 h ; but for the stellar content of ordinary luminous galaxies it is 1–10."
# Cyans
"The ices of Callisto do not seem to have exploded at all."
If the age of the Galilean satellites is "cosmogonic ( ≈ 4 x 109 yr) it is clear that there are no grounds for postulating a cosmogonic crater age "
"The comet data suggest that there should be released simultaneously about two orders of magnitude less (QCN/QH2O ≈ 10-3 by Schloerb et al. (1987)) of cyan compounds, ≈ 2 x 1015 g."
# Greens
"There the deceased states that “I have strewed green stones",8 most likely with the intention of identifying himself with the time when Amun became the supreme god of the Egyptian pantheon, the creation “He (Amun) created the heaven and made it luminous through the stars."11 In the myths and mythologems discussed above, the stars came into being in a later phase of cosmogony. However, we also know of myths reflecting different views. stage of the birth of the universe.12"
# Yellows
"The behavior of groups of massive stars in open clusters is examined. The high concentration of binaries and yellow giants toward the center of the open cluster NGC 2632 (Praesepe) is not a singular phenomenon. It can be found in the Hyades and in the Coma-Berenices cluster, which are nearly of equal age, but not in younger and older objects. This phenomenon depending on the mean mass of a star group, its evolutionary phase, the mean age of the cluster and the time of star formation within it, can be explained by the diagram of the evolution of star clusters, i.e., by cosmogonic reasons. It is not caused by gravitational effects."
# Oranges
"Then, as that long period was drawing to a close, these Gods directed the orange colored force of life into the smaller matrices of Divine Mind and brought into physical being the lichens and the mussels and all the lowest forms of life on land and sea."
# Reds
"To prepare for the Dawn spacecraft's visit to Vesta, astronomers used Hubble's Wide Field Planetary Camera 2 to snap new images of the asteroid. The image at right was taken on May 14 and 16, 2007. Using Hubble, astronomers mapped Vesta's southern hemisphere, a region dominated by a giant impact crater formed by a collision billions of years ago. The crater is 285 miles (456 kilometers) across, which is nearly equal to Vesta's 330-mile (530-kilometer) diameter. If Earth had a crater of proportional size, it would fill the Pacific Ocean basin. The impact broke off chunks of rock, producing more than 50 smaller asteroids that astronomers have nicknamed "vestoids." The collision also may have blasted through Vesta's crust. Vesta is about the size of Arizona."
"Previous Hubble images of Vesta's southern hemisphere were taken in 1994 and 1996 with the wide-field camera. In this new set of images, Hubble's sharp "eye" can see features as small as about 37 miles (60 kilometers) across. The image shows the difference in brightness and color on the asteroid's surface. These characteristics hint at the large-scale features that the Dawn spacecraft when it arrives at Vesta."
"Hubble's view reveals extensive global features stretching longitudinally from the northern hemisphere to the southern hemisphere. The image also shows widespread differences in brightness in the east and west, which probably reflects compositional changes. Both of these characteristics could reveal volcanic activity throughout Vesta. The size of these different regions varies. Some are hundreds of miles across."
"The brightness differences could be similar to the effect seen on the Moon, where smooth, dark regions are more iron-rich than the brighter highlands that contain minerals richer in calcium and aluminum. When Vesta was forming 4.5 billion years ago, it was heated to the melting temperatures of rock. This heating allowed heavier material to sink to Vesta's center and lighter minerals to rise to the surface."
"Astronomers combined images of Vesta in two colors to study the variations in iron-bearing minerals. From these minerals, they hope to learn more about Vesta's surface structure and composition."
"The simplest model for the genesis of the HED meteorites involves a series of partial melting and crystallization events of a small parent body whose bulk composition is more or less consistent with cosmic abundances but is depleted in the moderately volatile elements Na and K ."
"Why should both Vesta and the Moon be rich in oxidized Fe but depleted in Na and K?"
"How did the HEDs get here from Vesta? The discovery of a string of Vesta-like asteroids in orbits linking Vesta to nearby orbital resonances has shown that arguments for material originating at Vesta to reach Earth-crossing orbits are valid."
"An alternative theory is based on electromagnetic heating during an episode of strong solar wind from the early proto-Sun when our star experienced a T Tauri phase, as predicted by modern stellar astrophysics."
# Infrareds
"The deuterium enrichment of cometary water is one of the most important cosmogonic indicators in comets. The (D/H)H2O ratio preserves information about the conditions under which comet material formed, and tests the possible contribution of comets in delivering water for Earth's oceans. Water (H2O) and HDO were sampled in comet 8P/Tuttle from 2008 January 27 to 2008 February 3 using the new IR spectrometer (Cryogenic Infrared Echelle Spectrograph) at the 8.2 m Antu telescope of the Very Large Telescope Observatory atop Cerro Paranal, Chile."
# Submillimeters
Stars "believed to have circumstellar disks similar to the primitive solar nebula based on the criteria :
- high far-infrared optical depths around visible stars,
- shallow spectral energy densities longward of 5 µm, and
- large millimeter-wave flux densities indicative of ≳ 0.01 M⊙ of H2."
"Evidence for changes in particle composition, size, or shape, reflected in the emissivity index, could therefore be relevant to theories of cosmogony."
"The observations were carried out at the Caltech Submillimeter Observatory (CSO) in Hawaii during 1989 November through December 4, and 1990 December 4 through 9. The detector was a silicon composite bolometer fed by a Winston cone and cooled to a few tenths of a degree with a 3He refrigerator. The filtering employed standard techniques: a scattering filter of black polyethylene fused to fluorogold at 77 K blocked wavelengths in the far-infrared; a crystal quartz filter coated with black polyethylene at 4 K eliminated all near-infrared radiation; and bandpass filters made of metal mesh on nylon or polyethylene, defined the actual wavebands (e.g., Whitcomb & Keene 1980; Cunningham 1982). Different Winston cones were used with each filter to match the diffraction limit of the 10 m telescope, giving different beam sizes on the sky."
# Microwaves
"The existence of galaxies and clusters today requires that perturbations in the density must have become nonlinear before the present epoch. In a baryonic universe, for adiabatic perturbations at recombination, this implies present-day fluctuations in the microwave background an order of magnitude larger than the present observational upper limits of ~ 2 x 10–5 on scales of 2 arcmin (Uson & Wilkinson 1984)."
"For nonbaryonic dark matter, on the other hand, the predicted fluctuations in the microwave background are consistent with the observations—though only if Ωh4/3 > 0.2 (Bond & Efstathiou 1984)—since the baryonic fluctuations are small at recombination and only later grow to the same size as fluctuations in the dark matter. if the universe had inflated by just the amount needed to yield Ω of (say) 0.1, it would be unnatural to find such small amplitude anisotropies in the microwave background—this would require the pre-inflation geometry of our observable universe to have been rather special, with a curvature which was essentially constant (to 1 part in ~ 104) over scales of order the curvature radius."
"Hogan (1984) points out that, if large volumes of gas were raised to such high temperatures that pressure gradients could drive the requisite motions, the Sunyaev-Zeldovich effect might lead to smallscale anisotropies in the microwave background exceeding the measured limits. But, despite this constraint, there may be no insurmountable objection to this general possibility; it is conceivable that the configurations we now see could be determined by gas-dynamical rather than primarily gravitational effects."
# Radars
"Very low values of the radio brightness temperatures of the rings of Saturn indicate that their high radar reflectivity is not simply due to a gain effect in the backscatter direction. These two sets of observations are consistent with the ring particles having a very high single scattering albedo at radio wavelengths with multiple scattering effects being important. Comparison of scattering calculations for ice and silicate particles with radio and radar observations imply a mean particle radius of ~ 1 cm. The inferred mean size is consistent with a model in which meteoroid impacts have caused a substantial reduction in the mean particle size from its initial value."
# Radios
"Comets provide important clues to the physical and chemical processes that occurred during the formation and early evolution of the Solar System Comparing abundances and cosmogonic values (isotope and ortho:para (o/p) ratios) of cometary parent volatiles to those found in the interstellar medium, in disks around young stars, and between cometary families, is vital to understanding planetary system formation and the processing history experienced by organic matter in the so-called interstellar-comet connection . ground-based radio observations towards comets C/2009 P1 (Garradd) and C/2012 F6 (Lemmon) constrain the chemical history of these bodies."
# Superluminals
"One should prove whether specific predictions for linear alignments of substructures and multiple quasars, for superluminal velocities and for brightness variations of short time scale can be made on the basis of a macroscopic superstring. A macroscopic superstring cosmogony of the known astronomical objects seems possible. Some of the major obstacles of the usual cosmogonies, the origin of structure and angular momentum, are solved from the beginning."
# Plasma objects
Because "of the huge spatiotemporal scales of plasma objects in space, the basic accepted views about the theory of plasma stability, which is now better suited for laboratory applications, are already in need of revision."
# Gaseous objects
"In accord with modern cosmogonic concepts that are discussed later, three basic materials have been used to construct interior models of the giant planets: a solar mixture of elements dominated by hydrogen and helium ("gas"); water, methane, and ammonia with O, C, and N in solar proportions ("ice")2; and magnesium- and iron-containing silicates and metallic iron, with Mg, Fe, and Si in cosmic proportions ("rock"). Gaseous objects, such as stars, are the end products of one or several successive gravitational instabilities that occur in dense molecular clouds."
# Liquid objects
"Apart from the scientific interest for fluid sciences and material sciences in space, the rotating liquid drops have high interest for cosmogony, geophysics and nuclear physics as well."
# Rocky objects
"The generally accepted model for terrestrial-planet formation describes their hierarchical accumulation from smaller rocky objects. Developing scenarios that predict the formation of large terrestrial-type planets with low eccentricities represents a significant and as yet unsolved problem of cosmogony."
# Hydrogens
"The motions of hydrogen clouds and globular clusters offer probes for the gravitational potential in the outlying parts of massive galaxies; these data also suggest the presence of unseen mass."
"Even if gaseous bound systems of galactic mass can form, the types of galaxy they develop into may depend sensitively on the composition of the gas—in particular, whether it contains heavy elements, which permit more efficient cooling (and whether molecular hydrogen, an important coolant at T < 104K, can form)."
# Heliums
"The cosmic helium abundance can however be measured with sufficient precision to suggest that the primordial 4He is less than 26 per cent at the 3 σ level (Pagel 1982). This is compatible with Ωbh2) ≲ 0.1 but not with Ωbh2 = 1 (for ≥ 3 species of neutrinos)."
# Lithiums
"From the cosmogony point of view, there can be many different pathways to form a planet, and this casts some doubt that planet formation could be either an adequate physical quantity or a useful observational criterion to define what a planet is. In practice, it is convenient to adopt a planet definition that heavily relies on the mass of the object because the mass can be either measured directly or it has an impact on observable quantities such as surface gravity. For solar composition the boundary BDs and planets is determined by deuterium fusion, which ceases to be stable at around 13 Jupiter masses . Just as the lithium test has effectively been applied as a tool to distinguish between very low-mass stars and BDs , the deuterium test has been proposed to distinguish between BDs and planets but it has not been carried out yet because it is observationally very challenging. This important observational test may have to wait for the advent of the 30-meter class generation of ground-based telescopes such as the European Extremely Large Telescope or the American Thirty Meter Telescope. Particularly promising targets are nearby late-T dwarfs with effective temperatures around 500K that appear to have peculiar properties indicative of young age and planetary mass, such as for example ULASJ1335+11 ."
"A possible link between lithium depletion, rotational history and the presence of exoplanets has been explored for solar-type main-sequence stars ."
# Berylliums
"The foundation of modern planetary cosmogony is the Kant-Laplace hypothesis that the sun and planets were formed simultaneously from a primordial, cool, rotating gas-dust cloud."
"Stars with an initial mass less than the solar mass have a large deficiency of light elements — lithium, beryllium, and boron — which burn up almost completely both in the interior and in the convective envelope."
# Carbons
"Stellar evolution is the process of formation, life, and death of stars. It is one of the major topics of cosmogony."
"Once a medium size star (such as our Sun) has reached the red giant phase, its outer layers continue to expand, the core contracts inward, and helium atoms in the core fuse together to form carbon. This fusion releases energy and the star gets a temporary reprieve."
"However, in a Sun-sized star, this process might only take a few minutes! The atomic structure of carbon is too strong to be further compressed by the mass of the surrounding material. The core is stabilized and the end is near."
# Oxygens
An oxygen isotope "discrepancy was noted forty years ago in a stony meteorite that exploded over Pueblito de Allende, Mexico. It has since been confirmed in other meteorites, which are asteroids that fall to Earth. These meteorites are some of the oldest objects in the Solar System, believed to have formed nearly 4.6 billion years ago within the solar nebula’s first million years. The mix of oxygen-16 (the most abundant form with one neutron for each proton) and variants with an extra neutron or two is markedly different in the meteorites than that seen on terrestrial Earth, the moon or Mars."
“Oxygen isotopes in meteorites are hugely different from those of the terrestrial planets, ... With oxygen being the third most abundant element in the universe and one of the major rock forming elements, this variation among different solar system bodies is a puzzle that must be solved to understand how the solar system formed and evolved.”
"In most instances, oxygen isotopes sort out according to mass. Oxygen-17, for example, has just one extra neutron and is incorporated into molecules half as often as oxygen-18, which has two extra neutrons. In these meteorites, however, the rate at which they were incorporated was independent of their masses."
"One theory proposes that the mix of oxygen isotopes was different back when the earliest solid matter in the Solar System formed, perhaps enriched by matter blasted in from a nearby supernova. Another suggests a photochemical effect called self-shielding, which this team had previously ruled out. The final surviving theory was that a physical chemical principle called symmetry could account for the observed patterns of oxygen isotopes."
The final surviving theory was tested "by filling a hockey puck sized chamber with pure oxygen, varying amounts of pure hydrogen and a little black nugget of solid silicon monoxide. A laser was used to vaporize a plume of silicon monoxide gas into the mix. This mixture of ingredients is observed by radiotelescopes in interstellar clouds, the starting point for our Solar System."
"The oxygen and nitrogen reacted with the silicon monoxide gas to form silicon dioxide. This solid, which is the basis of silicate minerals like quartz that are so prevalent in the crust of the Earth, settled as dust in the chamber. The earliest solid materials in the Solar System were formed by these reactions of gases."
After a mix of oxygen isotopes that matched the anomalous pattern found in stony meteorites. The fact that the degree of the anomaly scaled with the percentage of the atmosphere that was hydrogen points to a reaction governed by symmetry."
“No matter what else happened early on in the nebula, this is the last step in making the first rocks from scratch, ... We’ve shown that you don’t need a magic recipe to generate this oxygen anomaly. It’s just a simple feature of physical chemistry.”
# Materials
"The amount of gas in the cores is not enough to satisfy the virial theorem—it is comparable with the amount in ‘luminous’ galactic material. if the universe were closed by hot gas, or by black holes which were not primordial, but formed by astrophysical processes from baryonic material, the cosmic abundances of the light elements would require some unorthodox explanations".
# Earth
"Current theories for the origin of Earth’s ocean require a contribution from both asteroids and comets, although the relative importances of the asteroidal and cometary fractions is still under investigation (Delsemme, 2000; Morbidelli et al., 2000)."
# Quasars
"Luminous quasars could only form after galactic sized systems had collapsed. A constant comoving density of luminous quasars between z=2 and z=4 is compatible with the CDM model if quasars are short-lived and radiate at about the Eddington limit. However, according to the CDM model the abundance of high-luminosity quasars must decline exponentially at higher redshifts at z~5."
# Hypotheses
- Orthogonality may have occurred before dimensionality.
"The cognitive theory of the young Steiner is at one and the same time an ontology and a cosmogony—a regression to the pre-modern naive movement of universal realism. Its aim is to show man his task and position in the universe through a process of self-reflection and to ensure that through the thought process man is able to achieve something which he once owed to a belief in revelation, namely the satisfaction of the mind.6"
"Steiner’s cosmogony takes the basic form of the gnostic myth: man must lose his worldliness and slavish dependence on material things so that the soul and the world can rise up to self-redemption and fuse once again with the divine spiritual origins which both bear within them. Modern man lives on the fourth planetary phase of development of the earth that entails an experience of individuation and the respiritualization of the individual."
"An earlier quantitative survey of former German pupils of the Rudolf Steiner schools (born in the year 1940/41) revealed significant differences between this group and a control group in the following areas: higher geographical and social mobility; more pronounced leisure activities in the areas of reading, interest in art, practice of a musical instrument and ability in craftwork; and an interest in further training.21"
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity. | Cosmogony
Editor-In-Chief: Henry A. Hoff
Cosmogony is any scientific theory concerning the coming into existence, or origin, of the cosmos or universe, or about how what sentient beings perceive as "reality" came to be.
Usually, the philosophy of cause and effect needs a beginning, a first cause. Modal logic may only require a probability rather than a sequence of events. The concept of uncountable suggests an unknown somewhere between a finite number of likely rationales and an infinite number of possibilities.
From a sense of time as moving forward from yesterday to today and onward to tomorrow, there is again a suggestion of a prehistoric time before the first hominins.
The use of any system of thought or emotion to perceive reality suggests that some existences may precede others.
When more detail becomes available an existence may be transformed into something, an entity, a source, an object, a rocky object, or out of existence.
As a topic in astronomy, cosmogony deals with the origin of each astronomical entity.
Observation, for example, using radiation astronomy may provide some details.
Theoretical astronomy may provide some understanding, or at least some perspective.
# Astronomy
In astronomy, cosmogony refers to the study of the origin of particular astrophysical objects or systems, and is most commonly used in reference to the origin of the solar system.[1][2]
# Cosmology
"Cosmology is the study of the structure and changes in the present universe, while the scientific field of cosmogony is concerned with the origin of the universe. Observations about our present universe may not only allow predictions to be made about the future, but they also provide clues to events that happened long ago when ... the cosmos began."[3]
# Astrogony
The hominins of Earth may have observed and recorded a genealogy, or a begetting, of astronomical objects. Such a begetting may be called an astrogony.
Their astronomical observations may have suggested a genealogy, a progression from one astronomical object to another from the point of view of Earth. These objects may have been recorded and perhaps regarded based on what was observed.
# Sun-system astrogony
At least in the northern hemisphere of Earth, the local hominins may have observed, recorded, and regarded a progression of astronomical objects in the sky.
These objects have been remarkable enough that they have made their presence known to the locals of Earth. The time frame could be as short as 10,000 years or as long as a million.
From the current state of knowledge about astronomical objects around other stars, especially nearby, it may be possible to imagine similar objects in the solar system to account for these observations.
Since hominins are recording these phenomena, it is reasonable that these phenomena occurred during an oral history into a written history in some form.
## Watery abyss
The image at right is Chaos magno, a primordial or first Greek god.
For specific cosmogonic details the most important piece of Mesopotamian literature is the Babylonian epic story of creation, Enuma Elish (ibid., 60–72). Here, as in Genesis, the priority of water is taken for granted, i.e., the primeval chaos consisted of a watery abyss. The name for this watery abyss, part of which is personified by the goddess Tiamat, is the etymological equivalent of the Hebrew tehom (Gen. 1:2), a proper name that always appears in the Bible without the definite article. (It should be noted, however, that whereas "Tiamat" is the name of a primal generative force, tehom is merely a poetic term for a lifeless mass of water.) In both Genesis (1:6–7) and Enuma Elish (4:137–40) the creation of heaven and earth resulted from the separation of the waters by a firmament. The existence of day and night precedes the creation of the luminous bodies (Gen. 1:5, 8, 13, and 14ff.; Enuma Elish 1:38).
Neptune was the Roman god of water and the sea[4] in Roman mythology and religion. He is the counterpart of the Greek god Poseidon. In the Greek-influenced tradition, Neptune was the brother of Jupiter. Italic Neptune has been securely identified as a god of freshwater sources as well as the sea.[4]
The orbit of Neptune is the furthest from the Sun of the planets. Its orbit may be slowly increasing as it moves further away from the Sun.
## Skies
Uranus, Ouranos meaning "sky" or "heaven", was the primal Greek god personifying the sky. His equivalent in Roman mythology was Caelus. In Ancient Greek literature, Uranus or Father Sky was the son and husband of Gaia, Mother Earth. According to Hesiod's Theogony, Uranus was conceived by Gaia alone, but other sources cite Aether as his father.[5]
The image at right is a painting by artist Giorgio Vasari (1511–1574). The main focus is on Cronus (Saturn) castrating Uranus (the Greek sky god). As both Uranus and Cronus are represented by men, this suggests that they were similar in nature. "[T]he ancients’ religions and mythology speak for their knowledge of Uranus; the dynasty of gods had Uranus followed by Saturn, and the latter by Jupiter. ... It is quite possible that the planet Uranus is the very planet known by this name to the ancients. The age of Uranus preceded the age of Saturn; it came to an end with the “removal” of Uranus by Saturn. Saturn is said to have emasculated his father Uranus."[6]
## Aphrodite
""Foam-born" Aphrodite is linked to the Moon through her epithet Pasiphaessa, the 'All-shinig One'. In Hesiod's Theogony, Aphrodite was conceived in the lap of the waves which were fertilized by semen from the severed genitals of Ouranos, Heaven, and was 'born in soft foam', as the Homeric Hymn to Aphrodite puts it.71"[7]
"Democritus and Anaxagoras taught that there was a time when the Earth was without the Moon.[8] Aristotle wrote that Arcadia in Greece, before being inhabited by the Hellenes, had a population of Pelasgians, and that these aborigines occupied the land already before there was a moon in the sky above the Earth; for this reason they were called Proselenes.[9][10]"[11]
"Apollonius of Rhodes mentioned the time “when not all the orbs were yet in the heavens, before the Danai and Deukalion races came into existence, and only the Arcadians lived, of whom it is said that they dwelt on mountains and fed on acorns, before there was a moon.”[12]"[11]
"Plutarch wrote in The Roman Questions: “There were Arcadians of Evander’s following, the so-called pre-Lunar people.”[13] Similarly wrote Ovid: “The Arcadians are said to have possessed their land before the birth of Jove, and the folk is older than the Moon.”[14] Hippolytus refers to a legend that “Arcadia brought forth Pelasgus, of greater antiquity than the moon.”[8] Lucian in his Astrology says that “the Arcadians affirm in their folly that they are older than the moon.”[15]"[11]
"Censorinus also alludes to the time in the past when there was no moon in the sky.[16][17]"[11]
"[T]he Moon’s formation took place away from the Earth,[18][19]."[11]
“The moon was formed independently of the earth and later captured, presumably by a three-body interaction, and these events were followed by the dissipation of the excess energy through tidal friction in a close encounter.”[19]
"[T]he Moon could not have been formed in orbit around the Earth".[20]
"[T]he planetary origin and capture of the Moon by the Earth becomes a strong dynamic possibility.”[21]
## Golden age
"An, the oldest and highest of the Sumero-Babylonian gods, whose primordial age was "the year of abundance," signified Saturn, according to Jensen.6"[22]
"There is one God, greatest among gods and men, neither in shape nor in thought like unto mortals ... He abides ever in the same place motionless, and it befits him not to wander hither and thither."[23]
"The motif of Saturn handing over power to Jupiter derives, of course, from Hesiod's account of the succession of the gods in his Theogony, and his story of the five successive ages of men -- the first, or golden, age being under the reign of Kronos (Saturn) and the following ages being under the reign of Zeus (Jupiter) -- in his Works and Days (110ff.). These stories were often retold. Ovid, for example, combines in his Metamorphoses the stories in the Theogony and Works and Days, telling us how, "when Saturn was consigned to the darkness of Tartarus, and the world passed under the rule of Jove, the age of silver replaced that of gold."8"[24]
Saturn is third furthest away from the Sun and its orbit may also be slowly getting further away from the Sun.
## Hermeneutes
Nabu (in Biblical Hebrew Nebo נבו) is the Assyrian and Babylonian god of wisdom and writing, worshipped by Babylonians as the son of Marduk and his consort, Sarpanitum, and as the grandson of Ea.
In Chaldean mythology, Nebo was a god whose worship was introduced into Assyria by Pul [Tiglath-pileser III] (Isa. 46:1; Jer. 48:1). The great temple at Birs Nimrud was dedicated to Nebo.
Hominins “lived without town or laws, speaking one tongue under the rule of Jove. But after Mercury explained the languages of men (whence he is called hermeneutes, ‘interpreter,’ for Mercury in Greek is called Hermes; he, too, divided the nations) then discord arose among mortals.”[25]
“The meaning is clearly that Hermes invented one language for one people, another for another. The whole account reminds one of the Biblical Tower of Babel.”[25]
"In my understanding Mercury was once a satellite of Jupiter, or possibly of Saturn. In the course of the events which followed Saturn’s interaction with Jupiter and its subsequent disruption, Mercury was pushed from its orbit and was directed to the sun by Jupiter. It could, however, have been a comet and the entwined snakes of the caduceus may memorialize the appearance it had when seen by the inhabitants of the Earth."[26]
## Silver and iron ages
In the ancient Greek religion, Zeus (Ancient Greek is the "Father of Gods and men". He is the god of sky and thunder in Greek mythology. His Roman counterpart is Jupiter and Etruscan counterpart is Tinia. Zeus is the child of Cronus and Rhea, and the youngest of his siblings. In most traditions he is married to Hera, although, at the oracle of Dodona, his consort is Dione: according to the Iliad, he is the father of Aphrodite by Dione.
## Morning star
The Greeks thought of the two as separate stars, Phosphorus [the morning star] and Hesperus [the evening star], until the time of Pythagoras in the sixth century BC.[27]
The Romans designated the morning aspect of Venus as Lucifer, literally "Light-Bringer", and the evening aspect as Vesper.
"During a rare period of very low density solar outflow, the ionosphere of Venus was observed to become elongated downstream, rather like a long-tailed comet. ... Under normal conditions, the solar wind has a density of 5 - 10 particles per cubic cm at Earth's orbit, but occasionally the solar wind almost disappears, as happened in May 1999. ... A rare opportunity to examine what happens when a tenuous solar wind arrives at Venus came 3 - 4 August 2010, following a series of large coronal mass ejections on the Sun. NASA's STEREO-B spacecraft, orbiting downstream from Venus, observed that the solar wind density at Earth's orbit dropped to the remarkably low figure of 0.1 particles per cubic cm and persisted at this value for an entire day."[28]
"The observations show that the night side ionosphere moved outward to at least 15 000 km from Venus' centre over a period of only a few hours," said Markus Fraenz, also from the Max Planck Institute for Solar System Research, who was the team leader and a co-author of the paper.[28] "It may possibly have extended for millions of kilometres, like an enormous tail."[28]
"Although we cannot determine the full length of the night-side ionosphere, since the orbit of Venus Express provides limited coverage, our results suggest that Venus' ionosphere resembled the teardrop-shaped ionosphere found around comets, rather than the more symmetrical, spherical shape which usually exists."[28]
"The side of Venus' ionosphere that faces away from the sun can billow outward like the tail of a comet, while the side facing the star remains tightly compacted, researchers said. ... "As this significantly reduced solar wind hit Venus, Venus Express saw the planet’s ionosphere balloon outwards on the planet’s ‘downwind’ nightside, much like the shape of the ion tail seen streaming from a comet under similar conditions," ESA officials said in a statement today (Jan. 29). It only takes 30 to 60 minutes for the planet's comet-like tail to form after the solar wind dies down. Researchers observed the ionosphere stretch to at least 7,521 miles (12,104 kilometers) from the planet, said Yong Wei, a scientist at the Max Planck Institute in Katlenburg, Germany who worked on this research."[29]
## The Children of Heracles
"Violent earthshocks and other perturbations of nature destroyed the Mycenaean citadels and left their defenders exposed to the assaults of migrant tribes, dislodged in the same upheavals, and calling themselves the Children of Heracles, or Mars."[30]
"At the end of the eighth century and the beginning of the seventh century before the present era, when every fifteen years Mars was approaching dangerously close to the Earth, Isaiah prophesied “the day of the Lord’s vengeance,” in which day “the streams [of Idumea] shall be turned into pitch, and the dust thereof into brimstone, and the land thereof shall become burning pitch.” (8) [Isaiah 34:9] A curse upon man and his land was that “brimstone shall be scattered upon his habitation.” (9) [Job 18:15] “Upon the wicked he shall rain pitch, fire and brimstone, and a horrible tempest.” (10) [Psalm 11:6] This eschatological vision was alive with Ezekiel in the days of the Babylonian Exile. He spoke about “an overflowing rain, and great hailstones [meteorites], fire and brimstone.” (11) [Ezekiel 38:22]"[31]
# Sun
Apparently from about 2687 b2k forward in time the only major astronomical objects, that is, objects with a visible disk, as viewed from Earth are the Sun and the Moon. All others are lesser in spectacle and regard. Comets still occur.
# Planetary sciences
"An aspect of current cosmogonic models is reviewed which until a few years ago had received little consideration: the transformation by accretion of kilometer-size objects into bodies comparable in size to the earth."[32]
# Colors
"We present a 9 million star color-magnitude diagram (9M CMD) of the Large Magellanic Cloud (LMC) bar. [...] The 9M CMD is assembled from MACHO Project two-color instrumental photometry calibrated to the standard Kron-Cousins V and R system (Alcock et al. 1999)."[33]
"It is important to study the stellar populations of nearby galaxies like the LMC in order to understand the processes of galaxy evolution. In particular, the formation of exponential disks is an outstanding problem in cosmogony (e.g. Freeman 1970, Fall & Efstathiou 1980, Dalcanton et al. 1997). [...] By studying the low-mass RR Lyrae variables, we make inferences to the nature of the old and metal-poor LMC field population. This elusive LMC population probes the formation epoch of the LMC, with general implications for cosmogony."[33]
"Juno [NSSDC/COSPAR ID: 2011-040A] is also carrying a colour camera, promising Earthlings "the first detailed glimpse of Jupiter's poles"."[34]
"The Juno mission was launched on 05 August 2011 to study Jupiter from polar orbit for approximately one year beginning in 2016. The primary scientific objectives of the mission are to collect data to investigate: (1) the formation and origin of Jupiter's atmosphere and the potential migration of planets through the measurement of Jupiter's global abundance of oxygen (water) and nitrogen (ammonia); (2) variations in Jupiter's deep atmosphere related to meteorology, composition, temperature profiles, cloud opacity, and atmospheric dynamics; (3) the fine structure of Jupiter's magnetic field, providing information on its internal structure and the nature of the dynamo; (4) the gravity field and distribution of mass inside the planet; and (5) Jupiter's three-dimensional polar magnetosphere and aurorae. Juno carries eight experiments to achieve these objectives."[35]
# Minerals
"A new cosmogony proposed by author bases on idea that formation of planets takes place on pre-solar stage of evolution of proto-stellar/proto-planetary nebula. [...] The hypothesis predicts that all particles in one stream are of the same mineral composition and of the same density."[36]
# Theoretical cosmogony
Def.
- the "study of the origin,[37] and sometimes the development,[38] of the universe or the solar system,[39] in astrophysics, religion, and other fields",[38]
- any "specific theory, model, [myth][40], [or other account][38] of the origin [...] of the universe",[41] or
- the "creation of the universe"[38] is called a cosmogony.
Def. the "origin and development of the cosmos"[42] is called a cosmogenesis.
Def.
- "the study of the physical universe, its structure, dynamics, origin and evolution,[43] and fate",[44]
- "a metaphysical study into the origin and nature of the universe",[43] or
- a "particular view (cultural or religious) of the structure and origin of the universe",[45] is called a cosmology.
## Cold dark matter cosmogony
Consider a universe "dominated by neutrinos and 'cold dark matter'".[46]
"The evidence for unseen mass [...] suggests that the cosmological density parameter Ω is at least 0.1-0.2 [rather than for an] Einstein-de-Sitter 'flat' universe with Ω = 1 [... This] can only be reconciled with the data if the galaxies are more 'clumped' than the overall mass distribution, and are poor tracers of the unseen mass even on scales of several Mpc."[46]
"Particle physicists have other particles ‘in reserve’ which could make a substantial (non-baryonic) contribution to Ω, but which differ from neutrinos in that their freestreaming velocity is negligible, so that small-scale adiabatic perturbations are not phase-mixed away. Such particles can be described as ‘cold dark matter’, in contrast to neutrinos whose free streaming velocity renders them ‘hot’."[46]
"There is no shortage of ‘cold dark matter’ candidate particles—although each of them is highly speculative, to say the least. The motivation for nonetheless considering the hypothesis that the universe is dominated by cold dark matter is that it leads to a cosmogonic scheme that avoids the difficulties of the neutrino-dominated scheme and correctly predicts many of the observed properties of galaxies, including their range of masses, irrespective of the identity of the cold particle (Peebles 1984; Blumenthal et al. 1984)."[46]
"In cosmogonic schemes involving cold dark matter, there is no equally obvious process that might inhibit galaxy formation in the incipient voids".[46]
# Entities
"I shall introduce the themes with several quotations which are representative of a number of popular contemporary writings on cosmogony. ... First, they each personify an entity or concept-'the laws of physics', 'chance' and 'natural selection' respectively."[47]
# Sources
"The amount of energy needed [to inhibit galaxy formation] is not exorbitant; however there are physical problems of coupling it to the gas in a suitable way. For instance, the most obvious possibility is photoionization. The temperature attained depends on the mean energy of an ejected photoelectron, and in a typical HII region is never more than a few times 104 K. At first sight, one might suppose that a source spectrum peaking sharply at photon energies 100 eV (e.g. a blackbody spectrum with Τ 106 K) would yield a correspondingly hot HII region. But this is not so (except in the implausible case of very sudden ionization) because a photoelectron would then collisionally ionize several neutral atoms before they had a chance to be photoionized, the energy of each photoelectron consequently being shared among several electrons and ions (Bardeen 1984, personal communication)."[46]
# Objects
Notation: let the symbol h, or h, "denotes the Hubble constant in units of 100 km s–1 Mpc–1".[46]
"Most of the initial baryons might have been incorporated in a population of stars that were either pregalactic, or else formed during the initial collapse phase of a protogalaxy: these stars, or their remnants, could perhaps now have a high M/L and contribute to the unseen mass. Ideally, one would like to be able to calculate what happens when a cloud of 105–107 M⊙ condenses out from primordial material: does it form one (or a few) supermassive objects [(SMOs)], or does fragmentation proceed efficiently down to low-mass stars?"[46]
"An uncertainty in the evolution of massive or supermassive stars is the amount of loss during H-burning; however the hypothesis that most mass goes into very massive objects (VMOs) of greater than about 103 Μ⊙ is compatible with the nucleosynthesis constraints."[46]
"Other possible ‘escape clauses’ [to Ωbh2) ≲ 0.1 but not with Ωbh2 = 1 (for ≥ 3 species of neutrinos)] can be invoked—for instance, there might be large-amplitude inhomogeneities in the initial baryon distribution, such that all the baryonic material we can now sample comes from underdense regions, the overdense regions having turned into dark population III objects (Rees 1983)."[46]
# Strong forces
"Due to the very low energy of the colliding protons in the Sun, only states with no angular momentum (s-waves) contribute significantly. One can consider it as a head-on collision, so that angular momentum plays no role. Consequently, the total angular momentum is the sum of the spins, and the spins alone control the reaction. Because of Pauli's exclusion principle, the incoming protons must have opposite spins. On the other hand, in the only bound state of deuterium, the spins of the neutron and proton are aligned. Hence a spin flip must take place [...] The strength of the nuclear force which holds the neutron and the proton together depends on the spin of the particles. The force between an aligned proton and neutron is sufficient to give a bound state, but the interaction between two protons does not yield a bound state under any circumstances. Deuterium has only one bound state."[48]
The "force acting between the protons and the neutrons [is] the strong force".[48]
"A potential of 36 MeV is needed to get just one energy state."[48]
The width of a bound proton and neutron is "2.02 x 10-13 cm".[48]
# Electromagnetics
"The first systematic attempt to base a theory of the origin of the solar system on electromagnetic or hydromagnetic effects was made in Alfvén (1942). The reason for doing so was that a basic difficulty with the old Laplacian hypothesis: how can a central body (Sun or planet) transfer angular momentum to the secondary bodies (planets or satellites) orbiting around it? It was demonstrated that this could be done by electromagnetic effects. No other acceptable mechanism has yet been worked out. [...] the electromagnetic transfer mechanism has been confirmed by observations, as described in the monograph Cosmic Plasma (Alfvén, 1981, pp. 28, 52, 53 0."[49]
"If charged particles (electrons, ions or charged grains) move in a magnetic dipole field - strong enough to dominate their motion - under the action of gravitation and the centrifugal force, they will find an equilibrium in a circular orbit if their centrifugal force is 2/3 of the gravitational force [...] The consequence of this is that if they become neutralized, so that electromagnetic forces disappear, the centrifugal force is too small to balance the gravitation. Their circular orbit changes to an elliptical orbit with the semi-major axis a = 3/4a0 and e = 1/3 (where a0 is the central distance where the neutralization takes place [...] Collisional (viscous) interaction between the condensed particles will eventually change the orbit into a new circular orbit with a = 2/3a0 and e = 0."[49]
"If [...] there is plasma in the region [collisional interaction results in] matter in the 2/3-[region]. [...] matter in the region [...] will produce a [cosmogonic] shadow in the region".[49]
# Weak forces
"If Egrav is the gravitational energy of a star and Etherm is its total thermal energy, then the binding energy of the star is given by Ebind = Egrav + Etherm < 0, where Egrav is negative and Etherm is positive. The temperature of the cores of stars is determined by the balance between the gravitational attraction and the gas pressure. Since the gravitational energy determines the gravitational force and the thermal energy determines the gas pressure, it is obvious that there exists a relation between the two. If the gas in the star behaves like an ideal gas, then 2Etherm + Egrav = 0, a result which is known as the viral theorem.14 The theorem is extremely simple and can be derived in just 6 lines.15"[48]
"14Poincaré, H., Lecons sur les hypothéses cosmogoniques, Librarie Scientifique, A. Hermann, 1811. This theorem is also the basis for the negative effective specific heat of stars. Only at this point do we need the Clausius connection between kinetic energy and temperature [Clausius, R.J.E., Phil. Mag. 2, 1 (1851); ibid. 102; ibid. 12, 81 (1856)]. The temperature is given by the kinetic energy divided by the Boltzmann constant. If the star loses energy L, it must contract, i.e., reduce its radius, and consequently lower its negative gravitational energy Egrav. The kinetic energy T is then more positive, so the temperature rises. In this way the star can lose energy and increases its temperature, in contrast to normal matter. This is one of Eddington's famous paradoxes about stars: they lose energy and heat up."[48]
"15 See Jeans, Astronomy and Cosmogony, Cambridge University Press, 1929, p. 67."[48]
"In 1937, Gamow and Teller36 postulated an extremely important addition to Fermi's β-decay theory. They realized that there are cases where the Fermi theory fails to explain the decays. Consequently, Gamow and Teller proposed an ad hoc solution to explain the discrepancy. [... simplifying] the difference between the Fermi and Gamow-Teller interactions as they are expressed in the reaction relevant to stars, namely p + p → 2D + e+ + ν. In a Fermi interaction which converts a proton into a neutron and vice versa, the sum of all spins of the particles does not change. In a Gamow-Teller interaction, the total spin must change by one unit."[48]
"What Gamow and Teller actually discovered was that the weak force, which is responsible for the β-decay, has two different components which behave and act differently and have different strengths. A good example is the electromagnetic force which can appear as a Coulomb force between electric charges or as a magnetic force acting on moving charges. The electric and magnetic components behave differently. Fierz37 generalized the theory by combining the Fermi and Gamow-Teller conditions into a unified theory of this complicated force."[48]
"37Fierz, M., Zeit. für Phys. 194, 553 (1937)."[48]
# Continua
"The problem of formation of generic structures in the Universe is addressed, whereby first the kinematics of inertial continua for coherent initial data is considered. The generalization to self-gravitating continua is outlined focused on the classification problem of singularities and metamorphoses arising in the density field."[50]
# Emissions
"The prismoidal method provides a good approximation of the dust emission peak for cold sources [...], but probably overestimates the long-wavelength flux for warmer, flatter [spectral energy distribution] SED sources [...], resulting in a bias toward lower Tbol."[51]
"In a binary formed via gravitational fragmentation, we would expect the separation to correspond to the local Jeans length (Jeans 1928):"[51]
"where cs is the local sound speed, and μp = 2.33 and n are the mean molecular weight and mean particle density, respectively. A Jeans length of 4200 AU would require a relatively high density (n ~ 6 x 105 cm−3, assuming cs = 0.2 km s−1). The mean density of the Per-Bolo 102 core, measured within an aperture of 104 AU, is 4 x 105 cm−3, close to the required value."[51]
# Absorptions
"Recent years have seen the emergence of a standard model for the growth of structure – the hierarchical clustering model – in which the gravitational effects of dark matter drive the evolution of structure from the near-uniform recombination epoch until the present day. Simple models for galaxy formation in the context of these CDM cosmogonies have been remarkably successful in reproducing the properties of the local galaxy population (Kauffmann, White, & Guiderdoni 1993; Cole et al. 1994) and have been extended to predict the sizes, surface densities and circular velocities of spiral galaxy disks (Dalcanton, Spergel, & Summers 1997; Mo, Mao, & White 1998)."[52]
"For quenched galaxies, the Hα absorption trough is deep and can be traced through the nucleus and along the major axis. It extends to a radius at or beyond 2 Rd [where Rd is the galaxy disk scale length] in all but three cases. This makes it possible to determine a velocity width from the optical spectrum as is done for emission line flux, with appropriate corrections between stellar and gas velocities (see discussion in Paper I, also Neistein, Maoz, Rix, & Tonry, 1999). In the few cases where a velocity width can also be measured from the H I data, it is found to be in good agreement with that taken from the Hα absorption line flux."[52]
"The extent of the Hα absorption trough along the major axes of the quenched spirals is significantly more truncated than the distribution of the Hα emission line for H I deficient galaxies. The distribution of the old stellar population contributing to the Hαext [extent of Hα] absorption of the quenched spirals may be partly responsible for this extreme truncation, if disks are built up from the inside to the outside over time."[52]
# Bands
"The hydromagnetic approach led to the discovery of two important observational regularities in the solar system: (1) the band structure [such as in the rings of Saturn and in the asteroid belt], and (2) the cosmogonic shadow effect (the two-thirds fall down effect)."[49]
# Backgrounds
"Although we cannot confidently predict what these so-called ‘population ΙΙI’ stars would be like (Kashlinsky & Rees 1983), there are several constraints which, in combination, imply that if there are enough of them to provide the unseen mass, the individual masses must either be less than 0.1 M⊙ or else in the range 103–106 Μ⊙. Masses above ~ 0.1 M⊙ would contribute too much background light unless they had all evolved and died, leaving dark remnants. But the remnants of ordinary massive stars of 10–100 M⊙ would produce too much material in the form of heavy elements."[46]
# Meteors
Current "knowledge of the orbital structure of the outer solar system, [is] mostly slanted towards that information which has been learned from the Canada-France-Ecliptic Plane
Survey (CFEPS: www.cfeps.net). Based on our current datasets (inside and outside CFEPS) outer solar system modeling is now entering the erra of precission cosmogony."[53]
"Since the discovery of the first members of the Kuiper belt (Jewitt and Luu, 1993) the growth in knowledge of the outer solar system has been marked (perhaps driven) by the discovery of individual objects whose dynamics pointed at previously unknown reserviours; for example: 1993 RO and the plutinos, 1996 TL66 and the ‘scattering disk’, 2003 CR103 and the detectatch disk, 90377 Sedna and the Inner Oort Cloud."[53]
The "‘main Kuiper belt’ is populated by dynamically ‘hot’ and ‘cold’ subcomponents
(Brown 2001), the dyncamically ‘cold’ component is further sub-divided into a ‘stirred’ and ‘kernel’ component (Petit et al., 2011). The plane of the Ecliptic does not match the ecliptic or invariable planes of the solar sytem (Elliot et al., 2005). Collisional families exists, Haumea (Brown et al., 2007)."[53]
# Cosmic rays
"Violent activity and Supernovae generate cosmic ray (suprathermal) particles. The speeds of individual particles may be ~ c, and their energy density, if they diffused uniformly through the universe, could well exceed 100 eV per baryon. Subrelativistic particles would be slowed down, and would transmit their energy to the thermal component. However, the relativistic particles could themselves exert a pressure if they were coupled (e.g. via magnetic fields) so that they constituted, with the thermal gas, a composite fluid, to which they contributed most of the pressure. Although there is here even less problem in fulfilling the energy density requirement than there is for ultraviolet radiation, there is uncertainty about how uniformly it can spread. If the cosmic-ray energy remains concentrated around the sources, it is irrelevant in the present context [of the cold dark matter cosmogony]; at the other extreme, if the particles diffuse too freely, they do not couple well enough to protogalactic gas for their pressure gradients to oppose gravitational collapse."[46]
# Neutrons
"Primordial nucleosynthesis depends on two things: the expansion timescale at 0.1–1 MeV and the baryon density at that same epoch (which is proportional to Ωbh2). The predicted 4He abundance is rather insensitive to the matter density: for Ωbh2 ≳ 10–2 the density of baryons is high enough to ensure that most of the neutrons that survive when the neutron-proton ratio ‘freezes out’ at kT ≃ 1 MeV get incorporated
in 4He."[46]
# Protons
"It is fair to note, however, that almost all theories which invoke non-baryonic matter require some level of coincidence in order that the luminous and unseen mass contribute comparable densities (to within one or two powers often). For instance, in a neutrino-dominated universe, (mv/mproton) must be within a factor ~ 10 of nb/nγ. The only model that seems to evade this requirement is Witten’s (1984) idea that the quark-hadron phase transition may leave comparable amounts of material in ‘ordinary’ baryons and in ‘nuggets’ of exotic matter."[46]
# Electrons
"Various gaps and density minima have been observed in the Saturnian ring system. Attempts have been made to attribute these observations to gravitational resonances with the inner satellites, thus causing the removal of particles from the dark regions of the ring system (Alexander 1953, 1962)."[54]
"According to an alternative theory (Alfvén and Arrhenius, 1976) the observed dark regions are the result of a 'cosmogonic shadow effect' produced by the 'two-thirds fall-down mechanism'. The basis of this mechanism is the following: plasma contained in the magnetic dipole field of a central (celestial) body is brought up to a state of partial corotation. In the corotating frame of reference, the plasma experiences an outward centrifugal force which drives a current of density J.[54]
The "charge on a dust particle changes with latitude, i.e., [going] from the equator up to the '2/3' points. The electrostatic charging of dust particles in a plasma [where] charging processes such as photo-emission, field emission thermo-ionic emission, and secondary emission can be neglected [...] contributions to the total charging current come mainly from thermal fluxes of electrons and ions, i.e., <math>I = I_i + I_e</math>. A dust grain acquires its equilibrium charge -qe (q > 0) when"[54]
"The electron and ion currents are given by (Mendis et al., 1984)"[54]
"where y = -q(e2/kTC), C being the grain capacitance[, ] rg is the grain radius, <math>n_e</math> the average electron density, and <math>n_p</math> is the average ion (plasma) density."[54]
# Positrons
"The two conversions of protons into neutrons are assumed to take place inside the nucleus, and the extra positive charge is emitted as a positron."[48]
# Neutrinos
"If neutrinos have negligible rest mass, the present density expected for relic neutrinos from the big bang is nν = 110 (Tγ/2.7 K)3 cm–3 for each two-component species. This is of order the photon density nγ, differing just by a factor 3/11 (i.e. a factor 3/4 because neutrinos are fermions rather than bosons, multiplied by 4/11, the factor by which the neutrinos are diluted when e+–e– annihilation boosts the photon density). This conclusion holds for non-zero masses, provided that mvc2 is far below the thermal energy (~ 5 MeV) at which neutrinos decoupled from other species and that the neutrinos are stable for the Hubble time. Comparison with the baryon density, related to Ω via nb = 1.5 x 10–5 Ωb h2 cm–3, shows that neutrinos outnumber baryons by such a big factor that they can be dynamically dominant over baryons even if their masses are only a few electron volts. In fact, a single species of neutrino would yield a contribution to Ω of Ωv = 0.01 h–2 (mv)eV, so if h = 0.5, only 25 eV is sufficient to provide the critical density."[46]
"Neutrinos of nonzero mass would be dynamically important not only for the expanding universe as a whole but also for large bound systems such as clusters of galaxies. This is because they would now be moving slowly: if the universe had cooled homogeneously, primordial neutrinos would now be moving at around 200 (mv)-1eV km s–1. They would be influenced even by the weak (~ 10–5 c2) gravitational potential fluctuations of galaxies and clusters. If the three (or more) types of neutrinos have different masses, then the heaviest will obviously be gravitationally dominant, since the numbers of each species should be the same."[46]
# Gamma rays
"Over the last few years, the cold dark matter cosmogony has become a fiducial model for the formation of structure. [...] The problem with detecting dark matter using annihilation radiation gamma rays has been that the expected signal is comparable to the background (Stecker 1988) and it would be difficult to separate a "cosmic-ray halo" from a dark halo."[55]
"The flux of annihilation gamma rays is given by"[55]
"where <math>(\sigma V)</math> is the cross section, <math>D</math> is the distance to the [dwarf spheroidals] dSph's, <math>m_\lambda</math> is the [weakly interacting massive particles] WIMP's mass, <math>X</math> is the average number of gamma rays in excess of 100 MeV per annihilation and depends weakly on <math>m_\lambda</math> (Stecker 1988)."[55]
In March 2010 it was announced that active galactic nuclei are not responsible for most gamma-ray background radiation.[56] Though active galactic nuclei do produce some of the gamma-ray radiation detected here on Earth, less than 30% originates from these sources. The search now is to locate the sources for the remaining 70% or so of all gamma-rays detected. Possibilities include star forming galaxies, galactic mergers, and yet-to-be explained dark matter interactions.
# X-rays
"The X-rays from clusters of galaxies reveal that hot gas is present, with temperature such that the sound speed is similar to the virial velocity (Forman & Jones 1982). The amount of gas in the cores is not enough to satisfy the virial theorem—it is comparable with the amount in ‘luminous’ galactic material. However, gas could provide a bigger fraction of the mass in the outlying parts—because the X-ray emission per unit mass goes as n, diffuse gas is less conspicuous. (The X-ray spectrum shows that this gas has a temperature consistent with being gravitationally bound in a cluster potential whose depth is inferred from the velocity dispersions of the galaxies. This fact argues against ‘radical’ ideals, such as that the clusters are not virialized, or that the galactic redshifts are not true velocity indicators.)"[46]
"Gas that gets heated to kT 10 keV would not be confined in cluster potential wells, but would constitute a roughly homogeneous intercluster medium. It has been suggested that such a gas is the prime contributor to the X-ray background at > 10 keV; even if it is not, the observed strength of this background constrains the density and thermal history of any such gas. More gas can be ‘hidden’ in intergalactic space if it is ultra-hot (~ 40 keV) rather than at a lower temperature. Indeed, there could be almost enough such gas to provide the critical density if it were heated up at a redshift z < 3. The difficulties with this idea stem from the very large energy input and special thermal history necessary to avoid conflict with various observational constraints (Fabian & Kembhavi 1982)."[46]
# Ultraviolets
"What about radiation pressure? The microwave background is of course the dominant energy density. However, it is too weakly coupled (via Thomson scattering) to exert any effective damping on non-Hubble flows at epochs z ≲ 100. A somewhat more hopeful possibility is the pressure of Lyman line radiation. If the protogalactic gas is not completely ionized, most of the cosmic background emitted in the ultraviolet would have been transformed into Lyman alpha, whose energy density could exceed 100 eV per ion. The cross-section is certainly large enough to ensure that radiation has a short mean free path. However, in a collapsing (or expanding) medium, the photons would be shifted out of the line wings after the density has changed by a fraction (~ 3Δν/ν). Even though the line width may be as much as 50 Å, this means that the effectively trapped energy density at any instant would be only a tenth of the total radiation background density in the ultraviolet."[46]
# Opticals
"For outside wave fields of the Moon and the Earth accept seismic and acoustic waves which characteristic frequencies first of all coincide with frequencies of orbital and own rotation of cosmogony objects (planets and their satellites, multiple star systems, pulsars)."[57]
"Besides wave (acoustic) processes in the top Earth atmosphere and also those from that its are accompanied also by optical effects (polar lights) and strongly connected with gas dust streams acting [4]."[57]
# Visuals
"Masses above ~ 0.1 M⊙ would contribute too much background light unless they had all evolved and died, leaving dark remnants."[46]
# Violets
"The abundance ratios of stable isotopes of the light elements in comets may provide clues of cosmogonical significance."[58]
"In 1997 we observed comet Hale-Bopp with the 2.6 m Nordic Optical Telescope on La Palma, Canary Islands, with a view to estimating the 12C/13C abundance ratio. About twenty high-resolution (λ /Δ λ ~ 70000) spectra of the strong CN Violet (0,0) band were secured with the SOFIN spectrograph from 7 to 13 April. The heliocentric and geocentric distances of the comet were then close to 0.9 AU and 1.4 AU, respectively. While the data do show the expected lines of the 13C14N isotopic molecule, we have been surprised to find in addition a number of very weak features, which are real and turn out to be positioned very near to the theoretical wavelengths of lines pertaining to the R branch of 12C15N."[58]
# Blues
"Modern data on Coma and other clusters bear out the same trend [for unseen mass]: the overall mass-to-blue-light ratio M/L within the virialized parts of clusters is ~ 300 h [...]; but for the stellar content of ordinary luminous galaxies it is 1–10."[46]
# Cyans
"The ices of Callisto do not seem to have exploded at all."[59]
If the age of the Galilean satellites is "cosmogonic ( ≈ 4 x 109 yr) [...] it is clear that there are no grounds for postulating a cosmogonic crater age [...] "[59]
"The comet data suggest [...] that there should be released simultaneously [...] about two orders of magnitude less (QCN/QH2O ≈ 10-3 by Schloerb et al. (1987)) of cyan compounds, ≈ 2 x 1015 g."[59]
# Greens
"There the deceased states that “I have strewed green stones",8 most likely with the intention of identifying himself with the [...] time when Amun became the supreme god of the Egyptian pantheon, the creation [...] “He (Amun) created the heaven and made it luminous through the stars."11 In the myths and mythologems discussed above, the stars came into being in a later phase of cosmogony. However, we also know of myths reflecting different views. [...] stage of the birth of the universe.12"[60]
# Yellows
"The behavior of groups of massive stars in open clusters is examined. The high concentration of binaries and yellow giants toward the center of the open cluster NGC 2632 (Praesepe) is not a singular phenomenon. It can be found in the Hyades and in the Coma-Berenices cluster, which are nearly of equal age, but not in younger and older objects. This phenomenon depending on the mean mass of a star group, its evolutionary phase, the mean age of the cluster and the time of star formation within it, can be explained by the diagram of the evolution of star clusters, i.e., by cosmogonic reasons. It is not caused by gravitational effects."[61]
# Oranges
"Then, as that long period was drawing to a close, these Gods directed the orange colored force of life into the smaller matrices of Divine Mind and brought into physical being the lichens and the mussels and all the lowest forms of life on land and sea."[62]
# Reds
"To prepare for the Dawn spacecraft's visit to Vesta, astronomers used Hubble's Wide Field Planetary Camera 2 to snap new images of the asteroid. The image at right was taken on May 14 and 16, 2007. Using Hubble, astronomers mapped Vesta's southern hemisphere, a region dominated by a giant impact crater formed by a collision billions of years ago. The crater is 285 miles (456 kilometers) across, which is nearly equal to Vesta's 330-mile (530-kilometer) diameter. If Earth had a crater of proportional size, it would fill the Pacific Ocean basin. The impact broke off chunks of rock, producing more than 50 smaller asteroids that astronomers have nicknamed "vestoids." The collision also may have blasted through Vesta's crust. Vesta is about the size of Arizona."[63]
"Previous Hubble images of Vesta's southern hemisphere were taken in 1994 and 1996 with the wide-field camera. In this new set of images, Hubble's sharp "eye" can see features as small as about 37 miles (60 kilometers) across. The image shows the difference in brightness and color on the asteroid's surface. These characteristics hint at the large-scale features that the Dawn spacecraft [sees] when it arrives at Vesta."[63]
"Hubble's view reveals extensive global features stretching longitudinally from the northern hemisphere to the southern hemisphere. The image also shows widespread differences in brightness in the east and west, which probably reflects compositional changes. Both of these characteristics could reveal volcanic activity throughout Vesta. The size of these different regions varies. Some are hundreds of miles across."[63]
"The brightness differences could be similar to the effect seen on the Moon, where smooth, dark regions are more iron-rich than the brighter highlands that contain minerals richer in calcium and aluminum. When Vesta was forming 4.5 billion years ago, it was heated to the melting temperatures of rock. This heating allowed heavier material to sink to Vesta's center and lighter minerals to rise to the surface."[63]
"Astronomers combined images of Vesta in two colors to study the variations in iron-bearing minerals. From these minerals, they hope to learn more about Vesta's surface structure and composition."[63]
"The simplest model for the genesis of the HED meteorites involves a series of partial melting and crystallization events [1] of a small parent body whose bulk composition is more or less consistent with cosmic abundances but is depleted in the moderately volatile elements Na and K [2]."[64]
"Why should both Vesta and the Moon be rich in oxidized Fe but depleted in Na and K?"[64]
"How did the HEDs get here from Vesta? The discovery of a string of Vesta-like asteroids in orbits linking Vesta to nearby orbital resonances [5] has shown that [...] arguments [...] for material originating at Vesta to reach Earth-crossing orbits are [...] valid."[64]
"An alternative theory is based on electromagnetic heating during an episode of strong solar wind from the early proto-Sun when our star experienced a T Tauri phase, as predicted by modern stellar astrophysics."[65]
# Infrareds
"The deuterium enrichment of cometary water is one of the most important cosmogonic indicators in comets. The (D/H)H2O ratio preserves information about the conditions under which comet material formed, and tests the possible contribution of comets in delivering water for Earth's oceans. Water (H2O) and HDO were sampled in comet 8P/Tuttle from 2008 January 27 to 2008 February 3 using the new IR spectrometer (Cryogenic Infrared Echelle Spectrograph) at the 8.2 m Antu telescope of the Very Large Telescope Observatory atop Cerro Paranal, Chile."[66]
# Submillimeters
Stars "believed to have circumstellar disks similar to the primitive solar nebula [are] based on the criteria [...]:
- high far-infrared optical depths around visible stars,
- shallow spectral energy densities longward of 5 µm, and
- large millimeter-wave flux densities indicative of ≳ 0.01 M⊙ of H2."[67]
"Evidence for changes in particle composition, size, or shape, reflected in the emissivity index, could therefore be relevant to theories of cosmogony."[67]
"The observations were carried out at the Caltech Submillimeter Observatory (CSO) in Hawaii during 1989 November through December 4, and 1990 December 4 through 9. The detector was a silicon composite bolometer fed by a Winston cone and cooled to a few tenths of a degree with a 3He refrigerator. The filtering employed standard techniques: a scattering filter of black polyethylene fused to fluorogold at 77 K blocked wavelengths in the far-infrared; a crystal quartz filter coated with black polyethylene at 4 K eliminated all near-infrared radiation; and bandpass filters made of metal mesh on nylon or polyethylene, defined the actual wavebands (e.g., Whitcomb & Keene 1980; Cunningham 1982). Different Winston cones were used with each filter to match the diffraction limit of the 10 m telescope, giving different beam sizes on the sky."[67]
# Microwaves
"The existence of galaxies and clusters today requires that perturbations in the density must have become nonlinear before the present epoch. In a baryonic universe, for adiabatic perturbations at recombination, this implies present-day fluctuations in the microwave background an order of magnitude larger than the present observational upper limits of ~ 2 x 10–5 on scales of 2 arcmin (Uson & Wilkinson 1984)."[46]
"For nonbaryonic dark matter, on the other hand, the predicted fluctuations in the microwave background are consistent with the observations—though only if Ωh4/3 > 0.2 (Bond & Efstathiou 1984)—since the baryonic fluctuations are small at recombination and only later grow to the same size as fluctuations in the dark matter. [...] if the universe had inflated by just the amount needed to yield Ω of (say) 0.1, it would be unnatural to find such small amplitude anisotropies in the microwave background—this would require the pre-inflation geometry of our observable universe to have been rather special, with a curvature which was essentially constant (to 1 part in ~ 104) over scales of order the curvature radius."[46]
"Hogan (1984) points out that, if large volumes of gas were raised to such high temperatures that pressure gradients could drive the requisite motions, the Sunyaev-Zeldovich effect might lead to smallscale anisotropies in the microwave background exceeding the measured limits. But, despite this constraint, there may be no insurmountable objection to this general possibility; it is conceivable that the configurations we now see could be determined by gas-dynamical rather than primarily gravitational effects."[46]
# Radars
"Very low values of the radio brightness temperatures of the rings of Saturn indicate that their high radar reflectivity is not simply due to a gain effect in the backscatter direction. These two sets of observations are consistent with the ring particles having a very high single scattering albedo at radio wavelengths with multiple scattering effects being important. Comparison of scattering calculations for ice and silicate particles with radio and radar observations imply a mean particle radius of ~ 1 cm. [...] The inferred mean size is consistent with a model in which meteoroid impacts have caused a substantial reduction in the mean particle size from its initial value."[68]
# Radios
"Comets provide important clues to the physical and chemical processes that occurred during the formation and early evolution of the Solar System [...] Comparing abundances and cosmogonic values (isotope and ortho:para (o/p) ratios) of cometary parent volatiles to those found in the interstellar medium, in disks around young stars, and between cometary families, is vital to understanding planetary system formation and the processing history experienced by organic matter in the so-called interstellar-comet connection [2]. [...] ground-based radio observations towards comets C/2009 P1 (Garradd) and C/2012 F6 (Lemmon) [...] constrain the chemical history of these bodies."[69]
# Superluminals
"One should prove whether specific predictions for linear alignments of substructures and multiple quasars, for superluminal velocities and for brightness variations of short time scale can be made on the basis of a macroscopic superstring. [...] A macroscopic superstring cosmogony of the known astronomical objects seems possible. Some of the major obstacles of the usual cosmogonies, the origin of structure and angular momentum, are solved from the beginning."[70]
# Plasma objects
Because "of the huge spatiotemporal scales of plasma objects in space, the basic accepted views about the theory of plasma stability, which is now better suited for laboratory applications, are already in need of revision."[71]
# Gaseous objects
"In accord with modern cosmogonic concepts that are discussed later, three basic materials have been used to construct interior models of the giant planets: a solar mixture of elements dominated by hydrogen and helium ("gas"); water, methane, and ammonia with O, C, and N in solar proportions ("ice")2; and magnesium- and iron-containing silicates and metallic iron, with Mg, Fe, and Si in cosmic proportions ("rock"). [...] Gaseous objects, such as stars, are the end products of one or several successive gravitational instabilities that occur in dense molecular clouds."[72]
# Liquid objects
"Apart from the scientific interest for fluid sciences and material sciences in space, the rotating liquid drops have high interest for cosmogony, geophysics and nuclear physics as well."[73]
# Rocky objects
"The generally accepted model for terrestrial-planet formation describes their hierarchical accumulation from smaller rocky objects. [...] Developing scenarios that predict the formation of large terrestrial-type planets with low eccentricities represents a significant and as yet unsolved problem of cosmogony."[74]
# Hydrogens
"The motions of hydrogen clouds and globular clusters offer probes for the gravitational potential in the outlying parts of massive galaxies; these data also suggest the presence of unseen mass."[46]
"Even if gaseous bound systems of galactic mass can form, the types of galaxy they develop into may depend sensitively on the composition of the gas—in particular, whether it contains heavy elements, which permit more efficient cooling (and whether molecular hydrogen, an important coolant at T < 104K, can form)."[46]
# Heliums
"The cosmic helium abundance can however be measured with sufficient precision to suggest that the primordial 4He is less than 26 per cent at the 3 σ level (Pagel 1982). This is compatible with Ωbh2) ≲ 0.1 but not with Ωbh2 = 1 (for ≥ 3 species of neutrinos)."[46]
# Lithiums
"From the cosmogony point of view, there can be many different pathways to form a planet, and this casts some doubt that planet formation could be either an adequate physical quantity or a useful observational criterion to define what a planet is. In practice, it is convenient to adopt a planet definition that heavily relies on the mass of the object because the mass can be either measured directly or it has an impact on observable quantities such as surface gravity. For solar composition the boundary [brown dwarfs] BDs and planets is determined by deuterium fusion, which ceases to be stable at around 13 Jupiter masses [18, 19]. Just as the lithium test has effectively been applied as a tool to distinguish between very low-mass stars and BDs [6, 43, 46, 62, 72], the deuterium test has been proposed to distinguish between BDs and planets [9] but it has not been carried out yet because it is observationally very challenging. This important observational test may have to wait for the advent of the 30-meter class generation of ground-based telescopes such as the European Extremely Large Telescope or the American Thirty Meter Telescope. Particularly promising targets are nearby late-T dwarfs with effective temperatures around 500K that appear to have peculiar properties indicative of young age and planetary mass, such as for example ULASJ1335+11 [37]."[75]
"A possible link between lithium depletion, rotational history and the presence of exoplanets has been explored for solar-type main-sequence stars [15]."[75]
# Berylliums
"The foundation of modern planetary cosmogony is the Kant-Laplace hypothesis that the sun and planets were formed simultaneously from a primordial, cool, rotating gas-dust cloud."[76]
"Stars with an initial mass less than the solar mass have a large deficiency of light elements — lithium, beryllium, and boron — which burn up almost completely both in the interior and in the convective envelope."[76]
# Carbons
"Stellar evolution is the process of formation, life, and death of stars. It is one of the major topics of cosmogony."[77]
"Once a medium size star (such as our Sun) has reached the red giant phase, its outer layers continue to expand, the core contracts inward, and helium atoms in the core fuse together to form carbon. This fusion releases energy and the star gets a temporary reprieve."[77]
"However, in a Sun-sized star, this process might only take a few minutes! The atomic structure of carbon is too strong to be further compressed by the mass of the surrounding material. The core is stabilized and the end is near."[77]
# Oxygens
An oxygen isotope "discrepancy was noted forty years ago in a stony meteorite that exploded over Pueblito de Allende, Mexico. It has since been confirmed in other meteorites, which are asteroids that fall to Earth. These meteorites are some of the oldest objects in the Solar System, believed to have formed nearly 4.6 billion years ago within the solar nebula’s first million years. The mix of oxygen-16 (the most abundant form with one neutron for each proton) and variants with an extra neutron or two is markedly different in the meteorites than that seen on terrestrial Earth, the moon or Mars."[78]
“Oxygen isotopes in meteorites are hugely different from those of the terrestrial planets, ... With oxygen being the third most abundant element in the universe and one of the major rock forming elements, this variation among different solar system bodies is a puzzle that must be solved to understand how the solar system formed and evolved.”[79]
"In most instances, oxygen isotopes sort out according to mass. Oxygen-17, for example, has just one extra neutron and is incorporated into molecules half as often as oxygen-18, which has two extra neutrons. In these meteorites, however, the rate at which they were incorporated was independent of their masses."[78]
"One theory proposes that the mix of oxygen isotopes was different back when the earliest solid matter in the Solar System formed, perhaps enriched by matter blasted in from a nearby supernova. Another suggests a photochemical effect called self-shielding, which this team had previously ruled out. The final surviving theory was that a physical chemical principle called symmetry could account for the observed patterns of oxygen isotopes."[78]
The final surviving theory was tested "by filling a hockey puck sized chamber with pure oxygen, varying amounts of pure hydrogen and a little black nugget of solid silicon monoxide. A laser was used to vaporize a plume of silicon monoxide gas into the mix. This mixture of ingredients is observed by radiotelescopes in interstellar clouds, the starting point for our Solar System."[78]
"The oxygen and nitrogen reacted with the silicon monoxide gas to form silicon dioxide. This solid, which is the basis of silicate minerals like quartz that are so prevalent in the crust of the Earth, settled as dust in the chamber. The earliest solid materials in the Solar System were formed by these reactions of gases."[78]
After [collecting and analyzing the dust] a mix of oxygen isotopes [was found] that matched the anomalous pattern found in stony meteorites. The fact that the degree of the anomaly scaled with the percentage of the atmosphere that was hydrogen points to a reaction governed by symmetry."[78]
“No matter what else happened early on in the nebula, this is the last step in making the first rocks from scratch, ... We’ve shown that you don’t need a magic recipe to generate this oxygen anomaly. It’s just a simple feature of physical chemistry.”[80]
# Materials
"The amount of gas in the cores is not enough to satisfy the virial theorem—it is comparable with the amount in ‘luminous’ galactic material. [...] if the universe were closed by hot gas, or by black holes which were not primordial, but formed by astrophysical processes from baryonic material, the cosmic abundances of the light elements would require some unorthodox explanations".[46]
# Earth
"Current theories for the origin of Earth’s ocean require a contribution from both asteroids and comets, although the relative importances of the asteroidal and cometary fractions is still under investigation (Delsemme, 2000; Morbidelli et al., 2000)."[81]
# Quasars
"Luminous quasars could only form after galactic sized systems had collapsed. A constant comoving density of luminous quasars between z=2 and z=4 is compatible with the CDM model if quasars are short-lived and radiate at about the Eddington limit. However, according to the CDM model the abundance of high-luminosity quasars must decline exponentially at higher redshifts [...] at z~5."[82]
# Hypotheses
- Orthogonality may have occurred before dimensionality.
"The cognitive theory of the young Steiner is at one and the same time an ontology and a cosmogony—a regression to the pre-modern naive movement of universal realism. Its aim is to show man his task and position in the universe through a process of self-reflection and to ensure that through the thought process [...] man is able to achieve something which he once owed to a belief in revelation, namely the satisfaction of the mind.6"[83]
"Steiner’s cosmogony takes the basic form of the gnostic myth: man must lose his worldliness and slavish dependence on material things so that the soul and the world can rise up to self-redemption and fuse once again with the divine spiritual origins which both bear within them. Modern man lives on the fourth planetary phase of development of the earth that entails an experience of individuation and the respiritualization of the individual."[83]
"An earlier quantitative survey of former German pupils of the Rudolf Steiner schools (born in the year 1940/41) revealed significant differences between this group and a control group in the following areas: higher geographical and social mobility; more pronounced leisure activities in the areas of reading, interest in art, practice of a musical instrument and ability in craftwork; and an interest in further training.21"[83]
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikiversity. | https://www.wikidoc.org/index.php/Cosmogony | |
0f3e8cc43a858d61e1741d96ded8150a14e97a5b | wikidoc | Coxa vara | Coxa vara
# Overview
A Coxa vara is a deformity of the hip, whereby the angle between the ball and the shaft of the femur is reduced to less than 120 degrees. This results in the leg being shortened, and therefore a limp occurs. It is commonly caused by injury, such as a fracture. It can also occur when the bone tissue in the neck of the femur is softer than normal, meaning it bends under the weight of the body. This may either be congenital, also known as Mau-Nilsonne Syndrome, or the result of a bone disorder.
# Pathophysiology
The most common cause of coxa vara is either congenital or developmental. Other common causes include metabolic bone diseases (e.g. Paget's disease of bone), post Perthes deformity, osteomyelitis, post traumatic (due to a malunion of a intertrochanteric fracture). Shepherds Crook deformity is a severe form of coxa vara where the proximal femur is severely deformed with a reduction in the neck shaft angle beyond 90 degrees. It is most commonly a sequelae of osteogenesis imperfecta, Paget's disease, osteomyelitis, tumor and tumor-like conditions (e.g. fibrous dysplasia).
# Diagnosis
## Symptoms
The condition is usually asymptomatic if congenital or developmental. However in unilateral cases (e.g. post traumatic), there maybe shortening, leading to a short limb gait characterized by limp which is seen as a vertical dip on the affected side during the stance phase (as opposed to a lurch characterized in a Trendelenburg gait). In severe cases abduction maybe severely restricted, causing a waddling type gait.
Usual symptoms include pain, stiffness, and difficulty in walking.
The biomechanics of the hip will be affected as the lever arm is lengthened causing more shear forces through the femoral neck predisposing it to stress fractures. This may also lead to progression of the deformity.
## Physical Examination
The patient may have a short limbed gait, or in severe cases a Trendelenburg gait (due to restriction of abduction). The Trendelenburg test maybe positive.
# Imaging
The diagnosis is mainly radiological. Clinical signs include a widened bitrochanteric measurement.
# Treatment
Treatment depends on the cause of the condition. Most cases do not require any treatment. If treatment is required, it is usually a valgus osteotomy of the femur fixed by an angled blade plate device or even a DHS. | Coxa vara
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A Coxa vara is a deformity of the hip, whereby the angle between the ball and the shaft of the femur is reduced to less than 120 degrees. This results in the leg being shortened, and therefore a limp occurs. It is commonly caused by injury, such as a fracture. It can also occur when the bone tissue in the neck of the femur is softer than normal, meaning it bends under the weight of the body. This may either be congenital, also known as Mau-Nilsonne Syndrome, or the result of a bone disorder.
# Pathophysiology
The most common cause of coxa vara is either congenital or developmental. Other common causes include metabolic bone diseases (e.g. Paget's disease of bone), post Perthes deformity, osteomyelitis, post traumatic (due to a malunion of a intertrochanteric fracture). Shepherds Crook deformity is a severe form of coxa vara where the proximal femur is severely deformed with a reduction in the neck shaft angle beyond 90 degrees. It is most commonly a sequelae of osteogenesis imperfecta, Paget's disease, osteomyelitis, tumor and tumor-like conditions (e.g. fibrous dysplasia).
# Diagnosis
## Symptoms
The condition is usually asymptomatic if congenital or developmental. However in unilateral cases (e.g. post traumatic), there maybe shortening, leading to a short limb gait characterized by limp which is seen as a vertical dip on the affected side during the stance phase (as opposed to a lurch characterized in a Trendelenburg gait). In severe cases abduction maybe severely restricted, causing a waddling type gait.
Usual symptoms include pain, stiffness, and difficulty in walking.
The biomechanics of the hip will be affected as the lever arm is lengthened causing more shear forces through the femoral neck predisposing it to stress fractures. This may also lead to progression of the deformity.
## Physical Examination
The patient may have a short limbed gait, or in severe cases a Trendelenburg gait (due to restriction of abduction). The Trendelenburg test maybe positive.
# Imaging
The diagnosis is mainly radiological. Clinical signs include a widened bitrochanteric measurement.
# Treatment
Treatment depends on the cause of the condition. Most cases do not require any treatment. If treatment is required, it is usually a valgus osteotomy of the femur fixed by an angled blade plate device or even a DHS. | https://www.wikidoc.org/index.php/Coxa_vara | |
e7d3c363306475d9654643d55c4f76b367d44ef6 | wikidoc | Crataegus | Crataegus
Hawthorn (Crataegus) is a large genus of shrubs and trees in the family Rosaceae, native to temperate regions of the Northern Hemisphere in Europe, Asia and North America. The name hawthorn was originally applied to the species native to northern Europe, especially the Common Hawthorn C. monogyna, and the unmodified name is often so used in Britain and Ireland. However the name is now also applied to the entire genus, and also to the related Asian genus Rhaphiolepis.
They are shrubs and small trees growing to 5-15 m tall, characterized by their small pome fruit and thorny branches. The bark is smooth grey in young individuals, developing shallow longitudinal fissures with narrow ridges in older trees. The fruits are sometimes known as "haws", from which the name derived. The thorns grow from branches, and are typically 1-3 cm long. The leaves grow spirally arranged on long shoots, and in clusters on spur shoots on the branches or twigs. The leaves themselves have lobed or serrate margins and are somewhat variable shape.
The number of species in the genus depends on taxonomic interpretation, with numerous apomictic microspecies; some botanists recognise a thousand or more species, while others reduce the number to 200 or fewer.
Hawthorns provide food and shelter for many species of birds and mammals, and the flowers are important for many nectar-feeding insects. Hawthorns are also used as food plants by the larvae of a large number Lepidoptera species.
Many species and hybrids are used as ornamental and street trees. The Common Hawthorn is extensively used in Europe as a hedge plant. Several cultivars of the Midland Hawthorn C. laevigata have been selected for their pink or red flowers. Hawthorns are among the trees most recommended for water-conservation landscapes.
# Selected species
# Uses
## Culinary use
The fruits of the species Crataegus pinnatifida (Chinese Hawthorn) are tart, bright red, and resemble small crabapple fruits. They are used to make many kinds of Chinese snacks, including haw flakes and tanghulu (糖葫芦). The fruits, which are called shānzhā (山楂) in Chinese, are also used to produce jams, jellies, juices, alcoholic beverages, and other drinks . In South Korea, a liquor called sansachun (산사춘) is made from the fruits.To the western palate, drinks made from the fruits taste similar to barbecue sauce.
The fruits of Crataegus pubescens are known in Mexico as tejocotes and are eaten raw, cooked, or in jam during the winter months. They are stuffed in the piñatas broken during the traditional pre-Christmas parties known as posadas. They are also cooked with other fruits to prepare a Christmas punch. The mixture of tejocote paste, sugar, and chili powder produces a popular Mexican candy called rielitos, which is manufactured by several brands.
In the southern United States fruits of three native species are collectively known as Mayhaws and are made into jellies which are considered a great delicacy.
The leaves are edible and, if picked in the months of April and May, they are tender enough to be used in salads.
## Medicinal use
The dried fruits of Crataegus pinnatifida (called 山楂 or shān zhā in Chinese) are used in naturopathic medicine and traditional Chinese medicine, primarily as a digestive aid. A closely related species, Crataegus cuneata (Japanese Hawthorn, called sanzashi in Japanese) is used in a similar manner. Other species (especially Crataegus laevigata) are used in Western herbal medicine, where the plant is believed to strengthen cardiovascular function . In recent years, this use has been noted and adopted by Chinese herbalists as well . Hawthorn is also used as an aid to lower blood pressure, and treat some heart related diseases.
Several clinical trials have assessed the ability of hawthorn to help improve exercise tolerance in people with NYHA class II cardiac insufficiency compared to placebo. One trial, at (300mg/day) for 4 to 8 weeks, found no difference from placebo. The second trial, including 78 subjects (600mg/day) for 8 weeks, found "significant improvement in exercise tolerance" and lower blood pressure and heart rate during exercise. The third trial, including 32 subjects (900mg/day) for 8 weeks, found improved exercise tolerance as well as a reduction in the "incidence and severity of symptoms such as dyspnea" and fatigue decreased by approximately 50% .
In the HERB-CHF (Hawthorn Extract Randomized Blinded Chronic HF Study) clinical trial, 120 patients took 450mg of hawthorn extract twice daily for 6 months in combination with standard therapy and a standardized exercise program. "No effects of hawthorn were seen on either quality-of-life endpoint (Tables 1 and 2), or when adjusted for LVEF" .
One study, consisting of 1011 patients taking one tablet (standardized to 84.3mg procyanidin) twice daily for 24 weeks, found "improvements in clinical symptoms (such as fatigue, palpitations, and exercise dyspnea), performance and exercise tolerance test, and ejection fraction" .
## Other uses
The wood of some hawthorn species is very hard and resistant to rot. In rural North America it was prized for use as tool handles and fence posts.
## Side effects
Overdose can cause cardiac arrhythmia and dangerously lower blood pressure. Milder side effects include nausea and sedation.
# Folklore
The custom of employing the flowering branches for decorative purposes on the 1st of May is of very early origin; but since the adoption of the Gregorian calendar in 1752, the tree has rarely been in full bloom in England before the second week of that month. In the Scottish Highlands the flowers may be seen as late as the middle of June. The saying "Ne'er cast a cloot til Mey's oot" conveys a warning not to shed any cloots (clothes) before the summer has fully arrived and the may flowers (hawthorn blossoms) are in full bloom.
The hawthorn has been regarded as the emblem of hope, and its branches are stated to have been carried by the ancient Greeks in wedding processions, and to have been used by them to deck the altar of Hymenaios. The supposition that the tree was the source of Jesus's crown of thorns gave rise doubtless to the tradition current (as of 1911) among the French peasantry that it utters groans and cries on Good Friday, and probably also to the old popular superstition in Great Britain and Ireland that ill-luck attended the uprooting of hawthorns. Branches of Glastonbury Thorn, C. Oxyacantha, var. praecox, which flowers both in December and in spring, were formerly highly valued in England, on account of the legend that the tree was originally the staff of Joseph of Arimathea.
In Celtic lore, the hawthorn plant was used commonly for rune inscriptions along with Yew and Apple. It was once said to heal the broken heart.
In Serbian folklore, a stake made of hawthorn wood was used to impale the corpses of suspected vampires.
- The fruit of Common Hawthorn (C. monogyna)
The fruit of Common Hawthorn (C. monogyna)
- Spring flowers of the probable hybrid C.laevigata x monogyna
Spring flowers of the probable hybrid C.laevigata x monogyna
- Crataegus pinnatifida fruit
Crataegus pinnatifida fruit
- Botanical drawing of Crataegus laevigata
Botanical drawing of Crataegus laevigata
# References and external links
- ↑ Richard Mabey, Food for Free, Collins, October 2001.
- ↑ Alternative Medicines for Cardiovascular Diseases--Hawthorn by Harry Fong & Jerry Bauman Journal of Cardiovascular Nursing 16(4):1-8 (July 2002).
- ↑ Aaronson K: HERB-CHF: Hawthorn Extract Randomized Blinded Chronic Heart Failure Trial. In, 2004
- ↑ Sweet JMRBV (2002). Hawthorn: Pharmacology and therapeutic uses. American Journal of Health-System Pharmacy 59: 417-422
- ↑ Sloan-Kettering - Hawthorn
- ↑ "Scuil Wab: Wird O The Month - Mey". Scottish Language Dictionaries. 2003. Retrieved 2008-05-28..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Ne'er cast a clout till May be out". The Phrase Finder. Retrieved 2008-05-28.
- ↑ "Hawthorn" article in the 1911 Encyclopedia
- Photos of Chinese haw berries
- Key to Crataegus of Western North America
- Medicinal uses of Hawthorn in Armenia
- Edible uses of hawthorns at Plants For A Future
- Crataegus phaenopyrum images at bioimages.vanderbilt.edu
ar:زعرور
be:Глог
be-x-old:Глог
da:Hvidtjørn
de:Weißdorne
eo:Kratago
gd:Sgitheach
ko:산사나무속
hsb:Hłohonc
io:Kratego
ka:კუნელი
lt:Gudobelė
hu:Galagonya
nl:Meidoorn
no:Hagtorner
simple:Hawthorn
sl:Glog
sr:Глог
fi:Orapihlajat
sv:Hagtornar
uk:Глід
bat-smg:Graužoks | Crataegus
Hawthorn (Crataegus) is a large genus of shrubs and trees in the family Rosaceae, native to temperate regions of the Northern Hemisphere in Europe, Asia and North America. The name hawthorn was originally applied to the species native to northern Europe, especially the Common Hawthorn C. monogyna, and the unmodified name is often so used in Britain and Ireland. However the name is now also applied to the entire genus, and also to the related Asian genus Rhaphiolepis.
They are shrubs and small trees growing to 5-15 m tall, characterized by their small pome fruit and thorny branches. The bark is smooth grey in young individuals, developing shallow longitudinal fissures with narrow ridges in older trees. The fruits are sometimes known as "haws", from which the name derived. The thorns grow from branches, and are typically 1-3 cm long. The leaves grow spirally arranged on long shoots, and in clusters on spur shoots on the branches or twigs. The leaves themselves have lobed or serrate margins and are somewhat variable shape.
The number of species in the genus depends on taxonomic interpretation, with numerous apomictic microspecies; some botanists recognise a thousand or more species, while others reduce the number to 200 or fewer.
Hawthorns provide food and shelter for many species of birds and mammals, and the flowers are important for many nectar-feeding insects. Hawthorns are also used as food plants by the larvae of a large number Lepidoptera species.
Many species and hybrids are used as ornamental and street trees. The Common Hawthorn is extensively used in Europe as a hedge plant. Several cultivars of the Midland Hawthorn C. laevigata have been selected for their pink or red flowers. Hawthorns are among the trees most recommended for water-conservation landscapes.
# Selected species
# Uses
## Culinary use
The fruits of the species Crataegus pinnatifida (Chinese Hawthorn) are tart, bright red, and resemble small crabapple fruits. They are used to make many kinds of Chinese snacks, including haw flakes and tanghulu (糖葫芦). The fruits, which are called shānzhā (山楂) in Chinese, are also used to produce jams, jellies, juices, alcoholic beverages, and other drinks [1]. In South Korea, a liquor called sansachun (산사춘) is made from the fruits.[2]To the western palate, drinks made from the fruits taste similar to barbecue sauce.
The fruits of Crataegus pubescens are known in Mexico as tejocotes and are eaten raw, cooked, or in jam during the winter months. They are stuffed in the piñatas broken during the traditional pre-Christmas parties known as posadas. They are also cooked with other fruits to prepare a Christmas punch. The mixture of tejocote paste, sugar, and chili powder produces a popular Mexican candy called rielitos, which is manufactured by several brands.
In the southern United States fruits of three native species are collectively known as Mayhaws and are made into jellies which are considered a great delicacy.
The leaves are edible and, if picked in the months of April and May, they are tender enough to be used in salads.[1]
## Medicinal use
The dried fruits of Crataegus pinnatifida (called 山楂 or shān zhā in Chinese) are used in naturopathic medicine and traditional Chinese medicine, primarily as a digestive aid. A closely related species, Crataegus cuneata (Japanese Hawthorn, called sanzashi in Japanese) is used in a similar manner. Other species (especially Crataegus laevigata) are used in Western herbal medicine, where the plant is believed to strengthen cardiovascular function [3]. In recent years, this use has been noted and adopted by Chinese herbalists as well [4]. Hawthorn is also used as an aid to lower blood pressure, and treat some heart related diseases.
Several clinical trials have assessed the ability of hawthorn to help improve exercise tolerance in people with NYHA class II cardiac insufficiency compared to placebo. One trial, at (300mg/day) for 4 to 8 weeks, found no difference from placebo. The second trial, including 78 subjects (600mg/day) for 8 weeks, found "significant improvement in exercise tolerance" and lower blood pressure and heart rate during exercise. The third trial, including 32 subjects (900mg/day) for 8 weeks, found improved exercise tolerance as well as a reduction in the "incidence and severity of symptoms such as dyspnea" and fatigue decreased by approximately 50% [2].
In the HERB-CHF (Hawthorn Extract Randomized Blinded Chronic HF Study) clinical trial, 120 patients took 450mg of hawthorn extract twice daily for 6 months in combination with standard therapy and a standardized exercise program. "No effects of hawthorn were seen on either quality-of-life endpoint (Tables 1 and 2), or when adjusted for LVEF" [3].
One study, consisting of 1011 patients taking one tablet (standardized to 84.3mg procyanidin) twice daily for 24 weeks, found "improvements in clinical symptoms (such as fatigue, palpitations, and exercise dyspnea), performance and exercise tolerance test, and ejection fraction" [4].
## Other uses
The wood of some hawthorn species is very hard and resistant to rot. In rural North America it was prized for use as tool handles and fence posts.
## Side effects
Overdose can cause cardiac arrhythmia and dangerously lower blood pressure. Milder side effects include nausea and sedation.
[5]
# Folklore
The custom of employing the flowering branches for decorative purposes on the 1st of May is of very early origin; but since the adoption of the Gregorian calendar in 1752, the tree has rarely been in full bloom in England before the second week of that month. In the Scottish Highlands the flowers may be seen as late as the middle of June. The saying "Ne'er cast a cloot til Mey's oot" conveys a warning not to shed any cloots (clothes) before the summer has fully arrived and the may flowers (hawthorn blossoms) are in full bloom.[6][7]
The hawthorn has been regarded as the emblem of hope, and its branches are stated to have been carried by the ancient Greeks in wedding processions, and to have been used by them to deck the altar of Hymenaios. The supposition that the tree was the source of Jesus's crown of thorns gave rise doubtless to the tradition current (as of 1911) among the French peasantry that it utters groans and cries on Good Friday, and probably also to the old popular superstition in Great Britain and Ireland that ill-luck attended the uprooting of hawthorns. Branches of Glastonbury Thorn, C. Oxyacantha, var. praecox, which flowers both in December and in spring, were formerly highly valued in England, on account of the legend that the tree was originally the staff of Joseph of Arimathea.[8]
In Celtic lore, the hawthorn plant was used commonly for rune inscriptions along with Yew and Apple. It was once said to heal the broken heart.
In Serbian folklore, a stake made of hawthorn wood was used to impale the corpses of suspected vampires.
- The fruit of Common Hawthorn (C. monogyna)
The fruit of Common Hawthorn (C. monogyna)
- Spring flowers of the probable hybrid C.laevigata x monogyna
Spring flowers of the probable hybrid C.laevigata x monogyna
- Crataegus pinnatifida fruit
Crataegus pinnatifida fruit
- Botanical drawing of Crataegus laevigata
Botanical drawing of Crataegus laevigata
# References and external links
- ↑ Richard Mabey, Food for Free, Collins, October 2001.
- ↑ Alternative Medicines for Cardiovascular Diseases--Hawthorn by Harry Fong & Jerry Bauman Journal of Cardiovascular Nursing 16(4):1-8 (July 2002).
- ↑ Aaronson K: HERB-CHF: Hawthorn Extract Randomized Blinded Chronic Heart Failure Trial. In, 2004
- ↑ Sweet JMRBV (2002). Hawthorn: Pharmacology and therapeutic uses. American Journal of Health-System Pharmacy 59: 417-422
- ↑ Sloan-Kettering - Hawthorn
- ↑ "Scuil Wab: Wird O The Month - Mey". Scottish Language Dictionaries. 2003. Retrieved 2008-05-28..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Ne'er cast a clout till May be out". The Phrase Finder. Retrieved 2008-05-28.
- ↑ "Hawthorn" article in the 1911 Encyclopedia
- Photos of Chinese haw berries
- Key to Crataegus of Western North America
- Medicinal uses of Hawthorn in Armenia
- Edible uses of hawthorns at Plants For A Future
- Crataegus phaenopyrum images at bioimages.vanderbilt.edu
ar:زعرور
be:Глог
be-x-old:Глог
da:Hvidtjørn
de:Weißdorne
eo:Kratago
gd:Sgitheach
ko:산사나무속
hsb:Hłohonc
io:Kratego
ka:კუნელი
lt:Gudobelė
hu:Galagonya
nl:Meidoorn
no:Hagtorner
simple:Hawthorn
sl:Glog
sr:Глог
fi:Orapihlajat
sv:Hagtornar
uk:Глід
bat-smg:Graužoks
Template:WS | https://www.wikidoc.org/index.php/Crataegus | |
86bbc38e6b3b72808f6ee2dbef4582de462b5c23 | wikidoc | Cremation | Cremation
Cremation is the act of reducing a corpse by burning, generally in a crematorium furnace or crematory fire. Contrary to popular belief, the remains (often called cremains) are not "ashes" in the usual sense, but rather dried bone fragments which have been pulverized in a device called a cremulator.
Cremation may serve as a funeral or post-funeral rite which is alternative to the interment of an intact body in a casket. Cremains, which are not a health risk, may be buried or immured in memorial sites or cemeteries, or they may be legally retained by relatives or dispersed in a variety of ways and locations.
# Modern cremation process
The cremation occurs in a 'crematorium' consisting of one or more cremator furnaces or cremation 'retorts' for the ashes. A cremator is an industrial furnace capable of generating 870-980 °C (1600-1800 °F) to ensure disintegration of the corpse. A crematorium may be part of chapel or a funeral home, or part of an independent facility or a service offered by a cemetery.
Modern cremator fuels include natural gas and propane. However, coal or coke were used until the early 1960s.
Modern cremators have adjustable control systems that monitor the furnace during cremation.
A cremation furnace is not designed to cremate more than one body at a time, which is illegal in many countries including the USA.
The chamber where the body is placed is called the retort. It is lined with refractory bricks that resist the heat. The bricks are typically replaced every five years due to thermal fatigue.
Modern cremators are computer-controlled to ensure legal and safe use, e.g. the door cannot be opened until the cremator has reached operating temperature. The coffin is inserted (charged) into the retort as quickly as possible to avoid heat loss through the top-opening door. The coffin may be on a charger (motorised trolley) that can quickly insert the coffin, or one that can tilt and tip the coffin into the cremator.
Some crematoria allow relatives to view the charging. This is sometimes done for religious reasons, such as traditional Hindu and Jain funerals.
Most cremators are a standard size. Typically, larger cities have access to an oversize cremator that can handle deceased in the 200+ kg range (441 pounds). Most large crematoriums have a small cremator installed for the disposal of fetal remains and infants.
## Body container
A body ready to be cremated must be placed in a container for cremation, which can be a simple corrugated cardboard box or a wooden casket. Most casket manufacturers provide a line of caskets specially built for cremation. Another option is a cardboard box that fits inside a wooden shell designed to look like a traditional casket. After the funeral service the interior box is removed from the shell before cremation, permitting the shell to be reused. Funeral homes may also offer rental caskets, which are traditional caskets used only for the duration of the services, after which the body is transferred to another container for cremation. Rental caskets are sometimes designed with removable beds and liners, replaced after each use.
In the UK, the body is not removed from the coffin, and is not placed into a container as described above. The body is cremated with the coffin, which is why all UK coffins that are to be used for cremation must be made of combustible material. The Code Of Cremation Practice forbids the opening of the coffin once it has arrived at the crematorium, and rules stipulate it must be cremated on the same day as the funeral service. Therefore, if a corpse is to be cremated in the UK, it will be done so in the same coffin as it is placed in at the funeral parlor. Jewellery is strongly advised to be removed before the coffin is sealed, as the coffin cannot be opened once it has been received at the crematorium. After the cremation process has been completed, the remains are passed through a magnetic field to remove any bits of metal, which will be interred elsewhere in the crematorium grounds. The ashes are then given to relatives or loved ones.
In Australia, the deceased are cremated in a coffin supplied by the undertaker. Reusable or cardboard coffins are unknown. If cost is an issue, a plain, particle-board coffin known in the trade as a 'chippie' will be offered. Handles (if fitted) are plastic and approved for use in a cremator. Coffins vary from unfinished particle board (covered with a velvet pall if there is a service) to solid timber. Most are veneered particle board.
Cremations can be 'delivery only' with no preceding chapel service at the crematorium (although a church service may have been held) or preceded by a service in one of the crematorium chapels. Delivery-only allows crematoriums to schedule cremations to make best use of the cremators, perhaps by holding the body overnight in a refrigerator. As a result a lower fee is applicable. Delivery-only may be referred to by industry jargon such as 'west chapel service'.
## Burning and ashes collection
The box containing the body is placed in the retort and incinerated at a temperature of 760 to 1150 °C (1400 to 2100 °F). During the cremation process, a large part of the body (especially the organs) and other soft tissue are vaporized and oxidized due to the heat, and the gases are discharged through the exhaust system. The entire process usually takes about two hours.
All that remains after cremation are dry bone fragments (mostly calcium phosphates and minor minerals). Their color is usually light gray. They represent very roughly 3.5% of the body's original mass (2.5% in children). Because the weight of dry bone fragments is so closely connected to skeletal mass, their weight varies greatly from person to person, although it is more closely connected with the person's height and sex than with their simple weight. The mean weight of adult cremains in a Florida, U.S. sample was 5.3 lb (approx. 2.4 kg) for adults (range 2 to 8 lb/900 g to 3.6 kg). This was found to be distributed bimodally according to sex, with the mean being 6 lb (2.7 kg) for men (range 4 to 8 lb/1.8 kg to 3.6 kg) and 4 lb (1.8 kg) for women (range 2 to 6 lb/900 g to 2.7 kg). In this sample, generally all adult cremated remains over 6 lb (2.7 kg) were from males, and those under 4 lb (1.8 kg) were from females.
Jewelry, such as wristwatches and rings, are ordinarily removed and returned to the family. The only non-natural item required to be removed is a pacemaker, as a pacemaker could explode and damage the cremator. In the United Kingdom, and possibly other countries, the undertaker is required to remove pacemakers prior to delivering the body to the crematorium, and sign a declaration stating that any pacemaker has been removed.
After the incineration is completed, the bone fragments are swept out of the retort and the operator uses a pulverizer called a cremulator (also known informally as a crembola) to process them into what are known as cremains which exhibit the appearance of grains of sand (note that this varies with the efficiency of the cremulator used, and recognizable chips of very dry bone may be seen in some final product cremated remains, depending on origin and facility). Cremulators usually use some kind of rotating or grinding mechanism to powder the bones, such as the heavy metal balls on older models.
In Japan and Taiwan, the bones are not pulverized unless requested beforehand, and are collected by the family.
This is one of the reasons cremated remains are called ashes although a technical term sometimes used is "cremains" (a portmanteau of "cremated" and "remains"). The ashes are placed in a container, which can be anything from a simple cardboard box to a fancy urn. An unavoidable consequence of cremation is that a tiny residue of bodily remains is left in the chamber after cremation and mixes with subsequent cremations.
Not all that remains is bone. There will be melted metal lumps from missed jewellery, casket furniture, and dental fillings, and surgical implants such as hip replacements. Large items such as titanium hip replacements are usually removed before grinding, as they may damage the grinder. After grinding, smaller bits of metal are sieved out and later interred in common, consecrated ground in a remote area of the cemetery.
# Methods of keeping or disposing of the cremated remains
Cremated remains are returned to the next of kin in a rectangular plastic container, contained within a further cardboard box or velvet sack, or in an urn if the family had already purchased one. An official certificate of cremation prepared under the authority of the crematorium accompanies the remains and if required by law the permit for disposition of human remains, which must remain with the cremains.
Cremated remains can be kept in an urn, sprinkled on a special field, mountain, in the sea, or buried in the ground at any location. In addition, there are several services which will scatter the cremated remains in a variety of ways and locations. Some examples are via a helium balloon, through fireworks, shot from shotgun shells or scattered from an airplane (this is not illegal in most jurisdictions, in part because laws prohibiting it would be difficult to enforce). One service will send a lipstick-tube sized sample of the cremains into low earth orbit, where they remain for years, but not permanently, before re-entering the atmosphere. Another company claims to turn part of the cremains into a diamond in an artificial diamond manufacturing machine. These converted grown diamonds can then be cut, polished, and mounted as would a real diamond into jewelry as a keepsake for the family. Cremains may also be incorporated, with urn and cement, into part of an artificial reef, or they can also be mixed into paint and made into a portrait of the deceased. Cremated remains can be scattered in national parks in the US, with a special permit. They can also be scattered on private property, with the owner's permission. A portion of the cremated remains may be retained in a specially designed locket known as a keepsake pendant. The cremated remains may also be entombed. Most cemeteries will grant permission for burial of cremains in occupied cemetery plots which have already been purchased or are in use by the families disposing of the cremains, without any additional charge or oversight.
The final disposition depends on the personal wishes of the deceased as well as their cultural and religious beliefs. Some religions will permit the cremated remains to be sprinkled or kept at home. Some religions, such as Roman Catholicism, insist on either burying or entombing the remains. Hinduism obliges the closest male relative (son, father, husband, etc.) of the deceased to immerse the cremated remains in the holy river Ganges, preferably at the holy city of Haridwar, India. The Sikhs and Punjabi Hindus immerse the remains in Sutlej, usually at Sri Harkiratpur. In Japan and Taiwan, the remaining bone fragments are given to the family and are used in a burial ritual before final interment (see Japanese funeral).
# Reasons for choosing cremation
Apart from religious reasons (discussed below), some people find they prefer cremation for personal reasons. For some people it is because they are not attracted to traditional burial. The thought of a long, slow decomposition process is unappealing to some; some people find that they prefer cremation because it disposes of the body immediately.
Other people view cremation as a way of simplifying their funeral process. These people view a traditional burial as an unneeded complication of their funeral process, and thus choose cremation to make their services as simple as possible.
The cost factor tends to make cremation attractive. Generally speaking, cremation costs less than traditional burial services, especially if direct cremation is chosen, in which the body is cremated as soon as legally possible without any sort of services. However, there is wide variation in the cost of cremation services, having mainly to do with the amount of service desired by the deceased or the family. A cremation can take place after a full traditional funeral service, which adds cost. The type of container used also influences cost.
Cremated remains can be scattered or buried. Cremation plots or columbarium niches usually cost less than a burial plot or mausoleum crypt, and require less space. Some religions, such as Roman Catholicism, require the burial or entombment of cremated remains, but burial of cremains may often be accomplished in the burial plot of another person, such as a family member, without any additional cost.
# Environmental impact
To some, cremation might be preferable for environmental reasons. Burial is a known source of certain environmental contaminants. Embalming fluids, for example, are known to contaminate groundwater with mercury, arsenic and formaldehyde. The coffins themselves are another known source of contamination. Another concern is contamination from radioisotopes that entered the body before death or burial. One possible source of isotopes is radiation therapy, although no accumulation of radiation occurs in the most common type of radiation therapy involving high energy photons. However, cremation has no effect on radioisotopes other than to return them to the environment more rapidly (beginning with some spread into the air). Thus, cremation is of no overall help with pollution from this source.
Yet another environmental concern, of sorts, is that traditional burial takes up a great deal of space. In a traditional burial the body is buried in a casket made from a variety of materials. In America the casket is often placed inside a concrete vault or liner before burial in the ground. While individually this may not take much room, combined with other burials it can over time cause serious space concerns. Many cemeteries, particularly in Japan and Europe as well as those in larger cities, have run out, or are starting to run out, of permanent space. In Tokyo, for example, traditional burial plots are extremely scarce and expensive, and in London, a space crisis led Harriet Harman to propose re-opening old graves for "double-decker" burials..
However, there is a growing body of research that indicates cremation has a significant impact on the environment:
The major emissions from crematories are: nitrogen oxides, carbon monoxide, sulfur dioxide, particulate matter, mercury, hydrogen fluoride (HF), hydrogen chloride (HCl), NMVOCs, and other heavy metals, in addition to Persistent Organic Pollutants (POP).
According to the United Nations Environment Programme report on POP Emission Inventory Guidebook, emissions from crematoria contribute 0.2% of the global emission of dioxins and furans.
# Religious views on cremation
## Indian religions
The Indian religions, such as Hinduism, Jainism and Buddhism, mandate open air cremation. In these religions the body is seen as an instrument to carry the soul. As an example the Bhagavad Gita quotes "Just as old clothes are cast off and new ones taken, the soul leaves the body after the death to take a new one". Hence, the dead body is not considered sacred since the soul has left the body and the cremation is regarded as ethical by the Eastern religions. In Sikhism, burial is not prohibited, although cremation is the preferred option for cultural reasons rather than religious.Since Sikhism has a lot of cultural similarity with Hinduism, Sikhs prefer cremation. They also scatter the ashes in holy rivers like Hindus.
According to Hindu traditions, the reasons for preference of destroying the corpse by fire over burying it into ground, is to induce a feeling of detachment into the freshly-disembodied spirit, which will be helpful to encourage it into passing to 'the other world' (the ultimate destination of the dead). This also explains the ground-burial of holy men (whose spirit is already 'detached' enough due to lifelong ascetic practices) and young children (the spirit has not lived long enough to grow attachments to this world). Hindu holy men are buried in lotus position and not in horizontal position as in other religions. Hindus have 16 rituals (Sanskars) like Name, Thread ceremony, beginning of student life, marriage, etc., and the last one is Cremation. Cremation is referred to as antim-samskara, literally meaning "the last rites". At the time of the cremation or "last rites" a "Puja" (ritual worship) is performed.Holy text of Rigveda, one of the most oldest Hindu scripture has many Ruchas(small poems) related to cremation stating that Lord Agni (God of Fire) will purify this body so instead of any other method let’s give this Parthiv (dead body) to Agni (Fire).
## Christianity
In Christian countries and cultures, cremation has typically been discouraged, but not forbidden.
### Roman Catholicism
The Roman Catholic Church's discouragement of cremation stemmed from several ideas: first, that the body, as the instrument through which the sacraments are received, is itself a sacramental, a holy object; second that as an integral part of the human person, it should be disposed of in a way that honours and reverences it, and many early practices involved with disposal of dead bodies were viewed as pagan in origin or an insult to the body; third, that in imitation of Jesus Christ's burial, the body of a Christian should be buried; and fourth, that it constituted a denial of the resurrection of the body. Cremation was not forbidden because it might interfere with God's ability to resurrect the body, however; this was refuted as early as Minucius Felix, in his dialogue Octavius.
Cremation was, in fact, not forbidden in and of itself; even in Medieval Europe cremation was practised in situations where there were multitudes of corpses simultaneously present, such as after a battle, after a pestilence or famine, and where there was an imminent danger of diseases spreading from the corpses, since individual burials with digging graves would take too long time and body decomposition begin before all the corpses had been interred. However, earth burial or entombment remained the law unless there were circumstances that required cremation for the public good.
Beginning in the Middle Ages, and even more so in the 18th century and later, rationalists and classicists began to advocate cremation again as a statement denying the resurrection and/or the afterlife, although the pro-cremation movement more often than not took care to address and refute theological concerns about cremation in their works. Sentiment within the Catholic Church against cremation became hardened in the face of the association of cremation with "professed enemies of God". Rules were made against cremation, which were softened in the 1960s. The Catholic Church still officially prefers the traditional burial or entombment of the deceased, but cremation is now freely permitted as long as it is not done to express a refusal to believe in the resurrection of the body.
Until 1997, Catholic liturgical regulations required that cremation take place after the funeral Mass, so that, if possible, the body might be present for the Mass - the body was present as a symbol, and to receive the blessings and be the subject of prayers in which it is mentioned. Once the Mass itself was concluded, the body could be cremated and a second service could be held at the crematorium or cemetery where the ashes were to be interred just as for a body burial. The liturgical regulations now allow for a Mass with the container of ashes present, but permission of the local bishop is needed for this. The Church still specifies requirements for the reverent disposition of ashes, normally that the ashes are to be buried or entombed in an appropriate container, such as an urn (rather than scattered or preserved in the family home). Catholic cemeteries today regularly receive cremated remains and many have columbaria.
### Protestantism
Protestant churches were much more welcoming of the use of cremation and at a much earlier date than the Catholic Church; pro-cremation sentiment was not unanimous among Protestants, however. The first crematoria in the Protestant countries were built in 1870s, and in 1908 the Dean and Chapter of Westminster Abbey, one of the most famous Anglican churches, required that remains be cremated for burial in the abbey's precincts. Scattering, or "strewing," is an acceptable practice in many Protestant denominations, and some churches have their own "garden of remembrance" on their grounds in which remains can be scattered. Other self-proclaiming Christian groups also support cremation. These include Jehovah's Witnesses
and the Seventh-day Adventist Church.
### Eastern Orthodox and others who forbid cremation
On the other hand, some branches of Christianity oppose cremation, including some minority Protestant groups. Most notably, the Eastern Orthodox Churches forbid cremation. Exceptions are made for circumstances where it may not be avoided (when civil authority demands it, or epidemics) or if it may be sought for good cause, but when a cremation is willfully chosen for no good cause by the one who is deceased, he or she is not permitted a funeral in the church and may also be permanently excluded from liturgical prayers for the departed. In Orthodoxy, cremation is a rejection of the dogma of the general resurrection, and as such is viewed harshly.
### Mormonism
Leaders of the The Church of Jesus Christ of Latter-day Saints have typically declared that cremation is strongly discouraged. This is based on the LDS belief that the body is holy, and that the body and soul will eventually be reunited. Prominent LDS leader Bruce R. McConkie wrote that "only under the most extraordinary and unusual circumstances" would cremation be consistent with LDS teachings.
## Judaism
Judaism traditionally disapproved of cremation in the past (it was the traditional means of disposing the dead in the neighboring Bronze Age cultures). It has also disapproved of preservation of the dead by means of embalming and mummifying, a practice of the ancient Egyptians. During the 19th and early 20th centuries, as the Jewish cemeteries in many European towns had become crowded and were running out of space, cremation became an approved means of corpse disposal amongst the Liberal Jews. Current liberal movements like Reform Judaism still support cremation, although divided burial remains the preferred option.
The Orthodox Jews have maintained a stricter line on cremation, and disapprove of it as Halakha (Jewish law) forbids it. This halakhic concern is grounded in the upholding of bodily resurrection as a core belief of traditional Judaism, as opposed to other ancient trends such as the Sadduccees, who denied it. Conservative Jewish groups also oppose cremation.
In more recent years, most Jews are opting against cremation due to The Holocaust, since many of the six million Jews executed by the Nazi's were burned alive in the furnaces at the death camps. Many of the former Nazi death camps today have mounds of ashes underneath a shallow layer of dirt.
## Zoroastrianism
Traditionally, Zoroastrianism disavows cremation or burial to preclude pollution of fire or earth. The traditional method of corpse disposal is through ritual exposure in a "Tower of Silence," but both burial and cremation are increasingly popular alternatives. Some contemporary figures of the faith have opted for cremation. Parsi-Zoroastrian singer Freddie Mercury of the group Queen was cremated after his death.
## Neopaganism
Of modern Neo-Pagan religions, Ásatrú favours cremation, as do forms of Celtic Paganism.
## Other religions that permit cremation
Ásatrú, Buddhism, Christianity (containing Church of Ireland, Church in Wales, United Church of Canada, Jehovah's Witnesses, Lutheranism, Methodism, Moravian Church, Salvation Army, Scottish Episcopal Church), Christian Science, Church of Scientology, Hinduism (mandatory except for sanyasis, eunuchs and children under five), Jainism, Sikhs, Society of Friends (Quakers), and Unitarian Universalism all permit cremation.
## Other religions that forbid cremation
The Bahá'í Faith forbids cremation. Neo-Confucianism under Zhu Xi strongly discourages cremation of one's parents' corpses as unfilial. In Egyptian Reconstructionism it is believed the Ka will be killed with cremation but it is not forbidden and during ancient times, was a practice of desposing of criminals who were executed in order for them to be deprived of an afterlife. In Islam the Islamic Law forbids Cremation.
# History
## Ancient
Cremation dates to at least 26,000 years ago in the archaeological record with the Mungo Lake cremation.
Alternative death rituals emphasizing one method of disposal of a body, inhumation (burial, cremation, and exposure), have gone through periods of preference throughout history.
In the Middle East and Europe both burial and cremation are evident in the archaeological record in the Neolithic. Cultural groups had their own preference and prohibitions. The ancient Egyptians developed an intricate transmigration of soul theology, which prohibited cremation, and this was adopted widely among other Semitic peoples. The Babylonians, according to Herodotus, embalmed their dead. Early Persians practiced cremation but this became prohibited during the Zoroastrian Period. Phoenicians practiced both cremation and burial. Ancient Greeks and Romans practiced both with cremation generally associated with military honours.
In Europe, there are traces of cremation dating to the Early Bronze Age (ca. 2000 BC) in the Pannonian Plain and along the middle Danube. The custom becomes dominant throughout Bronze Age Europe with the Urnfield culture (from ca. 1300 BC). In the Iron Age, inhumation becomes again more common, but cremation persisted in the Villanovan culture and elsewhere. Homer's account of Patroclus' burial describes cremation with subsequent burial in a tumulus similar to Urnfield burials, qualifying as the earliest description of cremation rites. This is mostly an anachronism, as during Mycenaean times burial was generally preferred, and Homer may have been reflecting more common use of cremation in the period in which the Iliad was written centuries later.
Criticism of burial rites is a common aspersion in competing religions and cultures and one is the association of cremation with fire sacrifice or human sacrifice.
Hinduism and Jainism are notable for not only allowing but prescribing cremation. Cremation in India is first attested in the Cemetery H culture (from ca. 1900 BC), considered the formative stage of Vedic civilization. The Rigveda contains a reference to the emerging practice, in RV 10.15.14, where the forefathers "both cremated (agnidagdhá-) and uncremated (ánagnidagdha-)" are invoked.
Cremation remained common, but not universal, in both Ancient Greece and Ancient Rome. According to Cicero, in Rome inhumation was considered the more archaic rite, while the most honoured citizens were most typically cremated, especially upper classes and members of imperial families.
Christianity frowned upon cremation, both influenced by the tenets of Judaism, and in an attempt to abolish Graeco-Roman pagan rituals. By the 5th century, the practice of cremation had practically disappeared from Europe.
In early Roman Britain cremation was usual but diminished by the fourth century. It then reappeared in the fifth and sixth centuries during the migration era, when sacrificed animals were sometimes included with the human bodies on the pyre, and the deceased were dressed in costume and with ornaments for the burning. That custom was also very widespread among the Germanic peoples of the northern continental lands from which the Anglo-Saxon migrants are supposed to have been derived, during the same period. These ashes were usually thereafter deposited in a vessel of clay or bronze in an 'urn cemetery'. The custom again died out with the Christian conversion among the Anglo-Saxons or Early English, during the seventh century, when inhumation of the corpse became general.
## In the Middle Ages
Throughout parts of Europe, cremation was forbidden by law, and even punishable by death if combined with heathen rites. Cremation was sometimes used by authorities as part of punishment for heretics, and this did not only include burning at the stake. For example, the body of John Wycliff was exhumed years after his death and cremated, with the ashes thrown in a river,. explicitly as a posthumous punishment for his denial of the Roman Catholic doctrine of transubstantiation. On the other hand, mass cremations were often performed because of necessity, when there was a danger of contagious diseases, such as after a battle, pestilence or famine. Retributory cremation continued into modern times. For example, after World War II, the bodies of the 12 men convicted of crimes against humanity at the Nuremberg Trials were not returned to their families, but were instead cremated, then disposed of at a secret location, as a specific part of a legal process intended to deny their use as a location for any sort of memorial. In Japan, however, a memorial building for many executed war criminals, who were also cremated, was allowed to be erected for their remains.
Many Communist countries used similar obliteration as an aggravated capital punishment: the bodies of the executed were cremated and the ashes ignominiously disposed, thus humiliating the families even further.
Even today, cremation bears the stigma of "human waste disposal" in many ex-Socialist countries and is considered ignominious or shameful.
## The modern era
In 1873, Paduan Professor Brunetti presented a cremation chamber at the Vienna Exposition. In Britain, the movement found the support of Queen Victoria's surgeon, Sir Henry Thompson, who together with colleagues founded the Cremation Society of England in 1874. The first crematoria in Europe were built in 1878 in Woking, England and Gotha, Germany, the first in North America in 1876 by Dr. Francis Julius LeMoyne in Washington, Pennsylvania. The second cremation in the United States was that of Charles F. Winslow in Salt Lake City, Utah on July 31 1877. The first cremation in Britain took place on 26th March 1886 at Woking.
Cremation was declared as legal in England and Wales when Dr William Price was prosecuted for cremating his son; formal legislation followed later with the passing of the Cremation Act 1902, (this Act did not extend to Ireland) which imposed procedural requirements before a cremation could occur and restricted the practice to authorised places. Some of the various Protestant churches came to accept cremation, with the rationale being, "God can resurrect a bowl of ashes just as conveniently as he can resurrect a bowl of dust". The 1908 Catholic Encyclopedia was critical about these efforts, referring to them as a "sinister movement" and associating them with Freemasonry, although it said that "there is nothing directly opposed to any dogma of the Church in the practice of cremation". In 1963, Pope Paul VI lifted the ban on cremation, and in 1966 allowed Catholic priests to officiate at cremation ceremonies.
Australia also started to establish modern cremation movements and societies. Australians had their first purpose-built modern crematorium and chapel in the West Terrace Cemetery in the South Australian capital Adelaide in 1901. This small building, resembling the buildings at Woking, remained largely unchanged from its 19th century style and in full operation until the late 1950s. The oldest operating Crematorium in Australia is at Rookwood in Sydney. It opened in 1925.
In the Netherlands, the foundation of the Association for Optional Cremation in 1874 ushered in a long debate about the merits and demerits of cremation. Laws against cremation were challenged and invalidated in 1915 (two years after the construction of the first crematorium in the Netherlands), though cremation did not become legally recognised until 1955.
# Negative experiences with cremation in recent history
## World War II
During the Holocaust, massive crematoria were constructed and operated by the Nazis within their concentration camps and extermination camps to dispose of the bodies of thousands of Jews, Gypsies, and other prisoners who were killed or died in the camps daily. In addition to the atrocity of mass murder, the remains of Jews were thus disposed of in a manner deeply offensive to Orthodox Judaism because Halakha, the Jewish law, forbids cremation and holds that the soul of a cremated person cannot find its final repose. Since then, cremation has carried an extremely negative connotation for many Jews.
## The Tri-State Crematory incident
A recent controversial event involved the failure to cremate, known as the Tri-State Crematory Incident. In the state of Georgia in the United States in early 2002, three hundred thirty-four corpses that were supposed to have been cremated in the previous few years at the Tri-State Crematory were found intact and decaying on the crematorium's grounds, having been dumped there by the crematorium's proprietor. Many of the corpses were beyond identification. In many cases the "ashes" that were returned to the family were not human remains - they were made of wood and concrete dust.
Eventually Ray Brent Marsh—who was the operator at the time the bodies were discovered—had 787 criminal charges filed against him. On November 19, 2004 Marsh pleaded guilty to all charges. Marsh was sentenced to two 12-year prison sentences from both Georgia and Tennessee which he is serving concurrently. Afterwards he will be on probation for 75 years.
Civil suits were filed against the Marsh family as well as a number of funeral homes who shipped bodies to Tri-State. These suits were ultimately settled. The property of the Marsh family has been sold, but collection of the full $80 million judgment remains doubtful. Families have expressed the desire to return the former Tri-State crematory to a natural, park like setting.
## The Indian Ocean tsunamis
The magnitude 9.0-9.3 2004 Indian Ocean Earthquake triggered a series of lethal tsunamis on December 26, 2004 that killed almost 300,000 people, making them the deadliest tsunamis in recorded history. The tsunamis killed people over an area ranging from the immediate vicinity of the quake in Indonesia, Thailand, and the north-western coast of Malaysia, to thousands of kilometres away in Bangladesh, India, Sri Lanka, the Maldives, and even as far as Somalia, Kenya, and Tanzania in eastern Africa.
Authorities had difficulties dealing with the large numbers of bodies, and as a result thousands of bodies were of necessity cremated together. Many of these bodies were not identified or viewed by relatives prior to cremation. A particular point of objection was that the bodies of Westerners were kept separate from those of Asian descent, who were mostly locals. This meant that the bodies of tourists from other Asian nations, such as Japan and Korea, were mass cremated rather than being returned to their country of origin for funeral rites. | Cremation
Cremation is the act of reducing a corpse by burning, generally in a crematorium furnace or crematory fire. Contrary to popular belief, the remains (often called cremains) are not "ashes" in the usual sense, but rather dried bone fragments which have been pulverized in a device called a cremulator.
Cremation may serve as a funeral or post-funeral rite which is alternative to the interment of an intact body in a casket. Cremains, which are not a health risk, may be buried or immured in memorial sites or cemeteries, or they may be legally retained by relatives or dispersed in a variety of ways and locations.
# Modern cremation process
The cremation occurs in a 'crematorium' consisting of one or more cremator furnaces or cremation 'retorts' for the ashes. A cremator is an industrial furnace capable of generating 870-980 °C (1600-1800 °F) to ensure disintegration of the corpse. A crematorium may be part of chapel or a funeral home, or part of an independent facility or a service offered by a cemetery.
Modern cremator fuels include natural gas and propane. However, coal or coke were used until the early 1960s.
Modern cremators have adjustable control systems that monitor the furnace during cremation.
A cremation furnace is not designed to cremate more than one body at a time, which is illegal in many countries including the USA.
The chamber where the body is placed is called the retort. It is lined with refractory bricks that resist the heat. The bricks are typically replaced every five years due to thermal fatigue.
Modern cremators are computer-controlled to ensure legal and safe use, e.g. the door cannot be opened until the cremator has reached operating temperature. The coffin is inserted (charged) into the retort as quickly as possible to avoid heat loss through the top-opening door. The coffin may be on a charger (motorised trolley) that can quickly insert the coffin, or one that can tilt and tip the coffin into the cremator.
Some crematoria allow relatives to view the charging. This is sometimes done for religious reasons, such as traditional Hindu and Jain funerals.[1]
Most cremators are a standard size. Typically, larger cities have access to an oversize cremator that can handle deceased in the 200+ kg range (441 pounds). Most large crematoriums have a small cremator installed for the disposal of fetal remains and infants.
## Body container
A body ready to be cremated must be placed in a container for cremation, which can be a simple corrugated cardboard box or a wooden casket. Most casket manufacturers provide a line of caskets specially built for cremation. Another option is a cardboard box that fits inside a wooden shell designed to look like a traditional casket. After the funeral service the interior box is removed from the shell before cremation, permitting the shell to be reused. Funeral homes may also offer rental caskets, which are traditional caskets used only for the duration of the services, after which the body is transferred to another container for cremation. Rental caskets are sometimes designed with removable beds and liners, replaced after each use.
In the UK, the body is not removed from the coffin, and is not placed into a container as described above. The body is cremated with the coffin, which is why all UK coffins that are to be used for cremation must be made of combustible material. The Code Of Cremation Practice forbids the opening of the coffin once it has arrived at the crematorium, and rules stipulate it must be cremated on the same day as the funeral service. Therefore, if a corpse is to be cremated in the UK, it will be done so in the same coffin as it is placed in at the funeral parlor. Jewellery is strongly advised to be removed before the coffin is sealed, as the coffin cannot be opened once it has been received at the crematorium. After the cremation process has been completed, the remains are passed through a magnetic field to remove any bits of metal, which will be interred elsewhere in the crematorium grounds. The ashes are then given to relatives or loved ones.
In Australia, the deceased are cremated in a coffin supplied by the undertaker. Reusable or cardboard coffins are unknown. If cost is an issue, a plain, particle-board coffin known in the trade as a 'chippie' will be offered. Handles (if fitted) are plastic and approved for use in a cremator. Coffins vary from unfinished particle board (covered with a velvet pall if there is a service) to solid timber. Most are veneered particle board.
Cremations can be 'delivery only' with no preceding chapel service at the crematorium (although a church service may have been held) or preceded by a service in one of the crematorium chapels. Delivery-only allows crematoriums to schedule cremations to make best use of the cremators, perhaps by holding the body overnight in a refrigerator. As a result a lower fee is applicable. Delivery-only may be referred to by industry jargon such as 'west chapel service'.
## Burning and ashes collection
The box containing the body is placed in the retort and incinerated at a temperature of 760 to 1150 °C (1400 to 2100 °F). During the cremation process, a large part of the body (especially the organs) and other soft tissue are vaporized and oxidized due to the heat, and the gases are discharged through the exhaust system. The entire process usually takes about two hours.
All that remains after cremation are dry bone fragments (mostly calcium phosphates and minor minerals). Their color is usually light gray. They represent very roughly 3.5% of the body's original mass (2.5% in children). Because the weight of dry bone fragments is so closely connected to skeletal mass, their weight varies greatly from person to person, although it is more closely connected with the person's height and sex than with their simple weight. The mean weight of adult cremains in a Florida, U.S. sample was 5.3 lb (approx. 2.4 kg) for adults (range 2 to 8 lb/900 g to 3.6 kg). This was found to be distributed bimodally according to sex, with the mean being 6 lb (2.7 kg) for men (range 4 to 8 lb/1.8 kg to 3.6 kg) and 4 lb (1.8 kg) for women (range 2 to 6 lb/900 g to 2.7 kg). In this sample, generally all adult cremated remains over 6 lb (2.7 kg) were from males, and those under 4 lb (1.8 kg) were from females.[2]
Jewelry, such as wristwatches and rings, are ordinarily removed and returned to the family. The only non-natural item required to be removed is a pacemaker, as a pacemaker could explode and damage the cremator. In the United Kingdom, and possibly other countries, the undertaker is required to remove pacemakers prior to delivering the body to the crematorium, and sign a declaration stating that any pacemaker has been removed.[3]
After the incineration is completed, the bone fragments are swept out of the retort and the operator uses a pulverizer called a cremulator[3] (also known informally as a crembola[citation needed]) to process them into what are known as cremains which exhibit the appearance of grains of sand (note that this varies with the efficiency of the cremulator used, and recognizable chips of very dry bone may be seen in some final product cremated remains, depending on origin and facility). Cremulators usually use some kind of rotating or grinding mechanism to powder the bones, such as the heavy metal balls on older models.[4]
In Japan and Taiwan, the bones are not pulverized unless requested beforehand, and are collected by the family.
This is one of the reasons cremated remains are called ashes although a technical term sometimes used is "cremains"[5][6] (a portmanteau of "cremated" and "remains"). The ashes are placed in a container, which can be anything from a simple cardboard box to a fancy urn. An unavoidable consequence of cremation is that a tiny residue of bodily remains is left in the chamber after cremation and mixes with subsequent cremations.
Not all that remains is bone. There will be melted metal lumps from missed jewellery, casket furniture, and dental fillings, and surgical implants such as hip replacements. Large items such as titanium hip replacements are usually removed before grinding, as they may damage the grinder. After grinding, smaller bits of metal are sieved out and later interred in common, consecrated ground in a remote area of the cemetery.
# Methods of keeping or disposing of the cremated remains
Cremated remains are returned to the next of kin in a rectangular plastic container, contained within a further cardboard box or velvet sack, or in an urn if the family had already purchased one. An official certificate of cremation prepared under the authority of the crematorium accompanies the remains and if required by law the permit for disposition of human remains, which must remain with the cremains.
Cremated remains can be kept in an urn, sprinkled on a special field, mountain, in the sea, or buried in the ground at any location. In addition, there are several services which will scatter the cremated remains in a variety of ways and locations. Some examples are via a helium balloon, through fireworks, shot from shotgun shells or scattered from an airplane (this is not illegal in most jurisdictions, in part because laws prohibiting it would be difficult to enforce). One service will send a lipstick-tube sized sample of the cremains into low earth orbit, where they remain for years, but not permanently, before re-entering the atmosphere. Another company claims to turn part of the cremains into a diamond in an artificial diamond manufacturing machine. These converted grown diamonds can then be cut, polished, and mounted as would a real diamond into jewelry as a keepsake for the family. Cremains may also be incorporated, with urn and cement, into part of an artificial reef, or they can also be mixed into paint and made into a portrait of the deceased. Cremated remains can be scattered in national parks in the US, with a special permit. They can also be scattered on private property, with the owner's permission. A portion of the cremated remains may be retained in a specially designed locket known as a keepsake pendant. The cremated remains may also be entombed. Most cemeteries will grant permission for burial of cremains in occupied cemetery plots which have already been purchased or are in use by the families disposing of the cremains, without any additional charge or oversight.
The final disposition depends on the personal wishes of the deceased as well as their cultural and religious beliefs. Some religions will permit the cremated remains to be sprinkled or kept at home. Some religions, such as Roman Catholicism, insist on either burying or entombing the remains. Hinduism obliges the closest male relative (son, father, husband, etc.) of the deceased to immerse the cremated remains in the holy river Ganges, preferably at the holy city of Haridwar, India. The Sikhs and Punjabi Hindus immerse the remains in Sutlej, usually at Sri Harkiratpur. In Japan and Taiwan, the remaining bone fragments are given to the family and are used in a burial ritual before final interment (see Japanese funeral).
# Reasons for choosing cremation
Apart from religious reasons (discussed below), some people find they prefer cremation for personal reasons. For some people it is because they are not attracted to traditional burial. The thought of a long, slow decomposition process is unappealing to some;[7] some people find that they prefer cremation because it disposes of the body immediately.[8]
Other people view cremation as a way of simplifying their funeral process. These people view a traditional burial as an unneeded complication of their funeral process, and thus choose cremation to make their services as simple as possible.
The cost factor tends to make cremation attractive. Generally speaking, cremation costs less than traditional burial services,[8] especially if direct cremation is chosen, in which the body is cremated as soon as legally possible without any sort of services. However, there is wide variation in the cost of cremation services, having mainly to do with the amount of service desired by the deceased or the family. A cremation can take place after a full traditional funeral service, which adds cost. The type of container used also influences cost.
Cremated remains can be scattered or buried. Cremation plots or columbarium niches usually cost less than a burial plot or mausoleum crypt, and require less space. Some religions, such as Roman Catholicism, require the burial or entombment of cremated remains, but burial of cremains may often be accomplished in the burial plot of another person, such as a family member, without any additional cost.
# Environmental impact
To some, cremation might be preferable for environmental reasons. Burial is a known source of certain environmental contaminants. Embalming fluids, for example, are known to contaminate groundwater with mercury, arsenic and formaldehyde. The coffins themselves are another known source of contamination.[9] Another concern is contamination from radioisotopes that entered the body before death or burial. One possible source of isotopes is radiation therapy, although no accumulation of radiation occurs in the most common type of radiation therapy involving high energy photons. However, cremation has no effect on radioisotopes other than to return them to the environment more rapidly (beginning with some spread into the air). Thus, cremation is of no overall help with pollution from this source.[10]
Yet another environmental concern, of sorts, is that traditional burial takes up a great deal of space. In a traditional burial the body is buried in a casket made from a variety of materials. In America the casket is often placed inside a concrete vault or liner before burial in the ground. While individually this may not take much room, combined with other burials it can over time cause serious space concerns. Many cemeteries, particularly in Japan[11] and Europe as well as those in larger cities, have run out, or are starting to run out, of permanent space. In Tokyo, for example, traditional burial plots are extremely scarce and expensive,[12] and in London, a space crisis led Harriet Harman to propose re-opening old graves for "double-decker" burials.[13].
However, there is a growing body of research that indicates cremation has a significant impact on the environment:
The major emissions from crematories are: nitrogen oxides, carbon monoxide, sulfur dioxide, particulate matter, mercury, hydrogen fluoride (HF), hydrogen chloride (HCl), NMVOCs, and other heavy metals, in addition to Persistent Organic Pollutants (POP).[citation needed]
According to the United Nations Environment Programme report on POP Emission Inventory Guidebook,[14] emissions from crematoria contribute 0.2% of the global emission of dioxins and furans.
# Religious views on cremation
Template:Contradiction
## Indian religions
The Indian religions, such as Hinduism, Jainism and Buddhism, mandate open air cremation. In these religions the body is seen as an instrument to carry the soul. As an example the Bhagavad Gita quotes "Just as old clothes are cast off and new ones taken, the soul leaves the body after the death to take a new one". Hence, the dead body is not considered sacred since the soul has left the body and the cremation is regarded as ethical by the Eastern religions. In Sikhism, burial is not prohibited, although cremation is the preferred option for cultural reasons rather than religious.Since Sikhism has a lot of cultural similarity with Hinduism, Sikhs prefer cremation. They also scatter the ashes in holy rivers like Hindus.
According to Hindu traditions, the reasons for preference of destroying the corpse by fire over burying it into ground, is to induce a feeling of detachment into the freshly-disembodied spirit, which will be helpful to encourage it into passing to 'the other world' (the ultimate destination of the dead).[15] This also explains the ground-burial of holy men (whose spirit is already 'detached' enough due to lifelong ascetic practices) and young children (the spirit has not lived long enough to grow attachments to this world).[citation needed] Hindu holy men are buried in lotus position and not in horizontal position as in other religions.[citation needed] Hindus have 16 rituals (Sanskars) like Name, Thread ceremony, beginning of student life, marriage, etc., and the last one is Cremation. Cremation is referred to as antim-samskara, literally meaning "the last rites". At the time of the cremation or "last rites" a "Puja" (ritual worship) is performed.Holy text of Rigveda, one of the most oldest Hindu scripture has many Ruchas(small poems) related to cremation stating that Lord Agni (God of Fire) will purify this body so instead of any other method let’s give this Parthiv (dead body) to Agni (Fire).
## Christianity
In Christian countries and cultures, cremation has typically been discouraged, but not forbidden.
### Roman Catholicism
The Roman Catholic Church's discouragement of cremation stemmed from several ideas: first, that the body, as the instrument through which the sacraments are received, is itself a sacramental, a holy object;[16] second that as an integral part of the human person,[17] it should be disposed of in a way that honours and reverences it, and many early practices involved with disposal of dead bodies were viewed as pagan in origin or an insult to the body;[18] third, that in imitation of Jesus Christ's burial, the body of a Christian should be buried; and fourth, that it constituted a denial of the resurrection of the body.[19] Cremation was not forbidden because it might interfere with God's ability to resurrect the body, however; this was refuted as early as Minucius Felix, in his dialogue Octavius.[20]
Cremation was, in fact, not forbidden in and of itself; even in Medieval Europe cremation was practised in situations where there were multitudes of corpses simultaneously present, such as after a battle, after a pestilence or famine, and where there was an imminent danger of diseases spreading from the corpses, since individual burials with digging graves would take too long time and body decomposition begin before all the corpses had been interred. However, earth burial or entombment remained the law unless there were circumstances that required cremation for the public good.[citation needed]
Beginning in the Middle Ages, and even more so in the 18th century and later, rationalists and classicists began to advocate cremation again as a statement denying the resurrection and/or the afterlife,[21] although the pro-cremation movement more often than not took care to address and refute theological concerns about cremation in their works.[22] Sentiment within the Catholic Church against cremation became hardened in the face of the association of cremation with "professed enemies of God".[22] Rules were made against cremation,[23] which were softened in the 1960s.[19] The Catholic Church still officially prefers the traditional burial or entombment of the deceased,[24] but cremation is now freely permitted as long as it is not done to express a refusal to believe in the resurrection of the body.[25]
Until 1997, Catholic liturgical regulations required that cremation take place after the funeral Mass, so that, if possible, the body might be present for the Mass - the body was present as a symbol, and to receive the blessings and be the subject of prayers in which it is mentioned. Once the Mass itself was concluded, the body could be cremated and a second service could be held at the crematorium or cemetery where the ashes were to be interred just as for a body burial. The liturgical regulations now allow for a Mass with the container of ashes present, but permission of the local bishop is needed for this[citation needed]. The Church still specifies requirements for the reverent disposition of ashes, normally that the ashes are to be buried or entombed in an appropriate container, such as an urn (rather than scattered or preserved in the family home). Catholic cemeteries today regularly receive cremated remains and many have columbaria.
### Protestantism
Protestant churches were much more welcoming of the use of cremation and at a much earlier date than the Catholic Church; pro-cremation sentiment was not unanimous among Protestants, however.[26] The first crematoria in the Protestant countries were built in 1870s, and in 1908 the Dean and Chapter of Westminster Abbey, one of the most famous Anglican churches, required that remains be cremated for burial in the abbey's precincts.[27] Scattering, or "strewing," is an acceptable practice in many Protestant denominations, and some churches have their own "garden of remembrance" on their grounds in which remains can be scattered. Other self-proclaiming Christian groups also support cremation. These include Jehovah's Witnesses[28]
and the Seventh-day Adventist Church.
### Eastern Orthodox and others who forbid cremation
On the other hand, some branches of Christianity oppose cremation, including some minority Protestant groups.[29] Most notably, the Eastern Orthodox Churches forbid cremation. Exceptions are made for circumstances where it may not be avoided (when civil authority demands it, or epidemics) or if it may be sought for good cause, but when a cremation is willfully chosen for no good cause by the one who is deceased, he or she is not permitted a funeral in the church and may also be permanently excluded from liturgical prayers for the departed. In Orthodoxy, cremation is a rejection of the dogma of the general resurrection, and as such is viewed harshly.[30][31]
### Mormonism
Leaders of the The Church of Jesus Christ of Latter-day Saints have typically declared that cremation is strongly discouraged. This is based on the LDS belief that the body is holy, and that the body and soul will eventually be reunited. Prominent LDS leader Bruce R. McConkie[32] wrote that "only under the most extraordinary and unusual circumstances" would cremation be consistent with LDS teachings.
## Judaism
Judaism traditionally disapproved of cremation in the past (it was the traditional means of disposing the dead in the neighboring Bronze Age cultures). It has also disapproved of preservation of the dead by means of embalming and mummifying,[33][34] a practice of the ancient Egyptians. During the 19th and early 20th centuries, as the Jewish cemeteries in many European towns had become crowded and were running out of space, cremation became an approved means of corpse disposal amongst the Liberal Jews. Current liberal movements like Reform Judaism still support cremation, although divided burial remains the preferred option.[35][7]
The Orthodox Jews have maintained a stricter line on cremation, and disapprove of it as Halakha (Jewish law) forbids it. This halakhic concern is grounded in the upholding of bodily resurrection as a core belief of traditional Judaism, as opposed to other ancient trends such as the Sadduccees, who denied it. Conservative Jewish groups also oppose cremation.[36][37]
In more recent years, most Jews are opting against cremation due to The Holocaust, since many of the six million Jews executed by the Nazi's were burned alive in the furnaces at the death camps. Many of the former Nazi death camps today have mounds of ashes underneath a shallow layer of dirt.
## Zoroastrianism
Traditionally, Zoroastrianism disavows cremation or burial to preclude pollution of fire or earth. The traditional method of corpse disposal is through ritual exposure in a "Tower of Silence," but both burial and cremation are increasingly popular alternatives. Some contemporary figures of the faith have opted for cremation. Parsi-Zoroastrian singer Freddie Mercury of the group Queen was cremated after his death.
## Neopaganism
Of modern Neo-Pagan religions, Ásatrú favours cremation, as do forms of Celtic Paganism.
## Other religions that permit cremation
Ásatrú, Buddhism, Christianity (containing Church of Ireland, Church in Wales, United Church of Canada, Jehovah's Witnesses, Lutheranism, Methodism, Moravian Church, Salvation Army, Scottish Episcopal Church), Christian Science, Church of Scientology, Hinduism (mandatory except for sanyasis, eunuchs and children under five), Jainism, Sikhs, Society of Friends (Quakers), and Unitarian Universalism all permit cremation.
## Other religions that forbid cremation
The Bahá'í Faith forbids cremation. Neo-Confucianism under Zhu Xi strongly discourages cremation of one's parents' corpses as unfilial. In Egyptian Reconstructionism it is believed the Ka will be killed with cremation but it is not forbidden and during ancient times, was a practice of desposing of criminals who were executed in order for them to be deprived of an afterlife. In Islam the Islamic Law forbids Cremation.
# History
## Ancient
Cremation dates to at least 26,000 years ago in the archaeological record with the Mungo Lake cremation.
Alternative death rituals emphasizing one method of disposal of a body, inhumation (burial, cremation, and exposure), have gone through periods of preference throughout history.
In the Middle East and Europe both burial and cremation are evident in the archaeological record in the Neolithic. Cultural groups had their own preference and prohibitions. The ancient Egyptians developed an intricate transmigration of soul theology, which prohibited cremation, and this was adopted widely among other Semitic peoples. The Babylonians, according to Herodotus, embalmed their dead. Early Persians practiced cremation but this became prohibited during the Zoroastrian Period. Phoenicians practiced both cremation and burial. Ancient Greeks and Romans practiced both with cremation generally associated with military honours.
In Europe, there are traces of cremation dating to the Early Bronze Age (ca. 2000 BC) in the Pannonian Plain and along the middle Danube. The custom becomes dominant throughout Bronze Age Europe with the Urnfield culture (from ca. 1300 BC). In the Iron Age, inhumation becomes again more common, but cremation persisted in the Villanovan culture and elsewhere. Homer's account of Patroclus' burial describes cremation with subsequent burial in a tumulus similar to Urnfield burials, qualifying as the earliest description of cremation rites. This is mostly an anachronism, as during Mycenaean times burial was generally preferred, and Homer may have been reflecting more common use of cremation in the period in which the Iliad was written centuries later.
Criticism of burial rites is a common aspersion in competing religions and cultures and one is the association of cremation with fire sacrifice or human sacrifice.
Hinduism and Jainism are notable for not only allowing but prescribing cremation. Cremation in India is first attested in the Cemetery H culture (from ca. 1900 BC), considered the formative stage of Vedic civilization. The Rigveda contains a reference to the emerging practice, in RV 10.15.14, where the forefathers "both cremated (agnidagdhá-) and uncremated (ánagnidagdha-)" are invoked.
Cremation remained common, but not universal, in both Ancient Greece and Ancient Rome. According to Cicero, in Rome inhumation was considered the more archaic rite, while the most honoured citizens were most typically cremated, especially upper classes and members of imperial families.
Christianity frowned upon cremation, both influenced by the tenets of Judaism, and in an attempt to abolish Graeco-Roman pagan rituals. By the 5th century, the practice of cremation had practically disappeared from Europe.
In early Roman Britain cremation was usual but diminished by the fourth century. It then reappeared in the fifth and sixth centuries during the migration era, when sacrificed animals were sometimes included with the human bodies on the pyre, and the deceased were dressed in costume and with ornaments for the burning. That custom was also very widespread among the Germanic peoples of the northern continental lands from which the Anglo-Saxon migrants are supposed to have been derived, during the same period. These ashes were usually thereafter deposited in a vessel of clay or bronze in an 'urn cemetery'. The custom again died out with the Christian conversion among the Anglo-Saxons or Early English, during the seventh century, when inhumation of the corpse became general.[38]
## In the Middle Ages
Throughout parts of Europe, cremation was forbidden by law, and even punishable by death if combined with heathen rites.[39] Cremation was sometimes used by authorities as part of punishment for heretics, and this did not only include burning at the stake. For example, the body of John Wycliff was exhumed years after his death and cremated, with the ashes thrown in a river,.[40] explicitly as a posthumous punishment for his denial of the Roman Catholic doctrine of transubstantiation.[41] On the other hand, mass cremations were often performed because of necessity, when there was a danger of contagious diseases, such as after a battle, pestilence or famine. Retributory cremation continued into modern times. For example, after World War II, the bodies of the 12 men convicted of crimes against humanity at the Nuremberg Trials were not returned to their families, but were instead cremated, then disposed of at a secret location, as a specific part of a legal process intended to deny their use as a location for any sort of memorial.[42] In Japan, however, a memorial building for many executed war criminals, who were also cremated, was allowed to be erected for their remains.[43]
Many Communist countries used similar obliteration as an aggravated capital punishment: the bodies of the executed were cremated and the ashes ignominiously disposed, thus humiliating the families even further.
Even today, cremation bears the stigma of "human waste disposal" in many ex-Socialist countries and is considered ignominious or shameful.
## The modern era
In 1873, Paduan Professor Brunetti presented a cremation chamber at the Vienna Exposition. In Britain, the movement found the support of Queen Victoria's surgeon, Sir Henry Thompson, who together with colleagues founded the Cremation Society of England in 1874. The first crematoria in Europe were built in 1878 in Woking, England and Gotha, Germany, the first in North America in 1876 by Dr. Francis Julius LeMoyne in Washington, Pennsylvania. The second cremation in the United States was that of Charles F. Winslow in Salt Lake City, Utah on July 31 1877. The first cremation in Britain took place on 26th March 1886 at Woking.[44]
Cremation was declared as legal in England and Wales when Dr William Price was prosecuted for cremating his son;[45] formal legislation followed later with the passing of the Cremation Act 1902, (this Act did not extend to Ireland) which imposed procedural requirements before a cremation could occur and restricted the practice to authorised places.[46] Some of the various Protestant churches came to accept cremation, with the rationale being, "God can resurrect a bowl of ashes just as conveniently as he can resurrect a bowl of dust". The 1908 Catholic Encyclopedia was critical about these efforts, referring to them as a "sinister movement" and associating them with Freemasonry, although it said that "there is nothing directly opposed to any dogma of the Church in the practice of cremation".[47] In 1963, Pope Paul VI lifted the ban on cremation,[19] and in 1966 allowed Catholic priests to officiate at cremation ceremonies.
Australia also started to establish modern cremation movements and societies. Australians had their first purpose-built modern crematorium and chapel in the West Terrace Cemetery in the South Australian capital Adelaide in 1901. This small building, resembling the buildings at Woking, remained largely unchanged from its 19th century style and in full operation until the late 1950s. The oldest operating Crematorium in Australia is at Rookwood in Sydney. It opened in 1925.
In the Netherlands, the foundation of the Association for Optional Cremation[48] in 1874 ushered in a long debate about the merits and demerits of cremation. Laws against cremation were challenged and invalidated in 1915 (two years after the construction of the first crematorium in the Netherlands), though cremation did not become legally recognised until 1955.[49]
# Negative experiences with cremation in recent history
## World War II
During the Holocaust, massive crematoria were constructed and operated by the Nazis within their concentration camps and extermination camps to dispose of the bodies of thousands of Jews, Gypsies, and other prisoners who were killed or died in the camps daily[citation needed]. In addition to the atrocity of mass murder, the remains of Jews were thus disposed of in a manner deeply offensive to Orthodox Judaism because Halakha, the Jewish law, forbids cremation and holds that the soul of a cremated person cannot find its final repose.[citation needed] Since then, cremation has carried an extremely negative connotation for many Jews.
## The Tri-State Crematory incident
A recent controversial event involved the failure to cremate, known as the Tri-State Crematory Incident. In the state of Georgia in the United States in early 2002, three hundred thirty-four corpses that were supposed to have been cremated in the previous few years at the Tri-State Crematory were found intact and decaying on the crematorium's grounds, having been dumped there by the crematorium's proprietor. Many of the corpses were beyond identification. In many cases the "ashes" that were returned to the family were not human remains - they were made of wood and concrete dust.
Eventually Ray Brent Marsh—who was the operator at the time the bodies were discovered—had 787 criminal charges filed against him. On November 19, 2004 Marsh pleaded guilty to all charges. Marsh was sentenced to two 12-year prison sentences from both Georgia and Tennessee which he is serving concurrently. Afterwards he will be on probation for 75 years.
Civil suits were filed against the Marsh family as well as a number of funeral homes who shipped bodies to Tri-State. These suits were ultimately settled. The property of the Marsh family has been sold, but collection of the full $80 million judgment remains doubtful. Families have expressed the desire to return the former Tri-State crematory to a natural, park like setting.
## The Indian Ocean tsunamis
The magnitude 9.0-9.3 2004 Indian Ocean Earthquake triggered a series of lethal tsunamis on December 26, 2004 that killed almost 300,000 people, making them the deadliest tsunamis in recorded history. The tsunamis killed people over an area ranging from the immediate vicinity of the quake in Indonesia, Thailand, and the north-western coast of Malaysia, to thousands of kilometres away in Bangladesh, India, Sri Lanka, the Maldives, and even as far as Somalia, Kenya, and Tanzania in eastern Africa.
Authorities had difficulties dealing with the large numbers of bodies, and as a result thousands of bodies were of necessity cremated together. Many of these bodies were not identified or viewed by relatives prior to cremation. A particular point of objection was that the bodies of Westerners were kept separate from those of Asian descent, who were mostly locals. This meant that the bodies of tourists from other Asian nations, such as Japan and Korea, were mass cremated rather than being returned to their country of origin for funeral rites. | https://www.wikidoc.org/index.php/Cremation | |
7ea53486c660b472c27782b5d46e16b28a55563a | wikidoc | Crime lab | Crime lab
A crime laboratory - often shortened to crime lab - is a scientific laboratory, using primarily forensic science for the purpose of examining evidence from criminal cases.
# Lab personnel
A typical crime lab has two sets of personnel:
- Field analysts - investigators that go to crime scenes, collect evidence, and process the scene. Job titles include:
Forensic evidence technician
Crime scene investigator
Scenes of crime officer (SOCO)
- Forensic evidence technician
- Crime scene investigator
- Scenes of crime officer (SOCO)
- Laboratory analysts - scientists who run tests on the evidence once it is brought to the lab (i.e., DNA tests, or bullet striations). Job titles include:
Forensic technician
Forensic scientist
Criminalist
Forensic Photographer
- Forensic technician
- Forensic scientist
- Criminalist
- Forensic Photographer
# Crime labs
## United States
In the United States, crime labs may be publicly or privately operated, although private laboratories typically do not respond to crime scenes to collect evidence. Public crime labs are organized at the city, county, state, or national level. A law enforcement agency that does not operate its own crime lab usually has free access to a higher level laboratory for analysis of their evidence.
- Most states have their own crime labs, for instance Oklahoma has the OSBI, many other places have smaller yet still sufficient crime labs.
### Well-known crime labs
Some well-known crime labs are:
- FBI Laboratory - under the jurisdiction of the FBI (located at FBI Headquarters; J. Edgar Hoover Building)
- Las Vegas Crime Lab - under the jurisdiction of the Las Vegas Metropolitan Police Department
- Miami-Dade Crime Lab - under the jurisdiction of the Miami-Dade Police Department
- New York City Crime Lab - under the jurisdiction of the New York City Police Department
- Los Angeles Crime Lab - under the jurisdiction of the Los Angeles Police Department
- Forensic Science Training and Research Center - under the jurisdiction of the FBI (located at the FBI Academy in Quantico, Virginia)
# Crime labs in popular culture
The term "crime lab" has become a part of popular culture, largely due to the TV dramas. Some of the more famous shows are:
- CSI: Crime Scene Investigation
- CSI: Miami
- CSI: NY.
- NCIS (Tv Series)
- Quincy, M.E. - a 1970's television show featuring crime lab personnel and procedures
Several non-fiction television programs, document the resolution of criminal cases based on the scientific analysis of the evidence:
- Forensic Files | Crime lab
A crime laboratory - often shortened to crime lab - is a scientific laboratory, using primarily forensic science for the purpose of examining evidence from criminal cases.
# Lab personnel
A typical crime lab has two sets of personnel:
- Field analysts - investigators that go to crime scenes, collect evidence, and process the scene. Job titles include:
Forensic evidence technician
Crime scene investigator
Scenes of crime officer (SOCO)
- Forensic evidence technician
- Crime scene investigator
- Scenes of crime officer (SOCO)
- Laboratory analysts - scientists who run tests on the evidence once it is brought to the lab (i.e., DNA tests, or bullet striations). Job titles include:
Forensic technician
Forensic scientist
Criminalist
Forensic Photographer
- Forensic technician
- Forensic scientist
- Criminalist
- Forensic Photographer
# Crime labs
## United States
In the United States, crime labs may be publicly or privately operated, although private laboratories typically do not respond to crime scenes to collect evidence. Public crime labs are organized at the city, county, state, or national level. A law enforcement agency that does not operate its own crime lab usually has free access to a higher level laboratory for analysis of their evidence.
- Most states have their own crime labs, for instance Oklahoma has the OSBI, many other places have smaller yet still sufficient crime labs.
### Well-known crime labs
Some well-known crime labs are:
- FBI Laboratory - under the jurisdiction of the FBI (located at FBI Headquarters; J. Edgar Hoover Building)
- Las Vegas Crime Lab - under the jurisdiction of the Las Vegas Metropolitan Police Department
- Miami-Dade Crime Lab - under the jurisdiction of the Miami-Dade Police Department
- New York City Crime Lab - under the jurisdiction of the New York City Police Department
- Los Angeles Crime Lab - under the jurisdiction of the Los Angeles Police Department
- Forensic Science Training and Research Center - under the jurisdiction of the FBI (located at the FBI Academy in Quantico, Virginia)
# Crime labs in popular culture
The term "crime lab" has become a part of popular culture, largely due to the TV dramas. Some of the more famous shows are:
- CSI: Crime Scene Investigation
- CSI: Miami
- CSI: NY.
- NCIS (Tv Series)
- Quincy, M.E. - a 1970's television show featuring crime lab personnel and procedures
Several non-fiction television programs, document the resolution of criminal cases based on the scientific analysis of the evidence:
- Forensic Files
# External links
- FBI Crime Lab
- Arkansas State Crime Lab
- US Postal Service Forensic Lab
- Reddy's Forensic Page - link to US and international forensic laboratories
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Crime_Lab | |
5569612c1b64156b10f40dca224821191cc45f48 | wikidoc | Crithidia | Crithidia
Crithidia are members of the trypanosome protozoa. They are parasites that exclusively parasitise arthropods, mainly insects. They pass from host to host as cysts in infective feaces and typically, the parasites develop in the digestive tracts of insects and interact with the intestinal epithelium using their flagellum. They display very low host-specificity and a single parasite can infect a large range of invertebrate hosts . At different points in its life-cycle, it passes through amastigote, promastigote, and epimastigote phases; the last is particularly characteristic, and similar stages in other trypanosomes are often called crithidial.
Crithidia bombi is perhaps the most well documented species and is a parasite of bumblebees. Other species include C. fasciculata,C. deanei, C. desouzai, C. oncopelti, C. guilhermei and C. luciliae. C. deanei is atypical of the Crithidia genus, and it has been argued not a member of the Crithidia at all. It is also not typical of trypanosomatids because of its unusual shape and it harbours endosymbiotic bacteria .
# Bibliography
Boulanger et al. (2001) Immune response of Drosophila melanogaster to infection of the flagellate parasite Crithidia spp. Insect Biochemistry and Molecular Biology
Camargo et al. (1992) Ribosomal DNA restriction analysis and synthetic oligonucleotide probing in the identification of genera of lower trypanosomatids The Journal of Parasitology | Crithidia
Crithidia are members of the trypanosome protozoa. They are parasites that exclusively parasitise arthropods, mainly insects. They pass from host to host as cysts in infective feaces and typically, the parasites develop in the digestive tracts of insects and interact with the intestinal epithelium using their flagellum. They display very low host-specificity and a single parasite can infect a large range of invertebrate hosts [1]. At different points in its life-cycle, it passes through amastigote, promastigote, and epimastigote phases; the last is particularly characteristic, and similar stages in other trypanosomes are often called crithidial.
Crithidia bombi is perhaps the most well documented species and is a parasite of bumblebees. Other species include C. fasciculata,C. deanei, C. desouzai, C. oncopelti, C. guilhermei and C. luciliae. C. deanei is atypical of the Crithidia genus, and it has been argued not a member of the Crithidia at all. It is also not typical of trypanosomatids because of its unusual shape and it harbours endosymbiotic bacteria [2].
# Bibliography
- ↑ [1]
- ↑ [2]
[1]Boulanger et al. (2001) Immune response of Drosophila melanogaster to infection of the flagellate parasite Crithidia spp. Insect Biochemistry and Molecular Biology
[2]Camargo et al. (1992) Ribosomal DNA restriction analysis and synthetic oligonucleotide probing in the identification of genera of lower trypanosomatids The Journal of Parasitology | https://www.wikidoc.org/index.php/Crithidia | |
2cec2b6cbc2c50fa54dcd104550e290b84db11fd | wikidoc | Indinavir | Indinavir
- Indinavir must be taken at intervals of 8 hours. For optimal absorption, Indinavir should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, Indinavir may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal, e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; or corn flakes, skim milk and sugar. To ensure adequate hydration, it is recommended that adults drink at least 1.5 liters (approximately 48 ounces) of liquids during the course of 24 hours.
# Concomitant Therapy
- Delavirdine: Dose reduction of Indinavir to 600 mg every 8 hours should be considered when administering delavirdine 400 mg three times a day.
- Didanosine: If indinavir and didanosine are administered concomitantly, they should be administered at least one hour apart on an empty stomach (consult the manufacturer's product circular for didanosine).
- Itraconazole: Dose reduction of Indinavir to 600 mg every 8 hours is recommended when administering itraconazole 200 mg twice daily concurrently.
- Ketoconazole: Dose reduction of Indinavir to 600 mg every 8 hours is recommended when administering ketoconazole concurrently.
- Rifabutin: Dose reduction of rifabutin to half the standard dose (consult the manufacturer's product circular for rifabutin) and a dose increase of Indinavir to 1000 mg every 8 hours are recommended when rifabutin and Indinavir are coadministered.
# Hepatic Insufficiency
- The dosage of Indinavir should be reduced to 600 mg every 8 hours in patients with mild-to-moderate hepatic insufficiency due to cirrhosis.
# Nephrolithiasis/Urolithiasis
- In addition to adequate hydration, medical management in patients who experience nephrolithiasis/urolithiasis may include temporary interruption (e.g., 1 to 3 days) or discontinuation of therapy.
- Dosage:
Monotherapy: 800 mg every 8 hours
Combined therapy: If combining with ritonavir, 800 mg indinavir and 100 mg ritonavir every 12 hours or 800 mg indinavir and 200 mg ritonavir every 12 hours
- Monotherapy: 800 mg every 8 hours
- Combined therapy: If combining with ritonavir, 800 mg indinavir and 100 mg ritonavir every 12 hours or 800 mg indinavir and 200 mg ritonavir every 12 hours
- Dosage:
Children (3 years to 12 years of age): 450 to 500 mg/m(2) PO q8h
Adolescents (13 years of age or greater): 800 mg PO 3 q8h
- Children (3 years to 12 years of age): 450 to 500 mg/m(2) PO q8h
- Adolescents (13 years of age or greater): 800 mg PO 3 q8h
- Inhibition of CYP3A4 by Indinavir can result in elevated plasma concentrations of the following drugs, potentially causing serious or life-threatening reactions:
# Nephrolithiasis/Urolithiasis
- Nephrolithiasis/urolithiasis has occurred with Indinavir therapy. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range across individual trials: 4.7% to 34.4%). The cumulative frequency of nephrolithiasis events increases with increasing exposure to Indinavir; however, the risk over time remains relatively constant. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur, (including flank pain, with or without hematuria or microscopic hematuria), temporary interruption (e.g., 1-3 days) or discontinuation of therapy may be considered. Adequate hydration is recommended in all patients treated with Indinavir.
# Hemolytic Anemia
- Acute hemolytic anemia, including cases resulting in death, has been reported in patients treated with Indinavir Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of Indinavir.
# Hepatitis
- Hepatitis including cases resulting in hepatic failure and death has been reported in patients treated with Indinavir Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between Indinavir and these events has not been established.
# Hyperglycemia
- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
# Drug Interactions
- Concomitant use of Indinavir with lovastatin or simvastatin is contraindicated due to an increased risk of myopathy including rhabdomyolysis. Caution should be exercised if Indinavir is used concurrently with atorvastatin or rosuvastatin. Titrate the atorvastatin and rosuvastatin doses carefully and use the lowest necessary dose with Indinavir.
- Midazolam is extensively metabolized by CYP3A4. Co-administration with Indinavir with or without ritonavir may cause a large increase in the concentration of this benzodiazepine. No drug interaction study has been performed for the co-administration of Indinavir with benzodiazepines. Based on data from other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore Indinavir should not be co-administered with orally administered midazolam, whereas caution should be used with co-administration of Indinavir and parenteral midazolam. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels. If Indinavir with or without ritonavir is co-administered with parenteral midazolam, it should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
- Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving indinavir. Coadministration of Indinavir with these medications is expected to substantially increase plasma concentrations of sildenafil, tadalafil, and vardenafil and may result in an increase in adverse events, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil.
- Concomitant use of Indinavir and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of Indinavir and St. John's wort has been shown to substantially decrease indinavir concentrations and may lead to loss of virologic response and possible resistance to Indinavir or to the class of protease inhibitors.
- Nephrolithiasis/urolithiasis, including flank pain with or without hematuria (including microscopic hematuria), has been reported in approximately 12.4% (301/2429; range across individual trials: 4.7% to 34.4%) of patients receiving Indinavir at the recommended dose in clinical trials with a median follow-up of 47 weeks (range: 1 day to 242 weeks; 2238 patient-years follow-up). The cumulative frequency of nephrolithiasis events increases with duration of exposure to Indinavir however, the risk over time remains relatively constant. Of the patients treated with Indinavir who developed nephrolithiasis/urolithiasis in clinical trials during the double-blind phase, 2.8% (7/246) were reported to develop hydronephrosis and 4.5% (11/246) underwent stent placement. Following the acute episode, 4.9% (12/246) of patients discontinued therapy.
- Asymptomatic hyperbilirubinemia (total bilirubin ≥2.5 mg/dL), reported predominantly as elevated indirect bilirubin, has occurred in approximately 14% of patients treated with Indinavir. In <1% this was associated with elevations in ALT or AST.
- Hyperbilirubinemia and nephrolithiasis/urolithiasis occurred more frequently at doses exceeding 2.4 g/day compared to doses ≤2.4 g/day.
Clinical adverse experiences reported in ≥2% of patients treated with Indinavir alone, Indinavir in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in TABLE 10
- In Phase I and II controlled trials, the following adverse events were reported significantly more frequently by those randomized to the arms containing Indinavir than by those randomized to nucleoside analogues: rash, upper respiratory infection, dry skin, pharyngitis, taste perversion.
Selected laboratory abnormalities of severe or life-threatening intensity reported in patients treated with Indinavir alone, Indinavir in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 11
- Cardiovascular System: cardiovascular disorders including myocardial infarction and angina pectoris; cerebrovascular disorder.
- Digestive System: liver function abnormalities; hepatitis including reports of hepatic failure; pancreatitis; jaundice; abdominal distention; dyspepsia.
- Hematologic: increased spontaneous bleeding in patients with hemophilia; acute hemolytic anemia.
- Endocrine/Metabolic: new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia.
- Hypersensitivity: anaphylactoid reactions; urticaria; vasculitis.
- Musculoskeletal System: arthralgia, periarthritis.
- Nervous System/Psychiatric: oral paresthesia; depression.
- Skin and Skin Appendage: rash including erythema multiforme and Stevens-Johnson syndrome; hyperpigmentation; alopecia; ingrown toenails and/or paronychia; pruritus.
- Urogenital System: nephrolithiasis/urolithiasis, in some cases resulting in renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia; interstitial nephritis sometimes with indinavir crystal deposits; in some patients, the interstitial nephritis did not resolve following discontinuation of Indinavir; renal insufficiency; renal failure; leukocyturia, crystalluria; dysuria.
- Laboratory Abnormalities: Increased serum triglycerides; increased serum cholesterol.
- Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of Indinavir and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir.
- In rabbits, at a maternal dose of 240 mg/kg/day, no drug was detected in fetal plasma 1 hour after dosing. Fetal plasma drug levels 2 hours after dosing were approximately 3% of maternal plasma drug levels. In dogs, at a maternal dose of 80 mg/kg/day, fetal plasma drug levels were approximately 50% of maternal plasma drug levels both 1 and 2 hours after dosing. In rats, at maternal doses of 40 and 640 mg/kg/day, fetal plasma drug levels were approximately 10 to 15% and 10 to 20% of maternal plasma drug levels 1 and 2 hours after dosing, respectively.
- Indinavir was administered to Rhesus monkeys during the third trimester of pregnancy (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, indinavir caused an exacerbation of the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately fourfold above controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester of pregnancy. In Rhesus monkeys, fetal plasma drug levels were approximately 1 to 2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily.
- Hyperbilirubinemia has occurred during treatment with Indinavir It is unknown whether Indinavir administered to the mother in the perinatal period will exacerbate physiologic hyperbilirubinemia in neonates.
- There are no adequate and well-controlled studies in pregnant patients. Indinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- A Indinavir dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). Given the substantially lower antepartum exposures observed and the limited data in this patient population, indinavir use is not recommended in HIV-infected pregnant patients
- Indinavir was rapidly absorbed in the fasted state with a time to peak plasma concentration (Tmax) of 0.8 ± 0.3 hours (mean ± S.D.) (n=11). A greater than dose-proportional increase in indinavir plasma concentrations was observed over the 200-1000 mg dose range. At a dosing regimen of 800 mg every 8 hours, steady-state area under the plasma concentration time curve (AUC) was 30,691 ± 11,407 nMhour (n=16), peak plasma concentration (Cmax) was 12,617 ± 4037 nM (n=16), and plasma concentration eight hours post dose (trough) was 251 ± 178 nM (n=16).
- Effect of Food on Oral Absorption: Administration of indinavir with a meal high in calories, fat, and protein (784 kcal, 48.6 g fat, 31.3 g protein) resulted in a 77% ± 8% reduction in AUC and an 84% ± 7% reduction in Cmax (n=10). Administration with lighter meals (e.g., a meal of dry toast with jelly, apple juice, and coffee with skim milk and sugar or a meal of corn flakes, skim milk and sugar) resulted in little or no change in AUC, Cmax or trough concentration.
# Distribution
- Indinavir was approximately 60% bound to human plasma proteins over a concentration range of 81 nM to 16,300 nM.
# Metabolism
- Following a 400-mg dose of 14C-indinavir, 83 ± 1% (n=4) and 19 ± 3% (n=6) of the total radioactivity was recovered in feces and urine, respectively; radioactivity due to parent drug in feces and urine was 19.1% and 9.4%, respectively. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites.
# Elimination
- Less than 20% of indinavir is excreted unchanged in the urine. Mean urinary excretion of unchanged drug was 10.4 ± 4.9% (n=10) and 12.0 ± 4.9% (n=10) following a single 700-mg and 1000-mg dose, respectively. Indinavir was rapidly eliminated with a half-life of 1.8 ± 0.4 hours (n=10). Significant accumulation was not observed after multiple dosing at 800 mg every 8 hours.
- No. 3756 — 200 mg capsules: semi-translucent white capsules coded "Indinavur™ 200 mg" in blue. Available as:
NDC 0006-0571-43 unit-of-use bottles of 360 (with desiccant).
- NDC 0006-0571-43 unit-of-use bottles of 360 (with desiccant).
- No. 3758 — 400 mg capsules: semi-translucent white capsules coded "Indinavur™ 400 mg" in green. Available as:
NDC 0006-0573-62 unit-of-use bottles of 180 (with desiccant)
- NDC 0006-0573-62 unit-of-use bottles of 180 (with desiccant)
- Indinavur Capsules are sensitive to moisture. Indinavur should be dispensed and stored in the original container. The desiccant should remain in the original bottle.
- ↑ "Imprimir Management Of Adults And Children With Nonoccupational Exposure To HIV". line feed character in |title= at position 9 (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Imprimir Management Of Adults And Children With Nonoccupational Exposure To HIV". line feed character in |title= at position 9 (help) | Indinavir
- Indinavir must be taken at intervals of 8 hours. For optimal absorption, Indinavir should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, Indinavir may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal, e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; or corn flakes, skim milk and sugar. To ensure adequate hydration, it is recommended that adults drink at least 1.5 liters (approximately 48 ounces) of liquids during the course of 24 hours.
### Concomitant Therapy
- Delavirdine: Dose reduction of Indinavir to 600 mg every 8 hours should be considered when administering delavirdine 400 mg three times a day.
- Didanosine: If indinavir and didanosine are administered concomitantly, they should be administered at least one hour apart on an empty stomach (consult the manufacturer's product circular for didanosine).
- Itraconazole: Dose reduction of Indinavir to 600 mg every 8 hours is recommended when administering itraconazole 200 mg twice daily concurrently.
- Ketoconazole: Dose reduction of Indinavir to 600 mg every 8 hours is recommended when administering ketoconazole concurrently.
- Rifabutin: Dose reduction of rifabutin to half the standard dose (consult the manufacturer's product circular for rifabutin) and a dose increase of Indinavir to 1000 mg every 8 hours are recommended when rifabutin and Indinavir are coadministered.
### Hepatic Insufficiency
- The dosage of Indinavir should be reduced to 600 mg every 8 hours in patients with mild-to-moderate hepatic insufficiency due to cirrhosis.
### Nephrolithiasis/Urolithiasis
- In addition to adequate hydration, medical management in patients who experience nephrolithiasis/urolithiasis may include temporary interruption (e.g., 1 to 3 days) or discontinuation of therapy.
- Dosage[1]:
Monotherapy: 800 mg every 8 hours
Combined therapy: If combining with ritonavir, 800 mg indinavir and 100 mg ritonavir every 12 hours or 800 mg indinavir and 200 mg ritonavir every 12 hours
- Monotherapy: 800 mg every 8 hours
- Combined therapy: If combining with ritonavir, 800 mg indinavir and 100 mg ritonavir every 12 hours or 800 mg indinavir and 200 mg ritonavir every 12 hours
- Dosage[2]:
Children (3 years to 12 years of age): 450 to 500 mg/m(2) PO q8h
Adolescents (13 years of age or greater): 800 mg PO 3 q8h
- Children (3 years to 12 years of age): 450 to 500 mg/m(2) PO q8h
- Adolescents (13 years of age or greater): 800 mg PO 3 q8h
- Inhibition of CYP3A4 by Indinavir can result in elevated plasma concentrations of the following drugs, potentially causing serious or life-threatening reactions:
### Nephrolithiasis/Urolithiasis
- Nephrolithiasis/urolithiasis has occurred with Indinavir therapy. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range across individual trials: 4.7% to 34.4%). The cumulative frequency of nephrolithiasis events increases with increasing exposure to Indinavir; however, the risk over time remains relatively constant. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur, (including flank pain, with or without hematuria or microscopic hematuria), temporary interruption (e.g., 1-3 days) or discontinuation of therapy may be considered. Adequate hydration is recommended in all patients treated with Indinavir.
### Hemolytic Anemia
- Acute hemolytic anemia, including cases resulting in death, has been reported in patients treated with Indinavir Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of Indinavir.
### Hepatitis
- Hepatitis including cases resulting in hepatic failure and death has been reported in patients treated with Indinavir Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between Indinavir and these events has not been established.
### Hyperglycemia
- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
### Drug Interactions
- Concomitant use of Indinavir with lovastatin or simvastatin is contraindicated due to an increased risk of myopathy including rhabdomyolysis. Caution should be exercised if Indinavir is used concurrently with atorvastatin or rosuvastatin. Titrate the atorvastatin and rosuvastatin doses carefully and use the lowest necessary dose with Indinavir.
- Midazolam is extensively metabolized by CYP3A4. Co-administration with Indinavir with or without ritonavir may cause a large increase in the concentration of this benzodiazepine. No drug interaction study has been performed for the co-administration of Indinavir with benzodiazepines. Based on data from other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore Indinavir should not be co-administered with orally administered midazolam, whereas caution should be used with co-administration of Indinavir and parenteral midazolam. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels. If Indinavir with or without ritonavir is co-administered with parenteral midazolam, it should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
- Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving indinavir. Coadministration of Indinavir with these medications is expected to substantially increase plasma concentrations of sildenafil, tadalafil, and vardenafil and may result in an increase in adverse events, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil.
- Concomitant use of Indinavir and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of Indinavir and St. John's wort has been shown to substantially decrease indinavir concentrations and may lead to loss of virologic response and possible resistance to Indinavir or to the class of protease inhibitors.
- Nephrolithiasis/urolithiasis, including flank pain with or without hematuria (including microscopic hematuria), has been reported in approximately 12.4% (301/2429; range across individual trials: 4.7% to 34.4%) of patients receiving Indinavir at the recommended dose in clinical trials with a median follow-up of 47 weeks (range: 1 day to 242 weeks; 2238 patient-years follow-up). The cumulative frequency of nephrolithiasis events increases with duration of exposure to Indinavir however, the risk over time remains relatively constant. Of the patients treated with Indinavir who developed nephrolithiasis/urolithiasis in clinical trials during the double-blind phase, 2.8% (7/246) were reported to develop hydronephrosis and 4.5% (11/246) underwent stent placement. Following the acute episode, 4.9% (12/246) of patients discontinued therapy.
- Asymptomatic hyperbilirubinemia (total bilirubin ≥2.5 mg/dL), reported predominantly as elevated indirect bilirubin, has occurred in approximately 14% of patients treated with Indinavir. In <1% this was associated with elevations in ALT or AST.
- Hyperbilirubinemia and nephrolithiasis/urolithiasis occurred more frequently at doses exceeding 2.4 g/day compared to doses ≤2.4 g/day.
Clinical adverse experiences reported in ≥2% of patients treated with Indinavir alone, Indinavir in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in TABLE 10
- In Phase I and II controlled trials, the following adverse events were reported significantly more frequently by those randomized to the arms containing Indinavir than by those randomized to nucleoside analogues: rash, upper respiratory infection, dry skin, pharyngitis, taste perversion.
Selected laboratory abnormalities of severe or life-threatening intensity reported in patients treated with Indinavir alone, Indinavir in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 11
- Cardiovascular System: cardiovascular disorders including myocardial infarction and angina pectoris; cerebrovascular disorder.
- Digestive System: liver function abnormalities; hepatitis including reports of hepatic failure; pancreatitis; jaundice; abdominal distention; dyspepsia.
- Hematologic: increased spontaneous bleeding in patients with hemophilia; acute hemolytic anemia.
- Endocrine/Metabolic: new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia.
- Hypersensitivity: anaphylactoid reactions; urticaria; vasculitis.
- Musculoskeletal System: arthralgia, periarthritis.
- Nervous System/Psychiatric: oral paresthesia; depression.
- Skin and Skin Appendage: rash including erythema multiforme and Stevens-Johnson syndrome; hyperpigmentation; alopecia; ingrown toenails and/or paronychia; pruritus.
- Urogenital System: nephrolithiasis/urolithiasis, in some cases resulting in renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia; interstitial nephritis sometimes with indinavir crystal deposits; in some patients, the interstitial nephritis did not resolve following discontinuation of Indinavir; renal insufficiency; renal failure; leukocyturia, crystalluria; dysuria.
- Laboratory Abnormalities: Increased serum triglycerides; increased serum cholesterol.
- Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of Indinavir and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir.
- In rabbits, at a maternal dose of 240 mg/kg/day, no drug was detected in fetal plasma 1 hour after dosing. Fetal plasma drug levels 2 hours after dosing were approximately 3% of maternal plasma drug levels. In dogs, at a maternal dose of 80 mg/kg/day, fetal plasma drug levels were approximately 50% of maternal plasma drug levels both 1 and 2 hours after dosing. In rats, at maternal doses of 40 and 640 mg/kg/day, fetal plasma drug levels were approximately 10 to 15% and 10 to 20% of maternal plasma drug levels 1 and 2 hours after dosing, respectively.
- Indinavir was administered to Rhesus monkeys during the third trimester of pregnancy (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, indinavir caused an exacerbation of the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately fourfold above controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester of pregnancy. In Rhesus monkeys, fetal plasma drug levels were approximately 1 to 2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily.
- Hyperbilirubinemia has occurred during treatment with Indinavir It is unknown whether Indinavir administered to the mother in the perinatal period will exacerbate physiologic hyperbilirubinemia in neonates.
- There are no adequate and well-controlled studies in pregnant patients. Indinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- A Indinavir dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). Given the substantially lower antepartum exposures observed and the limited data in this patient population, indinavir use is not recommended in HIV-infected pregnant patients
- Indinavir was rapidly absorbed in the fasted state with a time to peak plasma concentration (Tmax) of 0.8 ± 0.3 hours (mean ± S.D.) (n=11). A greater than dose-proportional increase in indinavir plasma concentrations was observed over the 200-1000 mg dose range. At a dosing regimen of 800 mg every 8 hours, steady-state area under the plasma concentration time curve (AUC) was 30,691 ± 11,407 nM•hour (n=16), peak plasma concentration (Cmax) was 12,617 ± 4037 nM (n=16), and plasma concentration eight hours post dose (trough) was 251 ± 178 nM (n=16).
- Effect of Food on Oral Absorption: Administration of indinavir with a meal high in calories, fat, and protein (784 kcal, 48.6 g fat, 31.3 g protein) resulted in a 77% ± 8% reduction in AUC and an 84% ± 7% reduction in Cmax (n=10). Administration with lighter meals (e.g., a meal of dry toast with jelly, apple juice, and coffee with skim milk and sugar or a meal of corn flakes, skim milk and sugar) resulted in little or no change in AUC, Cmax or trough concentration.
### Distribution
- Indinavir was approximately 60% bound to human plasma proteins over a concentration range of 81 nM to 16,300 nM.
### Metabolism
- Following a 400-mg dose of 14C-indinavir, 83 ± 1% (n=4) and 19 ± 3% (n=6) of the total radioactivity was recovered in feces and urine, respectively; radioactivity due to parent drug in feces and urine was 19.1% and 9.4%, respectively. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites.
### Elimination
- Less than 20% of indinavir is excreted unchanged in the urine. Mean urinary excretion of unchanged drug was 10.4 ± 4.9% (n=10) and 12.0 ± 4.9% (n=10) following a single 700-mg and 1000-mg dose, respectively. Indinavir was rapidly eliminated with a half-life of 1.8 ± 0.4 hours (n=10). Significant accumulation was not observed after multiple dosing at 800 mg every 8 hours.
- No. 3756 — 200 mg capsules: semi-translucent white capsules coded "Indinavur™ 200 mg" in blue. Available as:
NDC 0006-0571-43 unit-of-use bottles of 360 (with desiccant).
- NDC 0006-0571-43 unit-of-use bottles of 360 (with desiccant).
- No. 3758 — 400 mg capsules: semi-translucent white capsules coded "Indinavur™ 400 mg" in green. Available as:
NDC 0006-0573-62 unit-of-use bottles of 180 (with desiccant)
- NDC 0006-0573-62 unit-of-use bottles of 180 (with desiccant)
- Indinavur Capsules are sensitive to moisture. Indinavur should be dispensed and stored in the original container. The desiccant should remain in the original bottle.
- ↑ "Imprimir Management Of Adults And Children With Nonoccupational Exposure To HIV". line feed character in |title= at position 9 (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Imprimir Management Of Adults And Children With Nonoccupational Exposure To HIV". line feed character in |title= at position 9 (help) | https://www.wikidoc.org/index.php/Crixivan | |
7985f4adef5e04adef334b9dfb4adc7aaaec94ac | wikidoc | Crossbite | Crossbite
# Overview
Crossbite is an occlusal irregular condition where a lower tooth has a more buccal position than the antagonist upper tooth. Crossbite can involve a single tooth or a group of teeth. Crossbite can be classified as anterior or posterior.
- Anterior crossbite can also be referred as negative overjet, and is typical of class III skeletal relations (Progenism).
- Posterior crossbite is often correlated to a narrow maxilla and upper dental arch. A posterior cross-bite can be unilateral or bilateral.
Unilateral cross-bite often determines a lateral shift of the mandibular position, which can become structural if left untreated for a long time during growth, leading to skeletal asymmetries.
# Etiology
A crossbite may be associated with a pathological condition. A cleft palate patient may present both anterior and posterior crossbites with a narrow palate. Arthritis, acromegaly, Duchenne’s muscular dystrophy, condylar hyperplasia and osteochondroma are other factors. The majority of anterior crossbites a single tooth or a few teeth and are caused by dental factors: A congenitally-caused eruption pattern of the maxillary anteriors. Trauma to the primary dentition which leads to the displacement of the primary or permanent tooth bud. Trauma to permanent teeth that result in their being displaced by luxation.
Other factors include;
- Stomach sleeping posture
- Digit or pacifier sucking habits
- Oral respiration
- Low tongue position
- Tongue thrusting
# Further Classification and Related Terminology
## Buccal Crossbite
Buccal crossbite is due to the buccal displacement of the affected tooth or teeth as it relates to the antagonistic tooth or teeth in the posterior segments of the arch.
## Lingual Crossbite
Lingual crossbite is due to the lingual displacement of the mandibular affected tooth or teeth as it relates to the antagonistic tooth or teeth.
## Palatal Crossbite
Palatal crossbite is due to the palatal displacement of the maxillary affected tooth or teeth as it relates to the antagonistic tooth or teeth.
## Complete Mandibular Buccal Crossbite
Complete mandibular buccal crossbite is present when all the mandibular teeth are lingually positioned to the maxillary teeth due to a narrower mandibular arch than the maxillary arch.
## Complete Maxillary Palatal Crossbite
Complete maxillary palatal crossbite is present when all the maxillary teeth are palatal to the mandibular arch due to the narrower maxillary arch.
Both complete mandibular buccal crossbite and complete maxillary palatal crossbite could be referred as scissors-bite.
## Complete Crossbite
Complete crossbite is found when all teeth in one arch are positioned either inside or outside to the all teeth in the opposing arch.
## Scissors-bite
Scissors-bite is present when one or more of the adjacent posterior teeth are either positioned completely buccally or lingually to the antagonistic teeth and exhibit a vertical overlap.
## Anterior crossbite
Anterior crossbite is a malocclusion in which one or more of the upper anterior teeth occlude lingually to the mandibular incisors; the lingual malpositions of one or more maxillary anterior teeth in relation to the mandibular anterior teeth when the teeth are in centric relation occlusion.
## Posterior Crossbite
Posterior Crossbite is one or more posterior teeth locked in an abnormal relation with the opposing teeth of the opposite arch; can be either buccal or a lingual cross-bite and may be accompanied by a shift of the mandible.
## Centric occlusion
Centric occlusion is a static reproducible position of the mandible in which there is maximal contact of the inclined planes of the opposing teeth with balanced, unstrained relationship in the temporomandibular articulation.
# Treatment
There are several therapies that can be used to correct a cross bite:
- Multibrackets therapy (braces)
- Quad-Helix
- Hirex
- Removable Plates
- Invisalign
- Delaire Mask
The correct therapy should be decided by the orthodontist depending on the type and severity of the crossbite.
# Image Gallery
- Unilateral Posterior Crossbite
- Crossbite
- Crossbite
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted) | Crossbite
Editor in Chief: Berna Zorkun DMD [1]
# Overview
Crossbite is an occlusal irregular condition where a lower tooth has a more buccal position than the antagonist upper tooth. Crossbite can involve a single tooth or a group of teeth. Crossbite can be classified as anterior or posterior.
- Anterior crossbite can also be referred as negative overjet, and is typical of class III skeletal relations (Progenism).
- Posterior crossbite is often correlated to a narrow maxilla and upper dental arch. A posterior cross-bite can be unilateral or bilateral.
Unilateral cross-bite often determines a lateral shift of the mandibular position, which can become structural if left untreated for a long time during growth, leading to skeletal asymmetries.
# Etiology
A crossbite may be associated with a pathological condition. A cleft palate patient may present both anterior and posterior crossbites with a narrow palate. Arthritis, acromegaly, Duchenne’s muscular dystrophy, condylar hyperplasia and osteochondroma are other factors. The majority of anterior crossbites a single tooth or a few teeth and are caused by dental factors: A congenitally-caused eruption pattern of the maxillary anteriors. Trauma to the primary dentition which leads to the displacement of the primary or permanent tooth bud. Trauma to permanent teeth that result in their being displaced by luxation.
Other factors include;
- Stomach sleeping posture
- Digit or pacifier sucking habits
- Oral respiration
- Low tongue position
- Tongue thrusting
# Further Classification and Related Terminology
## Buccal Crossbite
Buccal crossbite is due to the buccal displacement of the affected tooth or teeth as it relates to the antagonistic tooth or teeth in the posterior segments of the arch.
## Lingual Crossbite
Lingual crossbite is due to the lingual displacement of the mandibular affected tooth or teeth as it relates to the antagonistic tooth or teeth.
## Palatal Crossbite
Palatal crossbite is due to the palatal displacement of the maxillary affected tooth or teeth as it relates to the antagonistic tooth or teeth.
## Complete Mandibular Buccal Crossbite
Complete mandibular buccal crossbite is present when all the mandibular teeth are lingually positioned to the maxillary teeth due to a narrower mandibular arch than the maxillary arch.
## Complete Maxillary Palatal Crossbite
Complete maxillary palatal crossbite is present when all the maxillary teeth are palatal to the mandibular arch due to the narrower maxillary arch.
Both complete mandibular buccal crossbite and complete maxillary palatal crossbite could be referred as scissors-bite.
## Complete Crossbite
Complete crossbite is found when all teeth in one arch are positioned either inside or outside to the all teeth in the opposing arch.
## Scissors-bite
Scissors-bite is present when one or more of the adjacent posterior teeth are either positioned completely buccally or lingually to the antagonistic teeth and exhibit a vertical overlap.
## Anterior crossbite
Anterior crossbite is a malocclusion in which one or more of the upper anterior teeth occlude lingually to the mandibular incisors; the lingual malpositions of one or more maxillary anterior teeth in relation to the mandibular anterior teeth when the teeth are in centric relation occlusion.
## Posterior Crossbite
Posterior Crossbite is one or more posterior teeth locked in an abnormal relation with the opposing teeth of the opposite arch; can be either buccal or a lingual cross-bite and may be accompanied by a shift of the mandible.
## Centric occlusion
Centric occlusion is a static reproducible position of the mandible in which there is maximal contact of the inclined planes of the opposing teeth with balanced, unstrained relationship in the temporomandibular articulation.
# Treatment
There are several therapies that can be used to correct a cross bite:
- Multibrackets therapy (braces)
- Quad-Helix
- Hirex
- Removable Plates
- Invisalign
- Delaire Mask
The correct therapy should be decided by the orthodontist depending on the type and severity of the crossbite.
# Image Gallery
- Unilateral Posterior Crossbite
- Crossbite
- Crossbite
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
- Crossbite (Image courtesy of Berna Zorkun DMD and copylefted)
# External links
http://www.braceface.com/Crossbite2.htm
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Crossbite | |
e347b7dce0b698c4dcb39e7b64f622204157e63d | wikidoc | Crustacea | Crustacea
The crustaceans (Crustacea) are a large group of arthropods, comprising almost 52,000 described species , and are usually treated as a subphylum . They include various familiar animals, such as crabs, lobsters, crayfish, shrimp and barnacles. The majority of them are aquatic, living in either marine or fresh water environments, but a few groups have adapted to life on land, such as terrestrial crabs, terrestrial hermit crabs and woodlice. Crustaceans are among the most successful animals, and are as abundant in the oceans as much as insects are on land. Over half of animals in the world are marine copepod crustaceans. The majority of crustaceans are also motile, moving about independently, although a few taxonomic units are parasitic and live attached to their hosts (including sea lice, fish lice, whale lice, tongue worms, and Cymothoa exigua, all of which may be referred to as "crustacean lice"), and adult barnacles live a sessile life — they are attached headfirst to the substrate and cannot move independently. Although most crustaceans are small, their morphology varies greatly and they include such large animals as lobsters 70 cm long and spider crabs with a leg span of nearly 4 m.
The scientific study of crustaceans is known as carcinology. Other names for carcinology are malacostracology, crustaceology and crustalogy, and a scientist who works in carcinology is a carcinologist, crustaceologist or crustalogist.
# Structure of crustaceans
Crustaceans have three distinct body parts: head, thorax, and abdomen (or pleon), although the head and thorax may fuse to form a cephalothorax, an excellent example of tagmatization. The head bears two pairs of antennae, three pairs of mouthparts, and usually eyes (two compound eyes, an unpaired eye, or both). The thorax and pleon bear a number of lateral appendages, including the gills, and the tail ends with a telson. Crustacean appendages are used for swimming, crawling, and feeding. They may be highly modified as jaws and other structures, or may be lost. Smaller crustaceans respire through their body surface by diffusion , and larger crustaceans respire with gills or, as shown by Birgus latro, with abdominal lungs . Both systems (diffusion and gills) were being used by various crustaceans as early as the Middle Cambrian .
As arthropods, crustaceans have a stiff exoskeleton, which must be shed to allow the animal to grow (ecdysis or molting). Various parts of the exoskeleton may be fused together; this is particularly noticeable in the carapace, the thick dorsal shield seen on many crustaceans that often forms a protective chamber for the gills. Crustacean appendages are typically biramous, meaning they are divided into two parts; this includes the second pair of antennae, but not the first, which is uniramous. There is some doubt whether this is a derived state, as had been traditionally assumed, or whether it may be a primitive state, with the branching of the limbs being lost in all extant arthropod groups except the crustaceans. One piece of evidence supporting the latter view is the biramous nature of trilobite limbs .
The main body cavity is an expanded circulatory system, through which blood is pumped by a heart located near the dorsum. The alimentary canal consists of a straight tube that often has a gizzard-like gastric mill for grinding food and a pair of digestive glands that absorb food. Structures that function as kidneys are located near the antennae. A brain exists in the form of ganglia close to the antennae, and a collection of major ganglia is found below the gut.
Despite their diversity of form, crustaceans are united by the special larval form known as the nauplius.
Although a few are hermaphroditic, most crustaceans have separate sexes, which are distinguished by appendages on the abdomen called swimmerets or, more technically, pleopods (penis). The first (and sometimes the second) pair of pleopods are specialised in the male for sperm transfer. Many terrestrial crustaceans (such as the Christmas Island red crab) mate seasonally and return to the sea to release the eggs. Others, such as woodlice lay their eggs on land, albeit in damp conditions. In many decapods, the females retain the eggs until they hatch into free-swimming larvae.
# Taxonomy
Although the classification of crustaceans has been quite variable, the system used by Martin and Davis is the most authoritative, and largely supersedes earlier works.
Six classes of crustaceans are generally recognised:
- Branchiopoda — including brine shrimp (Artemia) and Triops (Notostraca)
- Remipedia — a small class restricted to deep caves connected to salt water, called anchialine caves
- Cephalocarida — horseshoe shrimp
- Maxillopoda — various groups, including barnacles and copepods. It contains Mystacocarida and Branchiura, which are sometimes treated as their own classes.
- Ostracoda — small animals with bivalve shells
- Malacostraca — the largest class, with the largest and most familiar animals, such as crabs, lobsters, shrimp, krill and woodlice.
The exact relationships of the Crustacea to other taxa are not yet entirely clear. Under the Pancrustacea hypothesis , Crustacea and Hexapoda (insects and allies) are sister groups. Studies using DNA sequences tend to show a paraphyletic Crustacea, with the insects (but not necessarily other hexapods) nested within that clade.
# Fossil record
Those crustaceans that have soft exoskeletons reinforced with calcium carbonate, such as crabs and lobsters, tend to preserve well as fossils, but many crustaceans have only thin exoskeletons. Most of the fossils known are from coral reef or shallow sea floor environments, but many crustaceans live in open seas, on deep sea floors or in burrows. Crustaceans tend, therefore, to be more rare in the fossil record than trilobites. Some crustaceans are reasonably common in Cretaceous and Caenozoic rocks, but barnacles have a particularly poor fossil record, with very few specimens from before the Mesozoic era.
The Late Jurassic lithographic limestones of Solnhofen, Bavaria, which are famous as the home of Archaeopteryx, are relatively rich in decapod crustaceans, such as Eryon (an eryonoid), Aeger (a prawn) or Pseudastacus (a lobster). The "lobster bed" of the Greensand formation from the Cretaceous period, which occurs at Atherfield on the Isle of Wight, contains many well preserved examples of the small glypheoid lobster Mecochirus magna. Crabs have been found at a number of sites, such as the Cretaceous Gault clay and the Eocene London clay.
# Consumption
Many crustaceans are consumed by humans, and nearly 10,000,000 tons were produced in 2005 . The vast majority of this output is of decapod crustaceans: crabs, lobsters, shrimp and prawns. Over 70% by weight of all crustaceans caught for consumption are shrimp and prawns, and over 80% is produced in Asia, with China alone producing nearly half the world's total. Non-decapod crustaceans are not widely consumed, with only 130,000 tons of krill being caught, despite krill having one of the greatest biomasses on the planet. | Crustacea
The crustaceans (Crustacea) are a large group of arthropods, comprising almost 52,000 described species ,[1] and are usually treated as a subphylum .[2] They include various familiar animals, such as crabs, lobsters, crayfish, shrimp and barnacles. The majority of them are aquatic, living in either marine or fresh water environments, but a few groups have adapted to life on land, such as terrestrial crabs, terrestrial hermit crabs and woodlice. Crustaceans are among the most successful animals, and are as abundant in the oceans as much as insects are on land. Over half of animals in the world are marine copepod crustaceans. The majority of crustaceans are also motile, moving about independently, although a few taxonomic units are parasitic and live attached to their hosts (including sea lice, fish lice, whale lice, tongue worms, and Cymothoa exigua, all of which may be referred to as "crustacean lice"), and adult barnacles live a sessile life — they are attached headfirst to the substrate and cannot move independently. Although most crustaceans are small, their morphology varies greatly and they include such large animals as lobsters 70 cm long and spider crabs with a leg span of nearly 4 m.[3]
The scientific study of crustaceans is known as carcinology. Other names for carcinology are malacostracology, crustaceology and crustalogy, and a scientist who works in carcinology is a carcinologist, crustaceologist or crustalogist.
# Structure of crustaceans
Crustaceans have three distinct body parts: head, thorax, and abdomen (or pleon), although the head and thorax may fuse to form a cephalothorax, an excellent example of tagmatization. The head bears two pairs of antennae, three pairs of mouthparts, and usually eyes (two compound eyes, an unpaired eye, or both). The thorax and pleon bear a number of lateral appendages, including the gills, and the tail ends with a telson. Crustacean appendages are used for swimming, crawling, and feeding. They may be highly modified as jaws and other structures, or may be lost. Smaller crustaceans respire through their body surface by diffusion ,[4] and larger crustaceans respire with gills or, as shown by Birgus latro, with abdominal lungs .[5] Both systems (diffusion and gills) were being used by various crustaceans as early as the Middle Cambrian .[6]
As arthropods, crustaceans have a stiff exoskeleton, which must be shed to allow the animal to grow (ecdysis or molting). Various parts of the exoskeleton may be fused together; this is particularly noticeable in the carapace, the thick dorsal shield seen on many crustaceans that often forms a protective chamber for the gills. Crustacean appendages are typically biramous, meaning they are divided into two parts; this includes the second pair of antennae, but not the first, which is uniramous. There is some doubt whether this is a derived state, as had been traditionally assumed, or whether it may be a primitive state, with the branching of the limbs being lost in all extant arthropod groups except the crustaceans. One piece of evidence supporting the latter view is the biramous nature of trilobite limbs .[7]
The main body cavity is an expanded circulatory system, through which blood is pumped by a heart located near the dorsum. The alimentary canal consists of a straight tube that often has a gizzard-like gastric mill for grinding food and a pair of digestive glands that absorb food. Structures that function as kidneys are located near the antennae. A brain exists in the form of ganglia close to the antennae, and a collection of major ganglia is found below the gut.[3]
Despite their diversity of form, crustaceans are united by the special larval form known as the nauplius.
Although a few are hermaphroditic, most crustaceans have separate sexes, which are distinguished by appendages on the abdomen called swimmerets or, more technically, pleopods (penis). The first (and sometimes the second) pair of pleopods are specialised in the male for sperm transfer. Many terrestrial crustaceans (such as the Christmas Island red crab) mate seasonally and return to the sea to release the eggs. Others, such as woodlice lay their eggs on land, albeit in damp conditions. In many decapods, the females retain the eggs until they hatch into free-swimming larvae.
# Taxonomy
Although the classification of crustaceans has been quite variable, the system used by Martin and Davis [1] is the most authoritative, and largely supersedes earlier works.
Six classes of crustaceans are generally recognised:
- Branchiopoda — including brine shrimp (Artemia) and Triops (Notostraca)
- Remipedia — a small class restricted to deep caves connected to salt water, called anchialine caves
- Cephalocarida — horseshoe shrimp
- Maxillopoda — various groups, including barnacles and copepods. It contains Mystacocarida and Branchiura, which are sometimes treated as their own classes.
- Ostracoda — small animals with bivalve shells
- Malacostraca — the largest class, with the largest and most familiar animals, such as crabs, lobsters, shrimp, krill and woodlice.
The exact relationships of the Crustacea to other taxa are not yet entirely clear. Under the Pancrustacea hypothesis ,[8] Crustacea and Hexapoda (insects and allies) are sister groups. Studies using DNA sequences tend to show a paraphyletic Crustacea, with the insects (but not necessarily other hexapods) nested within that clade.
# Fossil record
Those crustaceans that have soft exoskeletons reinforced with calcium carbonate, such as crabs and lobsters, tend to preserve well as fossils, but many crustaceans have only thin exoskeletons. Most of the fossils known are from coral reef or shallow sea floor environments, but many crustaceans live in open seas, on deep sea floors or in burrows. Crustaceans tend, therefore, to be more rare in the fossil record than trilobites. Some crustaceans are reasonably common in Cretaceous and Caenozoic rocks, but barnacles have a particularly poor fossil record, with very few specimens from before the Mesozoic era.
The Late Jurassic lithographic limestones of Solnhofen, Bavaria, which are famous as the home of Archaeopteryx, are relatively rich in decapod crustaceans, such as Eryon (an eryonoid), Aeger (a prawn) or Pseudastacus (a lobster). The "lobster bed" of the Greensand formation from the Cretaceous period, which occurs at Atherfield on the Isle of Wight, contains many well preserved examples of the small glypheoid lobster Mecochirus magna. Crabs have been found at a number of sites, such as the Cretaceous Gault clay and the Eocene London clay.
# Consumption
Many crustaceans are consumed by humans, and nearly 10,000,000 tons were produced in 2005 .[9] The vast majority of this output is of decapod crustaceans: crabs, lobsters, shrimp and prawns. Over 70% by weight of all crustaceans caught for consumption are shrimp and prawns, and over 80% is produced in Asia, with China alone producing nearly half the world's total. Non-decapod crustaceans are not widely consumed, with only 130,000 tons of krill being caught, despite krill having one of the greatest biomasses on the planet. | https://www.wikidoc.org/index.php/Crustacea | |
79fce26ce79dfd2bb6e0fc97f2a6c9b497fb3752 | wikidoc | Cyclamate | Cyclamate
Cyclamate is an artificial sweetener that was discovered in 1937 at the University of Illinois by graduate student Michael Sveda.
Like many artificial sweeteners, the sweetness of cyclamate was discovered by accident. Michael Sveda was working in the lab on the synthesis of anti-fever medication. He put his cigarette down on the lab bench and when he put it back in his mouth he discovered the sweet taste of cyclamate. The patent for cyclamate was purchased by DuPont but later sold to Abbott Laboratories which undertook the necessary studies and submitted a New Drug Application in 1950. Abbott intended to use cyclamate to mask the bitterness of certain drugs such as antibiotics and pentobarbital. In the US in 1958 it was designated GRAS (Generally Recognized as Safe). Cyclamate was marketed in tablet form for use by diabetics as an alternative tabletop sweetener, as well as in a liquid form; one such product was named 'Sucaryl' and is still available in non-US markets.
Cyclamate is 30–50 times sweeter than sugar (depending on concentration; it is not a linear relationship), making it the least potent of the commercially used artificial sweeteners. Some people find it to have an unpleasant aftertaste, but generally less so than saccharin or acesulfame potassium. It is often used synergistically with other artificial sweeteners, especially saccharin; the mixture of 10 parts cyclamate to 1 part saccharin is common and masks the off-tastes of both sweeteners. It is less expensive than most sweeteners, including sucralose, and is stable under heating.
# Chemistry
Cyclamate is the sodium or calcium salt of cyclamic acid (cyclohexanesulfamic acid). It is prepared by the sulfonation of cyclohexylamine; this can be accomplished by reacting cyclohexylamine with either sulfamic acid or sulfur trioxide.
# Cancer
In 1966, a study reported that some intestinal bacteria could desulfonate cyclamate to produce cyclohexylamine, a compound suspected to have some chronic toxicity in animals. Further research resulted in a 1969 study which found the common 10:1 cyclamate:saccharin mixture to increase the incidence of bladder cancer in rats. The released study was showing that eight out of 240 rats fed a mixture of saccharin and cyclamates, at levels of humans ingesting 350 cans of diet soda per day, developed bladder tumors. Other studies implicated cyclohexylamine in testicular atrophy in mice. On October 18, 1969, the Food and Drug Administration citing the Delaney Amendment banned its sale in the United States and the United Kingdom followed suit the next year. Abbott Laboratories claimed that its own studies were unable to reproduce the 1969 study's results, and in 1973, Abbott petitioned the FDA to lift the ban on cyclamate. This petition was eventually denied in 1980 by FDA Commissioner Jere Goyan. Abbott Labs, together with the Calorie Control Council (a political lobby representing the diet foods industry), filed a second petition in 1982. Although the FDA has stated that a review of all available evidence does not implicate cyclamate as a carcinogen in mice or rats, cyclamate remains banned from food products in the United States. The petition is now held in abeyance (it is not actively being considered) though whether this is at the request of Abbott Labs themselves or because the petition is considered to be insufficient by the FDA is unclear. Cyclamate is approved as a sweetener in more than 55 countries: for example, the brand-name beverage sweetener Sweet'N Low, which contains only dextrose, saccharin, cream of tartar, and calcium silicate in the United States, contains cyclamate in Canada (where saccharin is banned except for diabetic usage). Similarly, Sugar Twin, the brand-name cyclamate sweetener in Canada, contains saccharin in the United States.
(October 1969)
# Male reproduction
One reported effect in animal studies (mice and primates) is irreversible testicular atrophy and an apparent impact on seminal vesicle function.
However, possible negative impacts on male reproductive ability and/or function may lie outside the remits of committees tasked to determine the safety of a product based only on its expected impact on life expectancy and/or cancer rates. Since a reduction in male testosterone levels is thought to be associated with a reduced incidence of certain cancers (such as testicular cancer), and an increased life expectancy, a substance that damages testosterone production may be easier to be classified as safe when life expectancy and carcinogenicity are the deciding criteria.
Since cyclamates appear to affect cells involved in the production of spermatozoa, the question has also been raised as to whether they may also be capable of damaging male reproductive DNA. There does not yet seem to be any direct evidence either for or against this.
# Cyclamate Sweetener Brands
- Assugrin (Switzerland, Brazil)
- Sucaryl
- Sugar Twin (Canada) | Cyclamate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cyclamate is an artificial sweetener that was discovered in 1937 at the University of Illinois by graduate student Michael Sveda.
Like many artificial sweeteners, the sweetness of cyclamate was discovered by accident. Michael Sveda was working in the lab on the synthesis of anti-fever medication. He put his cigarette down on the lab bench and when he put it back in his mouth he discovered the sweet taste of cyclamate. The patent for cyclamate was purchased by DuPont but later sold to Abbott Laboratories which undertook the necessary studies and submitted a New Drug Application in 1950. Abbott intended to use cyclamate to mask the bitterness of certain drugs such as antibiotics and pentobarbital. In the US in 1958 it was designated GRAS (Generally Recognized as Safe). Cyclamate was marketed in tablet form for use by diabetics as an alternative tabletop sweetener, as well as in a liquid form; one such product was named 'Sucaryl' and is still available in non-US markets.
Cyclamate is 30–50 times sweeter than sugar (depending on concentration; it is not a linear relationship), making it the least potent of the commercially used artificial sweeteners. Some people find it to have an unpleasant aftertaste, but generally less so than saccharin or acesulfame potassium. It is often used synergistically with other artificial sweeteners, especially saccharin; the mixture of 10 parts cyclamate to 1 part saccharin is common and masks the off-tastes of both sweeteners. It is less expensive than most sweeteners, including sucralose, and is stable under heating.
# Chemistry
Cyclamate is the sodium or calcium salt of cyclamic acid (cyclohexanesulfamic acid). It is prepared by the sulfonation of cyclohexylamine; this can be accomplished by reacting cyclohexylamine with either sulfamic acid or sulfur trioxide.
# Cancer
In 1966, a study reported that some intestinal bacteria could desulfonate cyclamate to produce cyclohexylamine, a compound suspected to have some chronic toxicity in animals. Further research resulted in a 1969 study which found the common 10:1 cyclamate:saccharin mixture to increase the incidence of bladder cancer in rats. The released study was showing that eight out of 240 rats fed a mixture of saccharin and cyclamates, at levels of humans ingesting 350 cans of diet soda per day, developed bladder tumors. Other studies implicated cyclohexylamine in testicular atrophy in mice. On October 18, 1969, the Food and Drug Administration citing the Delaney Amendment banned its sale in the United States and the United Kingdom followed suit the next year. Abbott Laboratories claimed that its own studies were unable to reproduce the 1969 study's results, and in 1973, Abbott petitioned the FDA to lift the ban on cyclamate. This petition was eventually denied in 1980 by FDA Commissioner Jere Goyan. Abbott Labs, together with the Calorie Control Council (a political lobby representing the diet foods industry), filed a second petition in 1982. Although the FDA has stated that a review of all available evidence does not implicate cyclamate as a carcinogen in mice or rats, cyclamate remains banned from food products in the United States. The petition is now held in abeyance (it is not actively being considered) though whether this is at the request of Abbott Labs themselves or because the petition is considered to be insufficient by the FDA is unclear. Cyclamate is approved as a sweetener in more than 55 countries: for example, the brand-name beverage sweetener Sweet'N Low, which contains only dextrose, saccharin, cream of tartar, and calcium silicate in the United States, contains cyclamate in Canada (where saccharin is banned except for diabetic usage). Similarly, Sugar Twin, the brand-name cyclamate sweetener in Canada, contains saccharin in the United States.
(October 1969)
# Male reproduction
One reported effect in animal studies (mice and primates) is irreversible testicular atrophy and an apparent impact on seminal vesicle function.
However, possible negative impacts on male reproductive ability and/or function may lie outside the remits of committees tasked to determine the safety of a product based only on its expected impact on life expectancy and/or cancer rates. Since a reduction in male testosterone levels is thought to be associated with a reduced incidence of certain cancers (such as testicular cancer), and an increased life expectancy, a substance that damages testosterone production may be easier to be classified as safe when life expectancy and carcinogenicity are the deciding criteria.
Since cyclamates appear to affect cells involved in the production of spermatozoa, the question has also been raised as to whether they may also be capable of damaging male reproductive DNA. There does not yet seem to be any direct evidence either for or against this.
# Cyclamate Sweetener Brands
- Assugrin (Switzerland, Brazil)
- Sucaryl
- Sugar Twin (Canada)
# External links
- http://www.rosalindfranklin.edu/cms/biochem/walters/sweet/cyclamate.html
- http://ec.europa.eu/food/fs/sc/scf/out53_en.pdf European Commission Revised Opinion On Cyclamic Acid
- http://www.cfsan.fda.gov/~dms/opa-abey.html US FDA Petitions Currently Held in Abeyance
- http://environmentalchemistry.com/yogi/chemicals/cn/Cyclohexanesulfamic%A0acid,%A0monosodium%A0salt.html List of other chemical and brand names for cyclamate
- http://www.hermesetas.com/data/en/specialised/sweeteners/history.php A brief history of sweeteners, including the discovery of cyclamate
- http://www.assugrin.ch/daten_f/maison.php Assugrin's website (French)
- http://www.foodcomm.org.uk/press_97_cyclams.htm concerns over potential "testicular wasting" in male users
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Template:WikiDoc Sources
Template:Jb1 | https://www.wikidoc.org/index.php/Cyclamate | |
1a28a88801deadd0f6426f45c53935757341a49a | wikidoc | Cyclin T2 | Cyclin T2
Cyclin-T2 is a protein that in humans is encoded by the CCNT2 gene.
# Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin and its kinase partner CDK9 were found to be subunits of the transcription elongation factor p-TEFb. The p-TEFb complex containing this cyclin was reported to interact with, and act as a negative regulator of human immunodeficiency virus type 1 (HIV-1) Tat protein. Two alternatively spliced transcript variants, which encode distinct isoforms, have been described.
# Interactions
Cyclin T2 has been shown to interact with CDK9 and Retinoblastoma protein. | Cyclin T2
Cyclin-T2 is a protein that in humans is encoded by the CCNT2 gene.[1][2][3]
# Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin and its kinase partner CDK9 were found to be subunits of the transcription elongation factor p-TEFb. The p-TEFb complex containing this cyclin was reported to interact with, and act as a negative regulator of human immunodeficiency virus type 1 (HIV-1) Tat protein. Two alternatively spliced transcript variants, which encode distinct isoforms, have been described.[3]
# Interactions
Cyclin T2 has been shown to interact with CDK9[1] and Retinoblastoma protein.[4] | https://www.wikidoc.org/index.php/Cyclin_T2 | |
31d536b791cd17e5fa7e27dae70b5f8c760a010f | wikidoc | Cyclotron | Cyclotron
A cyclotron is a type of particle accelerator. Cyclotrons accelerate charged particles using a high-frequency, alternating voltage (potential difference). A perpendicular magnetic field causes the particles to spiral almost in a circle so that they re-encounter the accelerating voltage many times.
Ernest Lawrence, of the University of California, Berkeley, is credited with the invention of the cyclotron in 1929. He used it in experiments that required particles with energy of up to 1 MeV.
# How the cyclotron works
The electrodes shown at the right would be in the vacuum chamber, which is flat, in a narrow gap between the two poles of a large magnet.
In the cyclotron, a high-frequency alternating voltage applied across the "D" electrodes (also called "dees") alternately attracts and repels charged particles. The particles, injected near the center of the magnetic field, accelerate only when passing through the gap between the electrodes. The perpendicular magnetic field (passing vertically through the "D" electrodes), combined with the increasing energy of the particles forces the particles to travel in a spiral path.
With no change in energy the charged particles in a magnetic field will follow a circular path. In the Cyclotron, energy is applied to the particles as they cross the gap between the dees and so they are accelerated (at the typical sub-relativistic speeds used) and will increase in mass as they approach the speed of light. Either of these effects (increased velocity or increased mass) will increase the radius of the circle and so the path will be a spiral.
(The particles move in a spiral, because a current of electrons or ions, flowing perpendicular to a magnetic field, experiences a perpendicular force. The charged particles move freely in a vacuum, so the particles follow a spiral path.)
The radius will increase until the particles hit a target at the perimeter of the vacuum chamber. Various materials may be used for the target, and the collisions will create secondary particles which may be guided outside of the cyclotron and into instruments for analysis. The results will enable the calculation of various properties, such as the mean spacing between atoms and the creation of various collision products. Subsequent chemical and particle analysis of the target material may give insight into nuclear transmutation of the elements used in the target.
# Uses of the cyclotron
For several decades, cyclotrons were the best source of high-energy beams for nuclear physics experiments; several cyclotrons are still in use for this type of research.
Cyclotrons can be used to treat cancer. Ion beams from cyclotrons can be used, as in proton therapy, to penetrate the body and kill tumors by radiation damage, while minimizing damage to healthy tissue along their path.
Cyclotron beams can be used to bombard other atoms to produce short-lived positron-emitting isotopes suitable for PET imaging.
# Problems solved by the cyclotron
The cyclotron was an improvement over the linear accelerators that were available when it was invented. A linear accelerator (also called a linac) accelerates particles in a straight line through an evacuated tube (or series of such tubes placed end to end). A set of electrodes shaped like flat donuts are arranged inside the length of the tube(s). These are driven by high-power radio waves that continuously switch between positive and negative voltage, causing particles traveling along the center of the tube to accelerate. In the 1920's, it was not possible to get high frequency radio waves at high power, so either the accelerating electrodes had to be far apart to accommodate the low frequency or more stages were required to compensate for the low power at each stage. Either way, higher-energy particles required longer accelerators than scientists could afford.
Modern linacs use high power Klystrons and other devices able to impart much more power at higher frequencies. But before these devices existed, cyclotrons were cheaper than linacs.
Cyclotrons accelerate particles in a spiral path. Therefore, a compact accelerator can contain much more distance than a linear accelerator, with more opportunities to accelerate the particles.
# Advantages of the cyclotron
- Cyclotrons have a single electrical driver, which saves both money and power, since more expense may be allocated to increasing efficiency.
- Cyclotrons produce a continuous stream of particles at the target, so the average power is relatively high.
- The compactness of the device reduces other costs, such as its foundations, radiation shielding, and the enclosing building.
# Limitations of the cyclotron
The spiral path of the cyclotron beam can only "synch up" with klystron-type (constant frequency) voltage sources if the accelerated particles are approximately obeying Newton's Laws of Motion. If the particles become fast enough that relativistic effects become important, the beam gets out of phase with the oscillating electric field, and cannot receive any additional acceleration. The cyclotron is therefore only capable of accelerating particles up to a few percent of the speed of light. To accommodate increased mass the magnetic field may be modified by appropriately shaping the pole pieces as in the isochronous cyclotrons, operating in a pulsed mode and changing the frequency applied to the dees as in the synchrocyclotrons, either of which is limited by the diminishing cost effectiveness of making larger machines. Cost limitations have been overcome by employing the more complex synchrotron or linear accelerator, both of which have the advantage of scalability, offering more power within an improved cost structure as the machines are made larger.
# Mathematics of the cyclotron
The centripetal force is provided by the transverse magnetic field B, and the force on a particle travelling in a magnetic field (which causes it to be angularly displaced, i.e spiral) is equal to Bqv. So,
(Where m is the mass of the particle, q is its charge, v is its velocity and r is the radius of its path.)
The speed at which the particles enter the cyclotron due to a potential difference, V.
Therefore,
v/r is equal to angular velocity, ω, so
And since the angular frequency is
Therefore,
This shows that for a particle of constant mass, the frequency does not depend upon the radius of the particle's orbit. As the beam spirals out, its frequency does not decrease, and it must continue to accelerate, as it is travelling more distance in the same time. As particles approach the speed of light, they acquire additional mass, requiring modifications to the frequency, or the magnetic field during the acceleration. This is accomplished in the synchrocyclotron.
The relativistic cyclotron frequency is
f=f_c\sqrt{1-v^2/c^2},
where f_c is the classical frequency, given above, of a charged particle with velocity v circling in a magnetic field.
The rest mass of an electron is 511 keV, so the frequency correction is 1% for a magnetic vacuum tube with a 5.11 kV direct current accelerating voltage. The proton mass is nearly two thousand times the electron mass, so the 1% correction energy is about 9 MeV, which is sufficient to induce nuclear reactions.
An alternative to the synchrocyclotron is the isochronous cyclotron, which has a magnetic field that increases with radius, rather than with time. The de-focusing effect of this radial field gradient is compensated by ridges on the magnet faces which vary the field azimuthally as well. This allows particles to be accelerated continuously, on every period of the radio frequency, rather than in bursts as in most other accelerator types. This principle that alternating field gradients have a net focusing effect is called strong focusing. It was obscurely known theoretically long before it was put into practice.
# Related technologies
- The spiraling of electrons in a cylindrical vacuum chamber within a transverse magnetic field is also employed in the magnetron, a device for producing high frequency radio waves (microwaves).
- The Synchrotron moves the particles through a path of constant radius, allowing it to be made as a pipe and so of much larger radius than is practical with the cyclotron and synchrocyclotron. The larger radius allows the use of numerous magnets, each of which imparts angular momentum and so allows particles of higher velocity (mass) to be kept within the bounds of the evacuated pipe. | Cyclotron
A cyclotron is a type of particle accelerator. Cyclotrons accelerate charged particles using a high-frequency, alternating voltage (potential difference). A perpendicular magnetic field causes the particles to spiral almost in a circle so that they re-encounter the accelerating voltage many times.
Ernest Lawrence, of the University of California, Berkeley, is credited with the invention of the cyclotron in 1929. He used it in experiments that required particles with energy of up to 1 MeV.
# How the cyclotron works
The electrodes shown at the right would be in the vacuum chamber, which is flat, in a narrow gap between the two poles of a large magnet.
In the cyclotron, a high-frequency alternating voltage applied across the "D" electrodes (also called "dees") alternately attracts and repels charged particles. The particles, injected near the center of the magnetic field, accelerate only when passing through the gap between the electrodes. The perpendicular magnetic field (passing vertically through the "D" electrodes), combined with the increasing energy of the particles forces the particles to travel in a spiral path.
With no change in energy the charged particles in a magnetic field will follow a circular path. In the Cyclotron, energy is applied to the particles as they cross the gap between the dees and so they are accelerated (at the typical sub-relativistic speeds used) and will increase in mass as they approach the speed of light. Either of these effects (increased velocity or increased mass) will increase the radius of the circle and so the path will be a spiral.
(The particles move in a spiral, because a current of electrons or ions, flowing perpendicular to a magnetic field, experiences a perpendicular force. The charged particles move freely in a vacuum, so the particles follow a spiral path.)
The radius will increase until the particles hit a target at the perimeter of the vacuum chamber. Various materials may be used for the target, and the collisions will create secondary particles which may be guided outside of the cyclotron and into instruments for analysis. The results will enable the calculation of various properties, such as the mean spacing between atoms and the creation of various collision products. Subsequent chemical and particle analysis of the target material may give insight into nuclear transmutation of the elements used in the target.
# Uses of the cyclotron
For several decades, cyclotrons were the best source of high-energy beams for nuclear physics experiments; several cyclotrons are still in use for this type of research.
Cyclotrons can be used to treat cancer. Ion beams from cyclotrons can be used, as in proton therapy, to penetrate the body and kill tumors by radiation damage, while minimizing damage to healthy tissue along their path.
Cyclotron beams can be used to bombard other atoms to produce short-lived positron-emitting isotopes suitable for PET imaging.
# Problems solved by the cyclotron
The cyclotron was an improvement over the linear accelerators that were available when it was invented. A linear accelerator (also called a linac) accelerates particles in a straight line through an evacuated tube (or series of such tubes placed end to end). A set of electrodes shaped like flat donuts are arranged inside the length of the tube(s). These are driven by high-power radio waves that continuously switch between positive and negative voltage, causing particles traveling along the center of the tube to accelerate. In the 1920's, it was not possible to get high frequency radio waves at high power, so either the accelerating electrodes had to be far apart to accommodate the low frequency or more stages were required to compensate for the low power at each stage. Either way, higher-energy particles required longer accelerators than scientists could afford.
Modern linacs use high power Klystrons and other devices able to impart much more power at higher frequencies. But before these devices existed, cyclotrons were cheaper than linacs.
Cyclotrons accelerate particles in a spiral path. Therefore, a compact accelerator can contain much more distance than a linear accelerator, with more opportunities to accelerate the particles.
# Advantages of the cyclotron
- Cyclotrons have a single electrical driver, which saves both money and power, since more expense may be allocated to increasing efficiency.
- Cyclotrons produce a continuous stream of particles at the target, so the average power is relatively high.
- The compactness of the device reduces other costs, such as its foundations, radiation shielding, and the enclosing building.
# Limitations of the cyclotron
The spiral path of the cyclotron beam can only "synch up" with klystron-type (constant frequency) voltage sources if the accelerated particles are approximately obeying Newton's Laws of Motion. If the particles become fast enough that relativistic effects become important, the beam gets out of phase with the oscillating electric field, and cannot receive any additional acceleration. The cyclotron is therefore only capable of accelerating particles up to a few percent of the speed of light. To accommodate increased mass the magnetic field may be modified by appropriately shaping the pole pieces as in the isochronous cyclotrons, operating in a pulsed mode and changing the frequency applied to the dees as in the synchrocyclotrons, either of which is limited by the diminishing cost effectiveness of making larger machines. Cost limitations have been overcome by employing the more complex synchrotron or linear accelerator, both of which have the advantage of scalability, offering more power within an improved cost structure as the machines are made larger.
# Mathematics of the cyclotron
The centripetal force is provided by the transverse magnetic field B, and the force on a particle travelling in a magnetic field (which causes it to be angularly displaced, i.e spiral) is equal to Bqv. So,
(Where m is the mass of the particle, q is its charge, v is its velocity and r is the radius of its path.)
The speed at which the particles enter the cyclotron due to a potential difference, V.
Therefore,
v/r is equal to angular velocity, ω, so
And since the angular frequency is
Therefore,
This shows that for a particle of constant mass, the frequency does not depend upon the radius of the particle's orbit. As the beam spirals out, its frequency does not decrease, and it must continue to accelerate, as it is travelling more distance in the same time. As particles approach the speed of light, they acquire additional mass, requiring modifications to the frequency, or the magnetic field during the acceleration. This is accomplished in the synchrocyclotron.
The relativistic cyclotron frequency is
<math>f=f_c\sqrt{1-v^2/c^2}</math>,
where <math>f_c</math> is the classical frequency, given above, of a charged particle with velocity <math>v</math> circling in a magnetic field.
The rest mass of an electron is 511 keV, so the frequency correction is 1% for a magnetic vacuum tube with a 5.11 kV direct current accelerating voltage. The proton mass is nearly two thousand times the electron mass, so the 1% correction energy is about 9 MeV, which is sufficient to induce nuclear reactions.
An alternative to the synchrocyclotron is the isochronous cyclotron, which has a magnetic field that increases with radius, rather than with time. The de-focusing effect of this radial field gradient is compensated by ridges on the magnet faces which vary the field azimuthally as well. This allows particles to be accelerated continuously, on every period of the radio frequency, rather than in bursts as in most other accelerator types. This principle that alternating field gradients have a net focusing effect is called strong focusing. It was obscurely known theoretically long before it was put into practice.
# Related technologies
- The spiraling of electrons in a cylindrical vacuum chamber within a transverse magnetic field is also employed in the magnetron, a device for producing high frequency radio waves (microwaves).
- The Synchrotron moves the particles through a path of constant radius, allowing it to be made as a pipe and so of much larger radius than is practical with the cyclotron and synchrocyclotron. The larger radius allows the use of numerous magnets, each of which imparts angular momentum and so allows particles of higher velocity (mass) to be kept within the bounds of the evacuated pipe. | https://www.wikidoc.org/index.php/Cyclotron | |
4ee0947641596c3a7d4d03532f737573db5eb7c6 | wikidoc | Cystocele | Cystocele
Steven C. Campbell, M.D., Ph.D.
# Overview
A cystocele (SIS-tuh-seal) is a medical condition that occurs when the wall between a woman's bladder and her vagina weakens and allows the bladder to droop into the vagina. This condition may cause discomfort and problems with emptying the bladder. A cystocele may result from muscle straining during childbirth, heavy lifting or repeated straining during bowel movements. Because the hormone estrogen helps keep the muscles around the vagina strong, cystocele is more common after menopause when levels of estrogen decrease.
A bladder that has dropped from its normal position may cause two kinds of problems—unwanted urine leakage and incomplete emptying of the bladder. In some women, a fallen bladder stretches the opening into the urethra, causing urine leakage when the woman coughs, sneezes, laughs, or moves in any way that puts pressure on the bladder.
A cystocele is mild (grade 1) when the bladder droops only a short way into the vagina. With more severe (grade 2) cystocele, the bladder sinks far enough to reach the opening of the vagina. The most advanced (grade 3) cystocele occurs when the bladder bulges out through the opening of the vagina.
A doctor may be able to diagnose a grade 2 or grade 3 cystocele from a description of symptoms and from physical examination of the vagina because the fallen part of the bladder will be visible. A 'voiding cystourethrogram' (sis-toe-yoo-REETH-roe-gram) is a test that involves taking x rays of the bladder during urination. This x-ray shows the shape of the bladder and lets the doctor see any problems that might block the normal flow of urine. Other tests may be needed to find or rule out problems in other parts of the urinary system.
Treatment options range from no treatment for a mild cystocele to surgery for a serious cystocele. If a cystocele is not bothersome, the doctor may only recommend avoiding heavy lifting or straining that could cause the cystocele to worsen. If symptoms are moderately bothersome, the doctor may recommend a pessary, a device placed in the vagina to hold the bladder in place. Pessaries come in a variety of shapes and sizes to allow the doctor to find the most comfortable fit for the patient. Pessaries must be removed regularly to avoid infection or ulcers.
Large cystoceles may require surgery to move the bladder back into a more normal position and keep it there. This operation may be performed by a gynecologist, a urologist, or a urogynecologist. The patient should be prepared to stay in the hospital for several days and take 4 to 6 weeks to recover fully. | Cystocele
For patient information, click here
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
A cystocele (SIS-tuh-seal) is a medical condition that occurs when the wall between a woman's bladder and her vagina weakens and allows the bladder to droop into the vagina. This condition may cause discomfort and problems with emptying the bladder. A cystocele may result from muscle straining during childbirth, heavy lifting or repeated straining during bowel movements. Because the hormone estrogen helps keep the muscles around the vagina strong, cystocele is more common after menopause when levels of estrogen decrease.
A bladder that has dropped from its normal position may cause two kinds of problems—unwanted urine leakage and incomplete emptying of the bladder. In some women, a fallen bladder stretches the opening into the urethra, causing urine leakage when the woman coughs, sneezes, laughs, or moves in any way that puts pressure on the bladder.
A cystocele is mild (grade 1) when the bladder droops only a short way into the vagina. With more severe (grade 2) cystocele, the bladder sinks far enough to reach the opening of the vagina. The most advanced (grade 3) cystocele occurs when the bladder bulges out through the opening of the vagina.
A doctor may be able to diagnose a grade 2 or grade 3 cystocele from a description of symptoms and from physical examination of the vagina because the fallen part of the bladder will be visible. A 'voiding cystourethrogram' (sis-toe-yoo-REETH-roe-gram) is a test that involves taking x rays of the bladder during urination. This x-ray shows the shape of the bladder and lets the doctor see any problems that might block the normal flow of urine. Other tests may be needed to find or rule out problems in other parts of the urinary system.
Treatment options range from no treatment for a mild cystocele to surgery for a serious cystocele. If a cystocele is not bothersome, the doctor may only recommend avoiding heavy lifting or straining that could cause the cystocele to worsen. If symptoms are moderately bothersome, the doctor may recommend a pessary, a device placed in the vagina to hold the bladder in place. Pessaries come in a variety of shapes and sizes to allow the doctor to find the most comfortable fit for the patient. Pessaries must be removed regularly to avoid infection or ulcers.
Large cystoceles may require surgery to move the bladder back into a more normal position and keep it there. This operation may be performed by a gynecologist, a urologist, or a urogynecologist. The patient should be prepared to stay in the hospital for several days and take 4 to 6 weeks to recover fully. | https://www.wikidoc.org/index.php/Cystocele | |
a5e0ecbda2817cc904913b494edae138d7543f07 | wikidoc | Cytokinin | Cytokinin
Cytokinins (CK) are a class of plant growth substances (plant hormones) active in promoting cell division, and are also involved in cell growth, differentiation, and other physiological processes. Their effects were first discovered through the use of coconut milk in the 1940s by a scientist at the University of Wisconsin-Madison named Folke Skoog.
There are two kinds of cytokinins, adenine-type cytokinins including kinetin, zeatin and 6-Benzylaminopurine and phenylurea-type cytokinins like diphenylurea. There is no evidence that any phenylurea cytokinins occur naturally in plant tissues. Adenine-type cytokinins are synthesised in stems, leaves and roots, but the root is the major site, furthermore cambium and possibly all actively dividing tissues are responsible for the synthesis of this group of plant hormones. Cytokinin is involved in both local and long distance signalling; as a long distance signal CK shares the same transport systems used by the plant for moving purines and nucleosides.
Cytokinins are involved in many plant processes, including cell division, shoot and root morphagenesis, chloroplast maturation, cell enlargement, auxiliary bud release and senescence. The ratio of auxin to cytokinin is crucial during cell division and the differentiation of plant tissues and auxin is known to regulate the biosynthesis of cytokinin. | Cytokinin
Cytokinins (CK) are a class of plant growth substances (plant hormones) active in promoting cell division, and are also involved in cell growth, differentiation, and other physiological processes. Their effects were first discovered through the use of coconut milk in the 1940s by a scientist at the University of Wisconsin-Madison named Folke Skoog.
There are two kinds of cytokinins, adenine-type cytokinins including kinetin, zeatin and 6-Benzylaminopurine and phenylurea-type cytokinins like diphenylurea. There is no evidence that any phenylurea cytokinins occur naturally in plant tissues.[1] Adenine-type cytokinins are synthesised in stems, leaves and roots, but the root is the major site, furthermore cambium and possibly all actively dividing tissues are responsible for the synthesis of this group of plant hormones.[2] Cytokinin is involved in both local and long distance signalling; as a long distance signal CK shares the same transport systems used by the plant for moving purines and nucleosides.[3]
Cytokinins are involved in many plant processes, including cell division, shoot and root morphagenesis, chloroplast maturation, cell enlargement, auxiliary bud release and senescence.[4] The ratio of auxin to cytokinin is crucial during cell division and the differentiation of plant tissues and auxin is known to regulate the biosynthesis of cytokinin.[5] | https://www.wikidoc.org/index.php/Cytokinin | |
c6d0bf8a8135218b83e8d796da5893e7fb05a138 | wikidoc | Cytopenia | Cytopenia
Cytopenia is a reduction in the number of cells circulating in the blood. It takes a number of forms:
- Low red blood cell count: anemia.
- Low white blood cell count: leukopenia or neutropenia (because neutrophils make up at least half of all white cells, they are almost always low in leukopenia).
- Low platelet count: thrombocytopenia.
- Low granulocyte count: granulocytopenia
- Low red blood cell, white blood cell, and platelet counts: pancytopenia. | Cytopenia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cytopenia is a reduction in the number of cells circulating in the blood. It takes a number of forms:
- Low red blood cell count: anemia.
- Low white blood cell count: leukopenia or neutropenia (because neutrophils make up at least half of all white cells, they are almost always low in leukopenia).
- Low platelet count: thrombocytopenia.
- Low granulocyte count: granulocytopenia
- Low red blood cell, white blood cell, and platelet counts: pancytopenia. | https://www.wikidoc.org/index.php/Cytopenia | |
f280e43b59c538e392e50aaf90713e99f8970ee7 | wikidoc | Cytoplasm | Cytoplasm
# Overview
Cytoplasm is a gelatinous, semi-transparent fluid that fills most cells. Eukaryotic cells contain a nucleus that is kept separate from the cytoplasm by a double membrane layer.
# Constituents
The cytoplasm has three major elements; the cytosol, organelles and inclusions. The cytosol is the gooey, semi-transparent fluid in which the other cytoplasmic elements are suspended. The cytoplasm holds organelles and protects them, such as the vacuole, endoplasmic recticulum, etc. Cytosol makes up about 70% of the cell and is composed of water, salts and organic molecules. The cytoskeleton, various proteins, ribosomes and enzymes that are necessary for the cell to catalyze reactions are also found throughout the cytosol. The inner, granular and more fluid portion of the cytoplasm is referred to as endoplasm.
The organelles are the metabolic machinery of the cell and are like little organs themselves. Some major organelles that are suspended in the cytosol are the mitochondria, the endoplasmic reticulum, the Golgi apparatus, lysosomes, and in plant cells chloroplasts.
The inclusions are chemical substances that store nutrients, secretory products and pigment granules.
# Function
The cytoplasm is the site where most cellular activities are done. The functions for cell expansion, growth and replication are carried out in the cytoplasm of the cell. The cytosol has enzymes that take molecules and break them down , so that the individual organelles can use them as they need to. The cytosol also contains the cytoskeleton which gives the cell its shape and can help in the movement of the cell. | Cytoplasm
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cytoplasm is a gelatinous, semi-transparent fluid that fills most cells. Eukaryotic cells contain a nucleus that is kept separate from the cytoplasm by a double membrane layer.
# Constituents
The cytoplasm has three major elements; the cytosol, organelles and inclusions. The cytosol is the gooey, semi-transparent fluid in which the other cytoplasmic elements are suspended. The cytoplasm holds organelles and protects them, such as the vacuole, endoplasmic recticulum, etc. Cytosol makes up about 70% of the cell and is composed of water, salts and organic molecules.[1] The cytoskeleton, various proteins, ribosomes and enzymes that are necessary for the cell to catalyze reactions are also found throughout the cytosol. The inner, granular and more fluid portion of the cytoplasm is referred to as endoplasm.
The organelles are the metabolic machinery of the cell and are like little organs themselves. Some major organelles that are suspended in the cytosol are the mitochondria, the endoplasmic reticulum, the Golgi apparatus, lysosomes, and in plant cells chloroplasts.
The inclusions are chemical substances that store nutrients, secretory products and pigment granules. [2]
# Function
The cytoplasm is the site where most cellular activities are done. The functions for cell expansion, growth and replication are carried out in the cytoplasm of the cell. The cytosol has enzymes that take molecules and break them down , so that the individual organelles can use them as they need to. The cytosol also contains the cytoskeleton which gives the cell its shape and can help in the movement of the cell.[3] | https://www.wikidoc.org/index.php/Cytoplasm | |
b5cc17c2aa01f06dbc3d5562456b058b7b356111 | wikidoc | DNA clamp | DNA clamp
A DNA clamp, also known as a sliding clamp, is a protein fold that serves as a processivity-promoting factor in DNA replication. As a critical component of the DNA polymerase III holoenzyme, the clamp protein binds DNA polymerase and prevents this enzyme from dissociating from the template DNA strand. The clamp-polymerase protein–protein interactions are stronger and more specific than the direct interactions between the polymerase and the template DNA strand; because one of the rate-limiting steps in the DNA synthesis reaction is the association of the polymerase with the DNA template, the presence of the sliding clamp dramatically increases the number of nucleotides that the polymerase can add to the growing strand per association event. The presence of the DNA clamp can increase the rate of DNA synthesis up to 1,000-fold compared with a nonprocessive polymerase.
# Structure
The DNA clamp fold is an α+β protein that assembles into a multimeric structure that completely encircles the DNA double helix as the polymerase adds nucleotides to the growing strand. The DNA clamp assembles on the DNA at the replication fork and "slides" along the DNA with the advancing polymerase, aided by a layer of water molecules in the central pore of the clamp between the DNA and the protein surface. Because of the toroidal shape of the assembled multimer, the clamp cannot dissociate from the template strand without also dissociating into monomers.
The DNA clamp fold is found in bacteria, archaea, eukaryotes and some viruses. In bacteria, the sliding clamp is a homodimer composed of two identical beta subunits of DNA polymerase III and hence is referred to as the beta clamp. In archaea and eukaryotes, it is a trimer composed of three molecules of PCNA. The T4 bacteriophage also uses a sliding clamp, called gp45 that is a trimer similar in structure to PCNA but lacks sequence homology to either PCNA or the bacterial beta clamp.
## Bacterial
The beta clamp is a specific DNA clamp and a subunit of the DNA polymerase III holoenzyme found in bacteria. Two beta subunits are assembled around the DNA by the gamma subunit and ATP hydrolysis; this assembly is called the pre-initiation complex. After assembly around the DNA, the beta subunits' affinity for the gamma subunit is replaced by an affinity for the alpha and epsilon subunits, which together create the complete holoenzyme. DNA polymerase III is the primary enzyme complex involved in prokaryotic DNA replication.
The gamma complex of DNA polymerase III, composed of γδδ'χψ subunits, catalyzes ATP to chaperone two beta subunits to bind to DNA. Once bound to DNA, the beta subunits can freely slide along double stranded DNA. The beta subunits in turn bind the αε polymerase complex. The α subunit possesses DNA polymerase activity and the ε subunit is a 3’-5’ exonuclease.
The beta chain of bacterial DNA polymerase III is composed of three topologically equivalent domains (N-terminal, central, and C-terminal). Two beta chain molecules are tightly associated to form a closed ring encircling duplex DNA.
## As a drug target
Certain NSAIDs (carprofen, bromfenac, and vedaprofen) exhibit some suppression of bacterial DNA replication by inhibiting bacterial DNA clamp.
## Eukaryote
The sliding clamp in eukaryotes is assembled from a specific subunit of DNA polymerase delta called the proliferating cell nuclear antigen (PCNA). The N-terminal and C-terminal domains of PCNA are topologically identical. Three PCNA molecules are tightly associated to form a closed ring encircling duplex DNA.
The sequence of PCNA is well conserved between plants, animals and fungi, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes. Homologues of PCNA have also been identified in the archaea (Euryarchaeota and Crenarchaeota) and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses.
## Viral
The viral gp45 sliding clamp subunit protein contains two domains. Each domain consists of two alpha helices and two beta sheets – the fold is duplicated and has internal pseudo two-fold symmetry. Three gp45 molecules are tightly associated to form a closed ring encircling duplex DNA.
# Assembly
Sliding clamps are loaded onto their associated DNA template strands by specialized proteins known as "sliding clamp loaders", which also disassemble the clamps after replication has completed. The binding sites for these initiator proteins overlap with the binding sites for the DNA polymerase, so the clamp cannot simultaneously associate with a clamp loader and with a polymerase. Thus the clamp will not be actively disassembled while the polymerase remains bound. DNA clamps also associate with other factors involved in DNA and genome homeostasis, such as nucleosome assembly factors, Okazaki fragment ligases, and DNA repair proteins. All of these proteins also share a binding site on the DNA clamp that overlaps with the clamp loader site, ensuring that the clamp will not be removed while any enzyme is still working on the DNA. The activity of the clamp loader requires ATP hydrolysis to "close" the clamp around the DNA. | DNA clamp
A DNA clamp, also known as a sliding clamp, is a protein fold that serves as a processivity-promoting factor in DNA replication. As a critical component of the DNA polymerase III holoenzyme, the clamp protein binds DNA polymerase and prevents this enzyme from dissociating from the template DNA strand. The clamp-polymerase protein–protein interactions are stronger and more specific than the direct interactions between the polymerase and the template DNA strand; because one of the rate-limiting steps in the DNA synthesis reaction is the association of the polymerase with the DNA template, the presence of the sliding clamp dramatically increases the number of nucleotides that the polymerase can add to the growing strand per association event. The presence of the DNA clamp can increase the rate of DNA synthesis up to 1,000-fold compared with a nonprocessive polymerase.[2]
# Structure
The DNA clamp fold is an α+β protein that assembles into a multimeric structure that completely encircles the DNA double helix as the polymerase adds nucleotides to the growing strand.[3] The DNA clamp assembles on the DNA at the replication fork and "slides" along the DNA with the advancing polymerase, aided by a layer of water molecules in the central pore of the clamp between the DNA and the protein surface. Because of the toroidal shape of the assembled multimer, the clamp cannot dissociate from the template strand without also dissociating into monomers.
The DNA clamp fold is found in bacteria, archaea, eukaryotes and some viruses. In bacteria, the sliding clamp is a homodimer composed of two identical beta subunits of DNA polymerase III and hence is referred to as the beta clamp. In archaea[4] and eukaryotes, it is a trimer composed of three molecules of PCNA. The T4 bacteriophage also uses a sliding clamp, called gp45 that is a trimer similar in structure to PCNA but lacks sequence homology to either PCNA or the bacterial beta clamp.[3]
## Bacterial
The beta clamp is a specific DNA clamp and a subunit of the DNA polymerase III holoenzyme found in bacteria. Two beta subunits are assembled around the DNA by the gamma subunit and ATP hydrolysis; this assembly is called the pre-initiation complex. After assembly around the DNA, the beta subunits' affinity for the gamma subunit is replaced by an affinity for the alpha and epsilon subunits, which together create the complete holoenzyme.[6][7][8] DNA polymerase III is the primary enzyme complex involved in prokaryotic DNA replication.
The gamma complex of DNA polymerase III, composed of γδδ'χψ subunits, catalyzes ATP to chaperone two beta subunits to bind to DNA. Once bound to DNA, the beta subunits can freely slide along double stranded DNA. The beta subunits in turn bind the αε polymerase complex. The α subunit possesses DNA polymerase activity and the ε subunit is a 3’-5’ exonuclease.[8]
The beta chain of bacterial DNA polymerase III is composed of three topologically equivalent domains (N-terminal, central, and C-terminal). Two beta chain molecules are tightly associated to form a closed ring encircling duplex DNA.
## As a drug target
Certain NSAIDs (carprofen, bromfenac, and vedaprofen) exhibit some suppression of bacterial DNA replication by inhibiting bacterial DNA clamp.[9]
## Eukaryote
The sliding clamp in eukaryotes is assembled from a specific subunit of DNA polymerase delta called the proliferating cell nuclear antigen (PCNA). The N-terminal and C-terminal domains of PCNA are topologically identical. Three PCNA molecules are tightly associated to form a closed ring encircling duplex DNA.
The sequence of PCNA is well conserved between plants, animals and fungi, indicating a strong selective pressure for structure conservation, and suggesting that this type of DNA replication mechanism is conserved throughout eukaryotes.[11][12] Homologues of PCNA have also been identified in the archaea (Euryarchaeota and Crenarchaeota) and in Paramecium bursaria Chlorella virus 1 (PBCV-1) and in nuclear polyhedrosis viruses.
## Viral
The viral gp45 sliding clamp subunit protein contains two domains. Each domain consists of two alpha helices and two beta sheets – the fold is duplicated and has internal pseudo two-fold symmetry.[14] Three gp45 molecules are tightly associated to form a closed ring encircling duplex DNA.
# Assembly
Sliding clamps are loaded onto their associated DNA template strands by specialized proteins known as "sliding clamp loaders", which also disassemble the clamps after replication has completed. The binding sites for these initiator proteins overlap with the binding sites for the DNA polymerase, so the clamp cannot simultaneously associate with a clamp loader and with a polymerase. Thus the clamp will not be actively disassembled while the polymerase remains bound. DNA clamps also associate with other factors involved in DNA and genome homeostasis, such as nucleosome assembly factors, Okazaki fragment ligases, and DNA repair proteins. All of these proteins also share a binding site on the DNA clamp that overlaps with the clamp loader site, ensuring that the clamp will not be removed while any enzyme is still working on the DNA. The activity of the clamp loader requires ATP hydrolysis to "close" the clamp around the DNA. | https://www.wikidoc.org/index.php/DNA_clamp | |
b16c7b9d1665012ed7aef4ca26ee8e49d00aa82b | wikidoc | Dandelion | Dandelion
The name Dandelion is given to species of the genus (Taraxacum), a large genus of flowering plants in the family Asteraceae. In the Asteraceae (formerly Compositae) the 'flowers' are morphologically a composite flower head consisting of many tiny flowers called florets. The dandelion is native to Europe and Asia, and has spread to many other places. In northern areas and places where the dandelion is not native, it has become a weedy species, exploiting disturbed ground in human environments. Taraxacum species reproduce asexually by means of apomixis and seed production commonly occurs without pollination.
# Description
Dandelion are tap-rooted biennial or perennial herbaceous plants, native to temperate areas of the Northern Hemisphere of the Old World. They are commonly known as weeds or ruderals.
The genus is taxonomically very complex, with numerous macrospecies, and polyploidy is also common; over 250 species have been recorded in the British Isles alone (Richards 1972). Some botanists take a much narrower viewpoint, and only accept a total of about 60 species.
The leaves are 5-25 cm long, simple and basal, entire or lobed, forming a rosette above the central taproot. As the leaves grow outward they push down the surrounding vegetation, such as grass in a lawn, killing the vegetation by cutting off the sunlight. A bright yellow flower head (which is open in the daytime but closes at night) is borne singly on a hollow stem (scape) which rises 4-30 cm above the leaves and exudes a milky sap (latex) when broken. A rosette may produce several flowering stems at a time. The flower head is 2-5 cm in diameter and consists entirely of ray florets.
Dandelions are used as food plants by the larvae of some species of Lepidoptera. See List of Lepidoptera which feed on Dandelions.
Away from their native regions, they have become established in the Americas, Australia and New Zealand as weeds. They are now common plants throughout all temperate regions.
## Dandelion clock
The flower matures into a globe of fine filaments that are usually distributed by wind, carrying away the seed-containing achenes. This globe (receptacle) is called the "clock".
## Seeds
The flower head is surrounded by bracts (sometimes mistakenly called sepals) in two series. The inner bracts are erect until the seeds mature, then flex down to allow the seeds to disperse; the outer bracts are always reflexed downward. Some species drop the "parachute" (called a pappus, modified sepals) from the achenes. Between the pappus and the achene, there is a stalk called a beak, which elongates as the fruit matures. The beak breaks off from the achene quite easily.
# Name
The name dandelion is derived from the French, dent-de-lion, which is literally "lion's tooth", referring to the sharply-lobed leaves of the plant. The English spelling reflects the French pronunciation at the time this French word was absorbed into English. The first written usage of the word occurs in a herbal dated 1373, but there is a 1363 document in which the word "dandelion" was used as a proper name (Willelmus Dawndelyon).
In Norwegian, the dandelion is called Løvetann, which is also translated as "lion's tooth", also Löwenzahn ("lions' tooth") in German. In bed", apparently referring to its diuretic properties. Likewise, "pissabeds" is an English folkname for this plant, and "piscialletto" is one of its folknames in Italian (with "dente di leone", meaning "lion's tooth"). Similarly in Spanish, it is known as the "meacamas", but also commonly "diente de león". In Portuguese, its common name is "dente-de-leão" meaning also "lion's tooth". In Turkish the dandelion is called "karahindiba" meaning "black endive". Hungarian names are kutyatej ("dog milk", referring to the white sap found in the stem) and gyermekláncfű
# Selected species
- Taraxacum officinale (syn. T. officinale subsp. vulgare), Common Dandelion. Found in many forms, but differs at least from the following species:
- Taraxacum albidum, a white-flowering Japanese dandelion.
- Taraxacum japonicum, Japanese dandelion. No ring of smallish, downward-turned leaves under the flowerhead.
- Taraxacum laevigatum (syn. T. erythrospermum), Red-seeded Dandelion; achenes reddish brown and leaves deeply cut throughout length. Inner bracts' tips are hooded.
# Seed development and genetics
As previously mentioned, the taxonomical situation of the genus is quite complex, mainly because many dandelions are genetically triploid. An odd number of chromosomes usually is associated with sterility, but dandelions with this karyotype can reproduce without fertilization, by a process called apomixis. In these individuals flowers are useless vestigial structures, although they may still produce a small percentage of fertile pollen, keeping some genetic contact with sexual individuals. Diploid dandelions develop seeds after cross-pollination and are outcrossing, or self-incompatible. In most zones of southern Europe and Asia, dandelion populations are sexual or mixed sexual-apomictic, while in northern countries only triploid and tetraploid apomicts are present, as is in the zones where it is not native. This seems to be linked to higher temperatures, survival of pre-glacial populations and human impact, but the subject is still being studied.
There are usually 54 to 172 seeds produced per head, but a single plant can produce more than 2000 seeds a year. It has been estimated that more than 97 000 000 seeds/hectare could be produced every year by a dense stand of dandelions.
# Dandelion Snow
After pollination, the dandelion flower dries out for about 10 days and then the seed-bearing parachutes expand and lift out of the dried flower head. The dried part of the flower drops off and the parachute ball opens into a full sphere. The parachute drops off when the seed strikes an obstacle. Often dandelions can be observed growing in a crevice near a wall, because the blowing fruits hit the wall and the feathery pappi drop off, sending the dandelion seeds to the base of the obstacle where they germinate. After the seed is released, the parachutes lose their feathered structure and take on a fuzzy, cotton-like appearance, often called "dandelion snow."
# Uses
While the dandelion is considered a weed by many gardeners and lawn owners, the plant does have several culinary and medicinal uses. Dandelions are grown commercially at a small scale as a leaf vegetable. The plant can be eaten cooked or raw in various forms, such as in soup or salad. They are probably closest in character to mustard greens. Usually the young leaves and unopened buds are eaten raw in salads, while older leaves are cooked. Raw leaves have a slightly bitter taste. Dandelion salad is often accompanied with hard boiled eggs. The leaves are high in vitamin A, vitamin C and iron, carrying more iron and calcium than spinach.
Dandelion flowers can be used to make dandelion wine. The recipe usually contains citrus fruit. Another recipe using the plant is dandelion flower jam. Ground roasted dandelion root can be used as a coffee substitute. Drunk before meals, it is believed to stimulate digestive functions. Sold in most health food stores, often in a mixture, it is considered an excellent cleansing tonic for the liver.
Dandelion root is a registered drug in Canada, sold as a diuretic. Dandelions are so potent in this effect, that children have been known to wet the bed the night after skin contact from playing with them. A leaf decoction can be drunk to "purify the blood", for the treatment of anemia, jaundice, and also for nervousness. The milky latex has been used as a mosquito repellent; the milk is also applied to warts, helping get rid of them without damaging the surrounding skin. A dye can also be obtained from the roots of the plant. A new mixture of roasted roots is sold as a product called DandyBlend which tastes like coffee after the inulin in the dandelion is roasted.
"Dandelion and Burdock" is a soft drink that has long been popular in the United Kingdom with authentic recipes sold by health food shops. It is unclear whether cheaper supermarket versions actually contain either plant.
This plant also is useful in farming, because its deep, strong roots break up hardpan.
## Antioxidant properties
Dandelion contains luteolin, an antioxidant, and has demonstrated antioxidant properties without cytotoxicity.
## Caffeic acid and carcinogenicity
Caffeic acid is a secondary plant metabolite produced in dandelion, yarrow, horsetail and whitethorn. Despite its name, it is totally unrelated to caffeine. Recent studies have revealed this acid may be carcinogenic. Caffeic acid was tested for carcinogenicity by oral administration in mice, it produced renal cell adenomas in females, and a high incidence of renal tubular cell hyperplasia in animals of each sex. However, more recent research shows that bacteria present in the rats' guts may alter the formation of metabolites of caffeic acid. and Also, there have been no known ill-effects of caffeic acid in humans.
# False dandelions
Dandelions are so similar to catsears (Hypochoeris) that catsears are also known as "false dandelions." Both plants carry similar flowers which form into windborne seeds. However, catsear flowering stems are forked and solid, whereas dandelions possess unforked stems that are hollow. Both plants have a rosette of leaves and a central taproot. However, the leaves of dandelions are jagged in appearance, whereas those of catsear are more lobe-shaped and hairy.
Other plants with similar flowers include hawkweeds (Hieracium) and hawksbeards (Crepis). These are both readily distinguished by their branched flowering stems. | Dandelion
Template:Cleanup
The name Dandelion is given to species of the genus (Taraxacum), a large genus of flowering plants in the family Asteraceae. In the Asteraceae (formerly Compositae) the 'flowers' are morphologically a composite flower head consisting of many tiny flowers called florets. The dandelion is native to Europe and Asia, and has spread to many other places. In northern areas and places where the dandelion is not native, it has become a weedy species, exploiting disturbed ground in human environments. Taraxacum species reproduce asexually by means of apomixis and seed production commonly occurs without pollination.[1]
# Description
Dandelion are tap-rooted biennial or perennial herbaceous plants, native to temperate areas of the Northern Hemisphere of the Old World. They are commonly known as weeds or ruderals.
The genus is taxonomically very complex, with numerous macrospecies, and polyploidy is also common; over 250 species have been recorded in the British Isles alone (Richards 1972). Some botanists take a much narrower viewpoint, and only accept a total of about 60 species.
The leaves are 5-25 cm long, simple and basal, entire or lobed, forming a rosette above the central taproot. As the leaves grow outward they push down the surrounding vegetation, such as grass in a lawn, killing the vegetation by cutting off the sunlight. A bright yellow flower head (which is open in the daytime but closes at night) is borne singly on a hollow stem (scape) which rises 4-30 cm above the leaves and exudes a milky sap (latex) when broken. A rosette may produce several flowering stems at a time. The flower head is 2-5 cm in diameter and consists entirely of ray florets.
Dandelions are used as food plants by the larvae of some species of Lepidoptera. See List of Lepidoptera which feed on Dandelions.
Away from their native regions, they have become established in the Americas, Australia and New Zealand as weeds. They are now common plants throughout all temperate regions.
## Dandelion clock
The flower matures into a globe of fine filaments that are usually distributed by wind, carrying away the seed-containing achenes. This globe (receptacle) is called the "clock".
## Seeds
The flower head is surrounded by bracts (sometimes mistakenly called sepals) in two series. The inner bracts are erect until the seeds mature, then flex down to allow the seeds to disperse; the outer bracts are always reflexed downward. Some species drop the "parachute" (called a pappus, modified sepals) from the achenes. Between the pappus and the achene, there is a stalk called a beak, which elongates as the fruit matures. The beak breaks off from the achene quite easily.
# Name
The name dandelion is derived from the French, dent-de-lion, which is literally "lion's tooth", referring to the sharply-lobed leaves of the plant. The English spelling reflects the French pronunciation at the time this French word was absorbed into English.[2] The first written usage of the word occurs in a herbal dated 1373, but there is a 1363 document in which the word "dandelion" was used as a proper name (Willelmus Dawndelyon).
In Norwegian, the dandelion is called Løvetann, which is also translated as "lion's tooth", also Löwenzahn ("lions' tooth") in German. In bed", apparently referring to its diuretic properties. Likewise, "pissabeds" is an English folkname for this plant, and "piscialletto" is one of its folknames in Italian (with "dente di leone", meaning "lion's tooth"). Similarly in Spanish, it is known as the "meacamas", but also commonly "diente de león". In Portuguese, its common name is "dente-de-leão" meaning also "lion's tooth". In Turkish the dandelion is called "karahindiba" meaning "black endive". Hungarian names are kutyatej ("dog milk", referring to the white sap found in the stem) and gyermekláncfű
# Selected species
- Taraxacum officinale (syn. T. officinale subsp. vulgare), Common Dandelion. Found in many forms, but differs at least from the following species:
- Taraxacum albidum, a white-flowering Japanese dandelion.
- Taraxacum japonicum, Japanese dandelion. No ring of smallish, downward-turned leaves under the flowerhead.
- Taraxacum laevigatum (syn. T. erythrospermum), Red-seeded Dandelion; achenes reddish brown and leaves deeply cut throughout length. Inner bracts' tips are hooded.
# Seed development and genetics
As previously mentioned, the taxonomical situation of the genus is quite complex, mainly because many dandelions are genetically triploid. An odd number of chromosomes usually is associated with sterility, but dandelions with this karyotype can reproduce without fertilization, by a process called apomixis.[3] In these individuals flowers are useless vestigial structures, although they may still produce a small percentage of fertile pollen, keeping some genetic contact with sexual individuals. Diploid dandelions develop seeds after cross-pollination and are outcrossing, or self-incompatible. In most zones of southern Europe and Asia, dandelion populations are sexual or mixed sexual-apomictic, while in northern countries only triploid and tetraploid apomicts are present, as is in the zones where it is not native. This seems to be linked to higher temperatures, survival of pre-glacial populations and human impact, but the subject is still being studied.
There are usually 54 to 172 seeds produced per head, but a single plant can produce more than 2000 seeds a year. It has been estimated that more than 97 000 000 seeds/hectare could be produced every year by a dense stand of dandelions.
# Dandelion Snow
After pollination, the dandelion flower dries out for about 10 days and then the seed-bearing parachutes expand and lift out of the dried flower head. The dried part of the flower drops off and the parachute ball opens into a full sphere. The parachute drops off when the seed strikes an obstacle. Often dandelions can be observed growing in a crevice near a wall, because the blowing fruits hit the wall and the feathery pappi drop off, sending the dandelion seeds to the base of the obstacle where they germinate. After the seed is released, the parachutes lose their feathered structure and take on a fuzzy, cotton-like appearance, often called "dandelion snow."
# Uses
While the dandelion is considered a weed by many gardeners and lawn owners, the plant does have several culinary and medicinal uses. Dandelions are grown commercially at a small scale as a leaf vegetable. The plant can be eaten cooked or raw in various forms, such as in soup or salad. They are probably closest in character to mustard greens. Usually the young leaves and unopened buds are eaten raw in salads, while older leaves are cooked. Raw leaves have a slightly bitter taste. Dandelion salad is often accompanied with hard boiled eggs. The leaves are high in vitamin A, vitamin C and iron, carrying more iron and calcium than spinach.[4]
Dandelion flowers can be used to make dandelion wine. The recipe usually contains citrus fruit. Another recipe using the plant is dandelion flower jam. Ground roasted dandelion root can be used as a coffee substitute. Drunk before meals, it is believed to stimulate digestive functions. Sold in most health food stores, often in a mixture, it is considered an excellent cleansing tonic for the liver.
Dandelion root is a registered drug in Canada, sold as a diuretic. Dandelions are so potent in this effect, that children have been known to wet the bed the night after skin contact from playing with them.[2] A leaf decoction can be drunk to "purify the blood", for the treatment of anemia, jaundice, and also for nervousness. The milky latex has been used as a mosquito repellent; the milk is also applied to warts, helping get rid of them without damaging the surrounding skin. A dye can also be obtained from the roots of the plant. A new mixture of roasted roots is sold as a product called DandyBlend which tastes like coffee after the inulin in the dandelion is roasted.
"Dandelion and Burdock" is a soft drink that has long been popular in the United Kingdom with authentic recipes sold by health food shops. It is unclear whether cheaper supermarket versions actually contain either plant.
This plant also is useful in farming, because its deep, strong roots break up hardpan.
## Antioxidant properties
Dandelion contains luteolin, an antioxidant, and has demonstrated antioxidant properties without cytotoxicity.[5][1]
## Caffeic acid and carcinogenicity
Caffeic acid is a secondary plant metabolite produced in dandelion, yarrow, horsetail and whitethorn. Despite its name, it is totally unrelated to caffeine. Recent studies have revealed this acid may be carcinogenic. Caffeic acid was tested for carcinogenicity by oral administration in mice, it produced renal cell adenomas in females, and a high incidence of renal tubular cell hyperplasia in animals of each sex.[6] However, more recent research shows that bacteria present in the rats' guts may alter the formation of metabolites of caffeic acid. [2] and [3] Also, there have been no known ill-effects of caffeic acid in humans.
# False dandelions
Dandelions are so similar to catsears (Hypochoeris) that catsears are also known as "false dandelions." Both plants carry similar flowers which form into windborne seeds. However, catsear flowering stems are forked and solid, whereas dandelions possess unforked stems that are hollow. Both plants have a rosette of leaves and a central taproot. However, the leaves of dandelions are jagged in appearance, whereas those of catsear are more lobe-shaped and hairy.
Other plants with similar flowers include hawkweeds (Hieracium) and hawksbeards (Crepis). These are both readily distinguished by their branched flowering stems. | https://www.wikidoc.org/index.php/Dandelion | |
da35aff14c9e5cba9084acffe81d909c358ea0f7 | wikidoc | Darexaban | Darexaban
- 365462-23-3 Y
- 365462-24-4 (maleate) Y
- Interactive image
- InChI=1S/C27H30N4O4/c1-30-15-4-16-31(18-17-30)21-11-7-19(8-12-21)27(34)29-25-23(5-3-6-24(25)32)28-26(33)20-9-13-22(35-2)14-10-20/h3,5-14,32H,4,15-18H2,1-2H3,(H,28,33)(H,29,34)Key: IJNIQYINMSGIPS-UHFFFAOYSA-N
- InChI=1/C27H30N4O4/c1-30-15-4-16-31(18-17-30)21-11-7-19(8-12-21)27(34)29-25-23(5-3-6-24(25)32)28-26(33)20-9-13-22(35-2)14-10-20/h3,5-14,32H,4,15-18H2,1-2H3,(H,28,33)(H,29,34)Key: IJNIQYINMSGIPS-UHFFFAOYAJ
- O=C(c1ccc(OC)cc1)Nc2cccc(O)c2NC(=O)c4ccc(N3CCCN(C)CC3)cc4
# Overview
Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.
# Factor Xa
Factor Xa (FXa) is an essential blood coagulation factor that is responsible for the initiation of the coagulation cascade. FXa cleaves prothrombin to its active form thrombin, which then acts to convert soluble fibrinogen to insoluble fibrin and to activate platelets. Stabilization of the platelet aggregation by fibrin mesh ultimately leads to clot formation.
# Metabolism
Darexaban is rapidly absorbed and extensively metabolized in the liver to its active metabolite, darexaban glucuronide (YM-222714) during first pass metabolism via glucuronidation. The metabolism of darexaban also occurs in the small intestine but to a much lesser extent. Glucuronidation of darexaban occurs quickly, thus the half life of darexaban itself is short. However, the resultant darexaban glucuronide metabolite has a long half life of approximately 14–18 hours, reaching its maximum levels in the blood 1-1.5 hour post dose. As a result, darexaban glucuronide is the main determinant of the antithrombotic effects. Darexaban shows minimal interaction with food and is excreted through the kidneys (urine) and feces.
# Mechanism of action
Darexaban and darexaban glucuronide selectively and competitively inhibit FXa, suppressing prothrombin activity at the sites of blood clot (thrombus) formation. This leads to a decrease in blood clot formation in a dose dependent manner. Reducing blood clot formation will decrease blood flow blockages, thus possibly lowering the risk of myocardial infarction, unstable angina, venous thrombosis, and ischemic stroke.
# Clinical uses
## Atrial fibrillation
Atrial fibrillation is an abnormal heart rhythm that causes a reduction in the cardiac output and blood flow to the brain. It also promotes the formation of blood clots in the atria. Atrial fibrillation is associated with an increased risk of embolic stroke due to the increased risk of blood clot development. Oral anticoagulant drugs such as Darexaban decrease the incidence and severity of stroke in patients with atrial fibrillation by preventing the formation of blood clots.
# Contraindictions
The RUBY-1 phase II trial results show that oral administration of darexaban in combination with the standard dual antiplatelet therapy used for ACS patients caused a two- to four-fold increase in bleeding rates and no effect on ACS. Though there were no cases of fatal bleeding or intracranial haemorrhage, the results of this study questions the concept of adding an oral anticoagulant to standard of care dual antiplatelet therapy in order to prevent recurrent ischemic events after ACS. The developpement of darexaban was discontinued in September 2011. | Darexaban
- 365462-23-3 Y
- 365462-24-4 (maleate) Y
- Interactive image
- 8088422
Template:Chembox E number
- 9912771
- InChI=1S/C27H30N4O4/c1-30-15-4-16-31(18-17-30)21-11-7-19(8-12-21)27(34)29-25-23(5-3-6-24(25)32)28-26(33)20-9-13-22(35-2)14-10-20/h3,5-14,32H,4,15-18H2,1-2H3,(H,28,33)(H,29,34)Key: IJNIQYINMSGIPS-UHFFFAOYSA-N
- InChI=1/C27H30N4O4/c1-30-15-4-16-31(18-17-30)21-11-7-19(8-12-21)27(34)29-25-23(5-3-6-24(25)32)28-26(33)20-9-13-22(35-2)14-10-20/h3,5-14,32H,4,15-18H2,1-2H3,(H,28,33)(H,29,34)Key: IJNIQYINMSGIPS-UHFFFAOYAJ
- O=C(c1ccc(OC)cc1)Nc2cccc(O)c2NC(=O)c4ccc(N3CCCN(C)CC3)cc4
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma.[1] It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation[2] and possibly ischemic events in acute coronary syndrome.[3] It is used in form of the maleate. The development of darexaban was discontinued in September 2011.
# Factor Xa
Factor Xa (FXa) is an essential blood coagulation factor[2] that is responsible for the initiation of the coagulation cascade. FXa cleaves prothrombin to its active form thrombin, which then acts to convert soluble fibrinogen to insoluble fibrin and to activate platelets. Stabilization of the platelet aggregation by fibrin mesh ultimately leads to clot formation.[4]
# Metabolism
Darexaban is rapidly absorbed and extensively metabolized in the liver to its active metabolite, darexaban glucuronide (YM-222714) during first pass metabolism via glucuronidation.[5] The metabolism of darexaban also occurs in the small intestine but to a much lesser extent.[2] Glucuronidation of darexaban occurs quickly, thus the half life of darexaban itself is short. However, the resultant darexaban glucuronide metabolite has a long half life of approximately 14–18 hours, reaching its maximum levels in the blood 1-1.5 hour post dose.[2] As a result, darexaban glucuronide is the main determinant of the antithrombotic effects.[3] Darexaban shows minimal interaction with food and is excreted through the kidneys (urine) and feces.[6]
# Mechanism of action
Darexaban and darexaban glucuronide selectively and competitively inhibit FXa, suppressing prothrombin activity at the sites of blood clot (thrombus) formation. This leads to a decrease in blood clot formation in a dose dependent manner.[2] Reducing blood clot formation will decrease blood flow blockages, thus possibly lowering the risk of myocardial infarction, unstable angina, venous thrombosis, and ischemic stroke.[7]
# Clinical uses
## Atrial fibrillation
Atrial fibrillation is an abnormal heart rhythm that causes a reduction in the cardiac output and blood flow to the brain. It also promotes the formation of blood clots in the atria.[4] Atrial fibrillation is associated with an increased risk of embolic stroke due to the increased risk of blood clot development.[8] Oral anticoagulant drugs such as Darexaban decrease the incidence and severity of stroke in patients with atrial fibrillation by preventing the formation of blood clots.[9]
# Contraindictions
The RUBY-1 phase II trial results show that oral administration of darexaban in combination with the standard dual antiplatelet therapy used for ACS patients caused a two- to four-fold increase in bleeding rates and no effect on ACS.[6] Though there were no cases of fatal bleeding or intracranial haemorrhage, the results of this study questions the concept of adding an oral anticoagulant to standard of care dual antiplatelet therapy in order to prevent recurrent ischemic events after ACS. The developpement of darexaban was discontinued in September 2011. | https://www.wikidoc.org/index.php/Darexaban | |
71b40b44539356073b231250bbdb342881bcbdf8 | wikidoc | Darunavir | Darunavir
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Darunavir is a protease inhibitor that is FDA approved for the treatment of human immunodeficiency virus (HIV-1) infection. Common adverse reactions include diarrhea, nausea, rash, headache, abdominal pain and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Darunavir must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer Darunavir with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.
- Treatment-Naïve Adult Patients
- The recommended oral dose of Darunavir is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL of a 80 mg/mL ritonavir oral solution) once daily and with food. An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe.
- Treatment-Experienced Adult Patients
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Darunavir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Darunavir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The indication for treatment-experienced pediatric patients 3 to less than 18 years of age is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from two open-label Phase 2 trials in antiretroviral treatment-experienced pediatric subjects(24-week analysis for one trial in patients 6 to less than 18 years of age; 48-week analysis for one trial in patients 3 to less than 6 years of age) . The indication for treatment-naïve pediatric patients or antiretroviral treatment-experienced patients with no darunavir resistance associated substitutions is based on one open-label Phase 2 trial of 48 weeks duration in antiretroviral treatment-naïve subjects 12 to less than 18 years of age and pharmacokinetic modeling and simulation for patients 3 to less than 12 years of age.
- In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with Darunavir/ritonavir:
- Treatment history and, when available, genotypic or phenotypic testing should guide the use of Darunavir/ritonavir.
- The use of other active agents with Darunavir/ritonavir is associated with a greater likelihood of treatment response.
- Before prescribing Darunavir, children weighing greater than or equal to 15 kg should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of Darunavir oral suspension should be considered.
- The recommended dose of Darunavir/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight (see Tables 2, 3, 4, and 5) and should not exceed the recommended adult dose. Darunavir should be taken with ritonavir and with food.
- The recommendations for the Darunavir/ritonavir dosage regimens were based on the following:
- Twice daily dosing
Results from two trials in treatment-experienced pediatric subjects 3 to less 18 years of age demonstrating similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-experienced adults.
- Results from two trials in treatment-experienced pediatric subjects 3 to less 18 years of age demonstrating similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-experienced adults.
- Once daily dosing
- Results from one trial in treatment-naive pediatric subjects 12 to less than 18 years of age demonstrating similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-naive adults.
- Results from population pharmacokinetic modeling and simulation in children 3 to less than 12 years of age predicting similar darunavir plasma exposures compared to treatment-naïve adults. Although no clinical trial was conducted to collect exposure-safety data, the predicted exposures from the once daily dosing is supported by exposures observed in a pediatric clinical trial where twice-daily dosing was administered.
- Dosing recommendations for treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions
- Pediatric patients weighing at least 10 kg but less than 15 kg
- The weight-based dose in antiretroviral treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions is Darunavir 35 mg/kg once daily with ritonavir 7 mg/kg once daily using the following table.
- Pediatric patients weighing at least 15 kg
- Pediatric patients weighing at least 15 kg can be dosed with Darunavir oral tablet(s) or suspension using the following table:
- Dosing recommendations for treatment-experienced pediatric patients with at least one darunavir resistance associated substitutions
- Pediatric patients weighing at least 10 kg but less than 15 kg
- The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir resistance associated substitution is Darunavir 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the following table:
- Pediatric patients weighing at least 15 kg
- Pediatric patients weighing at least 15 kg can be dosed with Darunavir oral tablet(s) or suspension using the following table:
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Darunavir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Darunavir in pediatric patients.
# Contraindications
- Co-administration of Darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed in Table 6
# Warnings
### Precautions
- General
- Darunavir must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer Darunavir with ritonavir and food may result in a loss of efficacy of darunavir.
- Please refer to ritonavir prescribing information for additional information on precautionary measures.
- Hepatotoxicity
- Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with Darunavir/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with Darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.
- Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with Darunavir/ritonavir therapy has not been established.
- Appropriate laboratory testing should be conducted prior to initiating therapy with Darunavir/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Darunavir/ritonavir treatment.
- Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on Darunavir/ritonavir should prompt consideration of interruption or discontinuation of treatment.
- Severe Skin Reactions
- During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported. Discontinue Darunavir/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
- Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with Darunavir/ritonavir. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using Darunavir/ritonavir was 0.5%.
- Rash occurred more commonly in treatment-experienced subjects receiving regimens containing Darunavir/ritonavir + raltegravir compared to subjects receiving Darunavir/ritonavir without raltegravir or raltegravir without Darunavir/ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
- Sulfa Allergy
- Darunavir contains a sulfonamide moiety. Darunavir should be used with caution in patients with a known sulfonamide allergy. In clinical studies with Darunavir/ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.
- Drug Interactions
- See Table 6 for a listing of drugs that are contraindicated for use with Darunavir/ritonavir due to potentially life-threatening adverse events, significant drug-drug interactions, or loss of therapeutic effect to Darunavir. Please refer to Table 11 for established and other potentially significant drug-drug interactions.
- Diabetes Mellitus / Hyperglycemia
- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established.
- Fat Redistribution
- Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Darunavir. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.
- Hemophilia
- There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.
- Resistance/Cross-Resistance
- Because the potential for HIV cross-resistance among PIs has not been fully explored in Darunavir/ritonavir treated patients, the effect therapy with Darunavir will have on the activity of subsequently administered PIs is unknown.
- Pediatric Patients
- Do not administer Darunavir/ritonavir in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age.
# Adverse Reactions
## Clinical Trials Experience
- Study TMC114-C211
- The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing Darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-1-infected adult subjects. The total mean exposure for subjects in the Darunavir/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 162.5 and 153.5 weeks, respectively.
- The majority of the adverse drug reactions (ADRs) reported during treatment with Darunavir/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to Darunavir/ritonavir 800/100 mg once daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the Darunavir/ritonavir arm discontinued treatment due to ADRs.
- ADRs to Darunavir/ritonavir 800/100 mg once daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult subjects are presented in Table 7 and subsequent text below the table.
- Less Common Adverse Reactions
- Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving Darunavir/ritonavir 800/100 mg once daily are listed below by body system:
Acute pancreatitis, dyspepsia, flatulence
Asthenia
Acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity)
Hypersensitivity, immune reconstitution syndrome
Diabetes mellitus
Myalgia, osteonecrosis
Abnormal dreams
Angioedema, pruritus, Stevens-Johnson Syndrome, urticaria
- Laboratory abnormalities:
- Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with Darunavir/ritonavir 800/100 mg once daily are presented in Table 8.
- Study TMC114-C214
- The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing Darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-experienced HIV-1-infected adult subjects. The total mean exposure for subjects in the Darunavir/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 80.7 and 76.4 weeks, respectively.
- The majority of the ADRs reported during treatment with Darunavir/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to Darunavir/ritonavir 600/100 mg twice daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the Darunavir/ritonavir arm discontinued treatment due to ADRs.
- ADRs to Darunavir/ritonavir 600/100 mg twice daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 9 and subsequent text below the table.
- Less Common Adverse Reactions
- Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving Darunavir/ritonavir 600/100 mg twice daily are listed below by body system:
Acute pancreatitis, flatulence
Myalgia
Abnormal dreams
Pruritus, urticaria
- Laboratory abnormalities:
- Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with Darunavir/ritonavir 600/100 mg twice daily are presented in Table 10.
- The following serious ADRs of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b studies and Phase 3 studies with Darunavir/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting.
- In subjects co-infected with hepatitis B or hepatitis C virus receiving Darunavir/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving Darunavir/ritonavir who were not co-infected, except for increased hepatic enzymes. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection.
- Darunavir/ritonavir has been studied in combination with other antiretroviral agents in 3 Phase II trials. TMC114-C212, in which 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to less than 18 years of age and weighing at least 20 kg were included, TMC114-C228, in which 21 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 6 years of age and weighing at least 10 kg were included, and TMC114-C230 in which 12 antiretroviral treatment-naïve HIV-1 infected pediatric patients aged from 12 to less than 18 years and weighing at least 40 kg were included. The TMC114-C212 and C228 trials evaluated Darunavir/ritonavir twice daily dosing and the TMC114-C230 trial evaluated Darunavir/ritonavir once daily dosing.
- Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults.
- Study TMC114-C212
- Clinical ADRs to Darunavir/ritonavir (all grades, greater than or equal to 3%), were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%) and fatigue (3%).
- Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%).
- Study TMC114-C228
- Clinical ADRs to Darunavir/ritonavir (all grades, greater than or equal to 5%), were diarrhea (24%), vomiting (19%),rash (19%), abdominal pain (5%) and anorexia (5%).
- There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study.
- Study TMC114-C230
- Clinical ADRs to Darunavir/ritonavir (all grades, greater than or equal to 3%), were vomiting (33%), nausea (25%), diarrhea (16.7%), abdominal pain (8.3%), decreased appetite (8.3%), pruritus (8.3%), and rash (8.3%).
- There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study.
## Postmarketing Experience
- The following events have been identified during post approval use of Darunavir. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Redistribution of body fat has been reported.
- Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and Darunavir/ritonavir) has been reported.
- In addition, toxic epidermal necrolysis,acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms have been reported rarely.
# Drug Interactions
- Darunavir co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of Darunavir and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Table 11).
- Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Table 11).
- Table 11 provides dosing recommendations as a result of drug interactions with Darunavir/ritonavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.
- In addition to the drugs included in Table 11, the interaction between Darunavir/ritonavir and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug: atazanavir, efavirenz, etravirine, nevirapine, omeprazole, ranitidine, rilpivirine, and tenofovir disoproxil fumarate. Using cross-trial comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of darunavir. Darunavir/ritonavir had no clinically significant effect on the pharmacokinetics of dolutegravir.
- Other nucleoside reverse transcriptase inhibitors (NRTIs):
- Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and Darunavir/ritonavir.
- Other PIs:
- The co-administration of Darunavir/ritonavir and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended.
- Integrase strand transfer inhibitors:
- Based on the pharmacokinetic data from literature references, either no clinically significant changes in darunavir concentrations or decreases in darunavir concentrations were observed with concomitant use of raltegravir. The potential decrease in darunavir concentrations does not appear to be clinically relevant. Darunavir/ritonavir and raltegravir can be used without dose adjustments.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- No adequate and well-controlled studies have been conducted in pregnant women. Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice and rats in the presence or absence of ritonavir as well as in rabbits with darunavir alone. In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.
- In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed with darunavir alone or in combination with ritonavir during lactation. This was due to exposure of pups to drug substances via the milk. Sexual development, fertility and mating performance of offspring were not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.
- In the juvenile toxicity study where rats were directly dosed with darunavir, deaths occurred from post-natal day 5 through 11 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma exposure levels.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Darunavir, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Darunavir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Darunavir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known whether darunavir is secreted in human milk, darunavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Darunavir.
### Pediatric Use
- Do not administer Darunavir/ritonavir in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age.
- The safety, pharmacokinetic profile, and virologic and immunologic responses of Darunavir/ritonavir were evaluated in treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighting at least 10 kg. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, 6 to less than 18 years of age) and TMC114-228 (21 subjects, 3 to less than 6 years of age). Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults.
- In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of Darunavir/ritonavir administered once daily were evaluated in treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects). Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults. Once daily dosing recommendations for pediatric patients 3 to less than 12 years of age were derived using population pharmacokinetic modeling and simulation. Although a Darunavir/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted Darunavir exposures for the dosing recommendations in this age group.
### Geriatic Use
- Clinical studies of Darunavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of Darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Darunavir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Darunavir with respect to specific racial populations.
### Renal Impairment
- Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30–60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis.
### Hepatic Impairment
- No dose adjustment of Darunavir/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of Darunavir/ritonavir in subjects with severe hepatic impairment. Therefore, Darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Darunavir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Darunavir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Darunavir/ritonavir treatment.
# IV Compatibility
There is limited information regarding IV Compatibility of Darunavir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Human experience of acute overdose with Darunavir/ritonavir is limited. Single doses up to 3200 mg of the oral solution of darunavir alone and up to 1600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
### Management
- No specific antidote is available for overdose with Darunavir. Treatment of overdose with Darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Darunavir in the drug label.
# Pharmacology
## Mechanism of Action
- Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.
## Structure
- Darunavir (darunavir) is an inhibitor of the human immunodeficiency virus (HIV-1) protease.
- Darunavir (darunavir), in the form of darunavir ethanolate, has the following chemical name: amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofurofuran-3-yl ester monoethanolate. Its molecular formula is C27H37N3O7S - C2H5OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:
- Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at 20°C.
- Darunavir 100 mg/mL oral suspension is available as a white to off-white opaque suspension for oral administration.
- Darunavir 75 mg tablets are available as white, caplet-shaped, film-coated tablets for oral administration. Darunavir 150 mg tablets are available as white, oval-shaped, film-coated tablets for oral administration. Darunavir 600 mg tablets are available as orange, oval-shaped, film-coated tablets for oral administration. Darunavir 800 mg tablets are available as dark red, oval-shaped, film-coated tablets for oral administration.
- Each mL of the oral suspension contains darunavir ethanolate equivalent to 100 mg darunavir. In addition, each mL contains the inactive ingredients hydroxypropyl cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, methylparaben sodium, citric acid monohydrate, sucralose, masking flavor, strawberry cream flavor, hydrochloric acid (for pH adjustment) and purified water.
- Each 75 mg tablet contains darunavir ethanolate equivalent to 75 mg of darunavir. Each 150 mg tablet contains darunavir ethanolate equivalent to 150 mg of darunavir. Each 600 mg tablet contains darunavir ethanolate equivalent to 600 mg of darunavir. Each 800 mg tablet contains darunavir ethanolate equivalent to 800 mg of darunavir. During storage, partial conversion from ethanolate to hydrate may occur; however, this does not affect product quality or performance. Each tablet also contains the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The 800 mg tablet also contains hypromellose. The 75 and 150 mg tablet film coating, OPADRY® White, contains polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. The 600 mg tablet film coating, OPADRY® Orange, contains FD&C Yellow No. 6, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. The 800 mg tablet film coating, OPADRY® Dark Red, contains iron oxide red, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.
- All dosages for Darunavir are expressed in terms of the free form of darunavir.
## Pharmacodynamics
- In an open-label, randomized, placebo- and active-controlled, four-way crossover trial, 40 healthy subjects were administered supratheraputic doses of darunavir/ritonavir 1600/100 mg once daily and 800/100 mg twice daily for seven days.
- At the mean maximum darunavir concentration of 6599 ng/mL observed in this study, the mean increase in QTcF was 2.2 ms with a 90% two-sided confidence interval (CI) of -2.0 to 6.3 ms. When evaluating the 2-sided 90% CI on the time-matched mean changes in QTcF versus placebo control, the upper bounds of both darunavir/ritonavir groups never exceeded the 10 ms boundary. In the setting of this trial, darunavir/ritonavir did not appear to prolong the QTc interval.
## Pharmacokinetics
- General
- Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of Darunavir 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, Darunavir should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.
- The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 12 displays the population pharmacokinetic estimates of darunavir after oral administration of Darunavir/ritonavir 600/100 mg twice daily and Darunavir/ritonavir 800/100 mg once daily to HIV-1-infected patients.
- Absorption and Bioavailability
- Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5–4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggest that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters.
- Effects of Food on Oral Absorption
- When Darunavir tablets were administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Therefore, Darunavir tablets, co-administered with ritonavir, should always be taken with food. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).
- Distribution
- Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).
- Metabolism
- In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1.
- Elimination
- A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.
- Special Populations
- Hepatic Impairment
- Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of Darunavir/ritonavir 600/100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated.
- Hepatitis B or Hepatitis C Virus Co-infection
- The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1-infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.
- Renal Impairment
- Results from a mass balance study with 14C-darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1-infected subjects with moderate renal impairment (CrCL between 30–60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or end stage renal disease.
- Gender
- Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1-infected females compared to males. This difference is not clinically relevant.
- Race
- Population pharmacokinetic analysis of darunavir in HIV-1-infected subjects indicated that race had no apparent effect on the exposure to darunavir.
- Geriatric Patients
- Population pharmacokinetic analysis in HIV-1-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected subjects (n=12, age greater than or equal to 65).
- Pediatric Patients
- Darunavir/ritonavir administered twice daily:
- The pharmacokinetics of darunavir in combination with ritonavir in 93 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg showed that the administered weight-based dosages resulted in similar darunavir exposure when compared to the darunavir exposure achieved in treatment-experienced adults receiving Darunavir/ritonavir 600/100 mg twice daily.
- Darunavir/ritonavir administered once daily:
- The pharmacokinetics of darunavir in combination with ritonavir in 12 antiretroviral treatment-naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 40 kg receiving Darunavir/ritonavir 800/100 mg once daily resulted in similar darunavir exposures when compared to the darunavir exposure achieved in treatment-naive adults receiving Darunavir/ritonavir 800/100 mg once daily.
- Based on population pharmacokinetic modeling and simulation, the proposed Darunavir/ritonavir once daily dosing regimens for pediatric patients 3 to less than 12 years of age is predicted to result in similar darunavir exposures when compared to the darunavir exposures achieved in treatment-naïve adults receiving Darunavir/ritonavir 800/100 mg once daily.
- The population pharmacokinetic parameters in pediatric subjects with Darunavir/ritonavir administered once or twice daily are summarized in the table below.
- Drug Interactions
- Darunavir co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events.
- Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir.
- Drug interaction studies were performed with darunavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir on the AUC, Cmax, and Cmin values are summarized in Table 14 (effect of other drugs on darunavir) and Table 15 (effect of darunavir on other drugs).
- Several interaction studies have been performed with a dose other than the recommended dose of the co-administered drug or darunavir; however, the results are applicable to the recommended dose of the co-administered drug and/or darunavir.
- Mechanism of Action
- Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.
- Antiviral Activity
- Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G), and group O primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, rilpivirine, efavirenz, etravirine, or nevirapine, and the fusion inhibitor enfuvirtide.
- Resistance
- Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and obtained from subjects treated with darunavir/ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.
- Clinical studies of Darunavir/ritonavir in treatment-experienced subjects: In a pooled analysis of the 600/100 mg Darunavir/ritonavir twice daily arms of Studies TMC114-C213, TMC114-C202, TMC114-C215, and the control arms of etravirine studies TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or M developed most frequently on Darunavir/ritonavir in 41% and 25%, respectively, of the treatment-experienced subjects who experienced virologic failure, either by rebound or by never being suppressed (less than 50 copies/mL). Other substitutions that developed frequently in Darunavir/ritonavir virologic failure isolates occurred at amino acid positions V11I, I15V, L33F, I47V, I50V, and L89V. These amino acid substitutions were associated with decreased susceptibility to darunavir; 90% of the virologic failure isolates had a greater than 7-fold decrease in susceptibility to darunavir at failure. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 4.3-fold at baseline and 85-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites in the Gag polyprotein of some Darunavir/ritonavir virologic failure isolates. In Study TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M developed most frequently in virologic failures on Darunavir/ritonavir.
- In the 96-week as-treated analysis of the Phase 3 Study TMC114-C214, the percent of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 21% (62/298) in the group of subjects receiving Darunavir/ritonavir 600/100 mg twice daily compared to 32% (96/297) of subjects receiving lopinavir/ritonavir 400/100 mg twice daily. Examination of subjects who failed on Darunavir/ritonavir 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that 7 subjects (7/43; 16%) developed PI substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the 7 had baseline PI resistance-associated substitutions and baseline darunavir phenotypes greater than 7. The most common emerging PI substitutions in these virologic failures were V32I, L33F, M46I or L, I47V, I54L, T74P and L76V. These amino acid substitutions were associated with 59- to 839-fold decreased susceptibility to darunavir at failure. Examination of individual subjects who failed in the comparator arm on lopinavir/ritonavir and had post-baseline genotypes and phenotypes showed that 31 subjects (31/75; 41%) developed substitutions on lopinavir treatment resulting in decreased susceptibility to lopinavir (greater than 10-fold) and the most common substitutions emerging on treatment were L10I or F, M46I or L, I47V or A, I54V and L76V. Of the 31 lopinavir/ritonavir virologic failure subjects, 14 had reduced susceptibility (greater than 10-fold) to lopinavir at baseline.
- In the 48-week analysis of the Phase 3 Study TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving Darunavir/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving Darunavir/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on Darunavir/ritonavir 800/100 mg once daily and had post-baseline genotypes showed that 8 subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to 5 subjects (5/39; 13%) on Darunavir/ritonavir 600/100 mg twice daily. Isolates from 2 subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; 1 subject isolate in the Darunavir/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with a 24-fold decreased susceptibility to darunavir, and 1 subject isolate in the Darunavir/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In the Darunavir/ritonavir 800/100 mg once daily and Darunavir/ritonavir 600/100 mg twice daily groups, isolates from 7 (7/60, 12%) and 4 (4/42, 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.
- Clinical studies of Darunavir/ritonavir in treatment-naive subjects: In the 192-week as-treated analysis censoring those who discontinued before Week 4 of the Phase 3 Study TMC114-C211, the percentage of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 22% (64/288) in the group of subjects receiving Darunavir/ritonavir 800/100 mg once daily compared to 29% (76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the Darunavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 11 of the virologic failures with post-baseline genotypic data (n=43). However, none of the darunavir virologic failures had a decrease in darunavir susceptibility (greater than 7-fold change) at failure. In the comparator lopinavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 17 of the virologic failures with post-baseline genotypic data (n=53), but none of the lopinavir/ritonavir virologic failures had decreased susceptibility to lopinavir (greater than 10-fold change) at failure. The reverse transcriptase M184V substitution and/or resistance to emtricitabine, which was included in the fixed background regimen, was identified in 4 virologic failures from the Darunavir/ritonavir arm and 7 virologic failures in the lopinavir/ritonavir arm.
- Cross-resistance
- Cross-resistance among PIs has been observed. Darunavir has a less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir.
- Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from PI-resistant viruses showed a fold change in EC50 values less than 3 for tipranavir, indicative of limited cross-resistance between darunavir and tipranavir. In Studies TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187) of subjects in the darunavir/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change greater than 3) achieved less than 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses isolated from subjects experiencing virologic failure on Darunavir/ritonavir 600/100 mg twice daily (greater than 7 fold change), 41% were still susceptible to tipranavir and 10% were susceptible to saquinavir while less than 2% were susceptible to the other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir or nelfinavir).
- In Study TMC114-C214, the 7 darunavir/ritonavir virologic failures with reduced susceptibility to darunavir at failure were also resistant to the approved PIs (fos)amprenavir, atazanavir, lopinavir, indinavir, and nelfinavir at failure. Six of these 7 were resistant to saquinavir and 5 were resistant to tipranavir. Four of these virologic failures were already PI-resistant at baseline.
- Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase inhibitors is unlikely because the viral targets are different.
- Baseline Genotype/Phenotype and Virologic Outcome Analyses
- Genotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before initiation of Darunavir/ritonavir 600/100 mg twice daily therapy. The effect of baseline genotype and phenotype on virologic response at 96 weeks was analyzed in as-treated analyses using pooled data from the Phase 2b studies (Studies TMC114-C213, TMC114-C202, and TMC114-C215) (n=439). The findings were confirmed with additional genotypic and phenotypic data from the control arms of etravirine Studies TMC125-C206 and TMC125-C216 at Week 24 (n=591).
- Diminished virologic responses were observed in subjects with 5 or more baseline IAS-defined primary protease inhibitor resistance-associated substitutions (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M) (see Table 16).
- The presence at baseline of two or more of the substitutions V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with a decreased virologic response to Darunavir/ritonavir. In subjects not taking enfuvirtide de novo, the proportion of subjects achieving viral load less than 50 plasma HIV-1 RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0–1, 2 and greater than or equal to 3 of these substitutions, respectively.
- Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 17. These baseline phenotype groups are based on the select patient populations in the Studies TMC114-C213, TMC114-C202, and TMC114-C215, and are not meant to represent definitive clinical susceptibility breakpoints for Darunavir/ritonavir. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir.
## Nonclinical Toxicology
- Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg was administered to rats. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).
- Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reserve mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
- No effects on fertility or early embryonic development were observed with darunavir in rats and darunavir has shown no teratogenic potential in mice or rats (in the presence or absence of ritonavir), and rabbits.
- In juvenile rats single doses of darunavir (20 mg/kg to 160 mg/kg at ages 5–11 days) or multiple doses of darunavir (40 mg/kg to 1000 mg/kg at age 12 days) caused mortality. The mortalities were associated with convulsions in some of the animals. Within this age range exposures in plasma, liver and brain were dose and age dependent and were considerably greater than those observed in adult rats. These findings were attributed to the ontogeny of the CYP450 liver enzymes involved in the metabolism of darunavir and the immaturity of the blood-brain barrier. No treatment-related mortalities were noted in juvenile rats after a single dose of darunavir at 1000 mg/kg on day 26 of age or after repeat dosing at 500 mg/kg from day 23 to 50 of age. The exposures and toxicity profile in the older animals (day 23 or day 26) were comparable to those observed in adult rats. Due to uncertainties regarding the rate of development of the human blood-brain barrier and liver enzymes, do not administer Darunavir/ritonavir in pediatric patients below 3 years of age.
# Clinical Studies
- The evidence of efficacy of Darunavir/ritonavir is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211) HIV-1-infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data are included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.
- Study TMC114-C211
- Study TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing Darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects. Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC).
- HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than or equal to 5000 copies/mL. Randomization was stratified by screening plasma viral load (HIV-1 RNA less than 100,000 copies/mL or greater than or equal to 100,000 copies/mL) and screening CD4+ cell count (less than 200 cells/mm3 or greater than or equal to 200 cells/mm3). Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 689 subjects in Study TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier.
- Demographics and baseline characteristics were balanced between the Darunavir/ritonavir arm and the lopinavir/ritonavir arm (see Table 18). Table 18 compares the demographic and baseline characteristics between subjects in the Darunavir/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg per day arm in Study TMC114-C211.
- Week 192 outcomes for subjects on Darunavir/ritonavir 800/100 mg once daily from Study TMC114-C211 are shown inTable 19.
- In Study TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258 cells/mm3 in the Darunavir/ritonavir 800/100 mg once daily arm and 263 cells/mm3 in the lopinavir/ritonavir 800/200 mg per day arm. Of the Darunavir/ritonavir subjects with a confirmed virologic response of < 50 copies/mL at Week 48, 81% remained undetectable at Week 192 versus 68% with lopinavir/ritonavir. In the 192 week analysis, statistical superiority of the Darunavir/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.
- Study TMC114-C229
- Study TMC114-C229 is a randomized, open-label trial comparing Darunavir/ritonavir 800/100 mg once daily to Darunavir/ritonavir 600/100 mg twice daily in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of greater than 1,000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of greater than or equal to 2 NRTIs selected by the investigator.
- HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.
- Table 20 compares the demographic and baseline characteristics between subjects in the Darunavir/ritonavir 800/100 mg once daily arm and subjects in the Darunavir/ritonavir 600/100 mg twice daily arm in Study TMC114-C229. No imbalances between the 2 arms were noted.
- Week 48 outcomes for subjects on Darunavir/ritonavir 800/100 mg once daily from Study TMC114-C229 are shown in Table 21.
- The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm3 and 112 cells/mm3 in the Darunavir/ritonavir 800/100 mg once daily arm and the Darunavir/ritonavir 600/100 mg twice daily arm, respectively).
- Study TMC114-C214
- Study TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing Darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naïve HIV-1-infected adult subjects. Both arms used an optimized background regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).
- HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than 1000 copies/mL and were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 400 copies/mL. Analyses included 595 subjects in Study TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier.
- Demographics and baseline characteristics were balanced between the Darunavir/ritonavir arm and the lopinavir/ritonavir arm (see Table 22). Table 22 compares the demographic and baseline characteristics between subjects in the Darunavir/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg twice daily arm in Study TMC114-C214.
- Week 96 outcomes for subjects on Darunavir/ritonavir 600/100 mg twice daily from Study TMC114-C214 are shown inTable 23.
- In Study TMC114-C214 at 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81 cells/mm3 in the Darunavir/ritonavir 600/100 mg twice daily arm and 93 cells/mm3 in the lopinavir/ritonavir 400/100 mg twice daily arm.
- Studies TMC114-C213 and TMC114-C202
- Studies TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to Darunavir/ritonavir received the recommended dose of 600/100 mg twice daily.
- HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA greater than 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide.
- The virologic response rate was evaluated in subjects receiving Darunavir/ritonavir plus an OBR versus a control group receiving an investigator-selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Selected PI(s) in the control arm included: lopinavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received a ritonavir boosted PI regimen out of which 23% of control subjects used dual-boosted PIs. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naïve. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log10 versus baseline.
- In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the Darunavir/ritonavir arm and the comparator PI arm (see Table 24). Table 24 compares the demographic and baseline characteristics between subjects in the Darunavir/ritonavir 600/100 mg twice daily arm and subjects in the comparator PI arm in the pooled analysis of Studies TMC114-C213 and TMC114-C202.
- Week 96 outcomes for subjects on the recommended dose Darunavir/ritonavir 600/100 mg twice daily from the pooled Studies TMC114-C213 and TMC114-C202 are shown inTable 25.
- In the pooled Studies TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA less than 400 copies/mL in the arm receiving Darunavir/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were –1.69 log10 copies/mL in the arm receiving Darunavir/ritonavir 600/100 mg twice daily and –0.37 log10 copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving Darunavir/ritonavir 600/100 mg twice daily (103 cells/mm3) than in the comparator PI arm (17 cells/mm3).
- The pharmacokinetic profile, safety and antiviral activity of Darunavir/ritonavir were evaluated in 3 randomized, open-label, multicenter studies.
- Study TMC114-C212
- Treatment-experienced pediatric subjects between the ages of 6 and less than 18 years and weighing at least 20 kg were stratified according to their weight (greater than or equal to 20 kg to less than 30 kg, greater than or equal to 30 kg to less than 40 kg, greater than or equal to 40 kg) and received Darunavir tablets with either ritonavir capsules or oral solution plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs. Eighty patients were randomized and received at least one dose of Darunavir/ritonavir. Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.
- The 80 randomized pediatric subjects had a median age of 14 (range 6 to less than 18 years), and were 71% male, 54% Caucasian, 30% Black, 9% Hispanic and 8% other. The mean baseline plasma HIV-1 RNA was 4.64 log10 copies/mL, and the median baseline CD4+ cell count was 330 cells/mm3 (range: 6 to 1505 cells/mm3). Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA ≥ 100,000 copies/mL. Most pediatric subjects (79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI.
- Seventy-seven pediatric subjects (96%) completed the 24-week period. Of the patients who discontinued, one patient discontinued treatment due to an adverse event. An additional 2 patients discontinued for other reasons, one patient due to compliance and another patient due to relocation.
- The proportion of pediatric subjects with HIV-1 RNA less than 400 copies/mL and less than 50 copies/mL was 64% and 50%, respectively. The mean increase in CD4+ cell count from baseline was 117 cells/mm3.
- Study TMC114-C228
- Treatment-experienced pediatric subjects between the ages of 3 and less than 6 years and weighing greater than or equal to 10 kg to less than 20 kg received Darunavir oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs. Twenty-one subjects received at least one dose of Darunavir/ritonavir.
- The 21 subjects had a median age of 4.4 years (range 3 to less than 6 years), and were 48% male, 57% Black, 29%, Caucasian and 14% other. The mean baseline plasma HIV-1 was 4.34 log10 copies/mL, the median baseline CD4+ cell count was 927 × 106 cells/l (range: 209 to 2,429 × 106 cells/l) and the median baseline CD4+ percentage was 27.7% (range: 15.6% to 51.1%). Overall, 24% of subjects had a baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL. All subjects had used greater than or equal to 2 NRTIs, 62% of subjects had used greater than or equal to 1 NNRTI and 76% had previously used at least one HIV PI.
- Twenty subjects (95%) completed the 48 week period. One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir.
- The proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 48 was 71%.. The mean increase in CD4+ percentage from baseline was 4%. The mean change in CD4+ cell count from baseline was 187 × 106 cells/L.
- Study TMC114-C230
- Treatment-naïve pediatric subjects between the ages of 12 and less than 18 years and weighing at least 40 kg received the adult recommended dose of Darunavir/ritonavir 800/100 mg once daily plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs.
- The 12 randomized pediatric subjects had a median age of 14.4 years (range 12.6 to 17.3 years), and were 33.3% male, 58.3% Caucasian and 41.7% Black. The mean baseline plasma HIV-1 RNA was 4.72 log10 copies/mL, and the median baseline CD4+ cell count was 282 cells/mm3 (range: 204 to 515 cells/mm3). Overall, 41.7% of pediatric subjects had baseline plasma HIV-1 RNA ≥ 100,000 copies/mL.
- All subjects completed the 48 week treatment period.
- The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was 83.3% and 91.7%, respectively. The mean increase in CD4+ cell count from baseline was 221 × 106 cells/L.
# How Supplied
- Darunavir (darunavir) 100 mg/mL oral suspension is a white to off-white opaque liquid supplied in amber-colored multiple-dose bottles containing darunavir ethanolate equivalent to 100 mg of darunavir per mL packaged with a 6 mL oral dosing syringe with 0.2 mL gradations.
- Darunavir (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with "75" on one side and "TMC" on the other side.
- Darunavir (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with "150" on one side and "TMC" on the other side.
- Darunavir (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 600 mg of darunavir per tablet. Each tablet is debossed with "600MG" on one side and "TMC" on the other side.
- Darunavir (darunavir) 800 mg tablets are supplied as dark red, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 800 mg of darunavir per tablet. Each tablet is debossed with "800" on one side and "T" on the other side.
- Darunavir is packaged in bottles in the following configuration:
- 100 mg/mL oral suspension – 200 mL bottles (NDC 59676-565-01)
- 75 mg tablets—bottles of 480 (NDC 59676-563-01)
- 150 mg tablets—bottles of 240 (NDC 59676-564-01)
- 600 mg tablets—bottles of 60 (NDC 59676-562-01)
- 800 mg tablets—bottles of 30 (NDC 59676-566-30)
- Storage:
- Darunavir Oral Suspension
- Store at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F).
- Do not refrigerate or freeze. Avoid exposure to excessive heat.
- Store in the original container.
- Shake well before each usage.
- Darunavir Tablets
- Store at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F).
## Storage
There is limited information regarding Darunavir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Darunavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PREZISTA®
# Look-Alike Drug Names
There is limited information regarding Darunavir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Darunavir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Darunavir is a protease inhibitor that is FDA approved for the treatment of human immunodeficiency virus (HIV-1) infection. Common adverse reactions include diarrhea, nausea, rash, headache, abdominal pain and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Darunavir must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer Darunavir with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.
- Treatment-Naïve Adult Patients
- The recommended oral dose of Darunavir is 800 mg (one 800 mg tablet or 8 mL of the oral suspension) taken with ritonavir 100 mg (one 100 mg tablet/capsule or 1.25 mL of a 80 mg/mL ritonavir oral solution) once daily and with food. An 8 mL darunavir dose should be taken as two 4 mL administrations with the included oral dosing syringe.
- Treatment-Experienced Adult Patients
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Darunavir in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Darunavir in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The indication for treatment-experienced pediatric patients 3 to less than 18 years of age is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from two open-label Phase 2 trials in antiretroviral treatment-experienced pediatric subjects(24-week analysis for one trial in patients 6 to less than 18 years of age; 48-week analysis for one trial in patients 3 to less than 6 years of age) . The indication for treatment-naïve pediatric patients or antiretroviral treatment-experienced patients with no darunavir resistance associated substitutions is based on one open-label Phase 2 trial of 48 weeks duration in antiretroviral treatment-naïve subjects 12 to less than 18 years of age and pharmacokinetic modeling and simulation for patients 3 to less than 12 years of age.
- In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with Darunavir/ritonavir:
- Treatment history and, when available, genotypic or phenotypic testing should guide the use of Darunavir/ritonavir.
- The use of other active agents with Darunavir/ritonavir is associated with a greater likelihood of treatment response.
- Before prescribing Darunavir, children weighing greater than or equal to 15 kg should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a tablet, the use of Darunavir oral suspension should be considered.
- The recommended dose of Darunavir/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight (see Tables 2, 3, 4, and 5) and should not exceed the recommended adult dose. Darunavir should be taken with ritonavir and with food.
- The recommendations for the Darunavir/ritonavir dosage regimens were based on the following:
- Twice daily dosing
Results from two trials in treatment-experienced pediatric subjects 3 to less 18 years of age demonstrating similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-experienced adults.
- Results from two trials in treatment-experienced pediatric subjects 3 to less 18 years of age demonstrating similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-experienced adults.
- Once daily dosing
- Results from one trial in treatment-naive pediatric subjects 12 to less than 18 years of age demonstrating similar darunavir plasma exposures, virologic response rate and safety profile compared to treatment-naive adults.
- Results from population pharmacokinetic modeling and simulation in children 3 to less than 12 years of age predicting similar darunavir plasma exposures compared to treatment-naïve adults. Although no clinical trial was conducted to collect exposure-safety data, the predicted exposures from the once daily dosing is supported by exposures observed in a pediatric clinical trial where twice-daily dosing was administered.
- Dosing recommendations for treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions
- Pediatric patients weighing at least 10 kg but less than 15 kg
- The weight-based dose in antiretroviral treatment-naïve pediatric patients or antiretroviral treatment-experienced pediatric patients with no darunavir resistance associated substitutions is Darunavir 35 mg/kg once daily with ritonavir 7 mg/kg once daily using the following table.
- Pediatric patients weighing at least 15 kg
- Pediatric patients weighing at least 15 kg can be dosed with Darunavir oral tablet(s) or suspension using the following table:
- Dosing recommendations for treatment-experienced pediatric patients with at least one darunavir resistance associated substitutions
- Pediatric patients weighing at least 10 kg but less than 15 kg
- The weight-based dose in antiretroviral treatment-experienced pediatric patients with at least one darunavir resistance associated substitution is Darunavir 20 mg/kg twice daily with ritonavir 3 mg/kg twice daily using the following table:
- Pediatric patients weighing at least 15 kg
- Pediatric patients weighing at least 15 kg can be dosed with Darunavir oral tablet(s) or suspension using the following table:
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Darunavir in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Darunavir in pediatric patients.
# Contraindications
- Co-administration of Darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed in Table 6
# Warnings
### Precautions
- General
- Darunavir must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer Darunavir with ritonavir and food may result in a loss of efficacy of darunavir.
- Please refer to ritonavir prescribing information for additional information on precautionary measures.
- Hepatotoxicity
- Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with Darunavir/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with Darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.
- Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with Darunavir/ritonavir therapy has not been established.
- Appropriate laboratory testing should be conducted prior to initiating therapy with Darunavir/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Darunavir/ritonavir treatment.
- Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on Darunavir/ritonavir should prompt consideration of interruption or discontinuation of treatment.
- Severe Skin Reactions
- During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported. Discontinue Darunavir/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
- Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with Darunavir/ritonavir. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using Darunavir/ritonavir was 0.5%.
- Rash occurred more commonly in treatment-experienced subjects receiving regimens containing Darunavir/ritonavir + raltegravir compared to subjects receiving Darunavir/ritonavir without raltegravir or raltegravir without Darunavir/ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.
- Sulfa Allergy
- Darunavir contains a sulfonamide moiety. Darunavir should be used with caution in patients with a known sulfonamide allergy. In clinical studies with Darunavir/ritonavir, the incidence and severity of rash were similar in subjects with or without a history of sulfonamide allergy.
- Drug Interactions
- See Table 6 for a listing of drugs that are contraindicated for use with Darunavir/ritonavir due to potentially life-threatening adverse events, significant drug-drug interactions, or loss of therapeutic effect to Darunavir. Please refer to Table 11 for established and other potentially significant drug-drug interactions.
- Diabetes Mellitus / Hyperglycemia
- New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established.
- Fat Redistribution
- Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Darunavir. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.
- Hemophilia
- There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. A causal relationship between PI therapy and these episodes has not been established.
- Resistance/Cross-Resistance
- Because the potential for HIV cross-resistance among PIs has not been fully explored in Darunavir/ritonavir treated patients, the effect therapy with Darunavir will have on the activity of subsequently administered PIs is unknown.
- Pediatric Patients
- Do not administer Darunavir/ritonavir in pediatric patients below 3 years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age.
# Adverse Reactions
## Clinical Trials Experience
- Study TMC114-C211
- The safety assessment is based on all safety data from the Phase 3 trial TMC114-C211 comparing Darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naïve HIV-1-infected adult subjects. The total mean exposure for subjects in the Darunavir/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 162.5 and 153.5 weeks, respectively.
- The majority of the adverse drug reactions (ADRs) reported during treatment with Darunavir/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to Darunavir/ritonavir 800/100 mg once daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the Darunavir/ritonavir arm discontinued treatment due to ADRs.
- ADRs to Darunavir/ritonavir 800/100 mg once daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-naïve HIV-1-infected adult subjects are presented in Table 7 and subsequent text below the table.
- Less Common Adverse Reactions
- Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving Darunavir/ritonavir 800/100 mg once daily are listed below by body system:
Acute pancreatitis, dyspepsia, flatulence
Asthenia
Acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity)
Hypersensitivity, immune reconstitution syndrome
Diabetes mellitus
Myalgia, osteonecrosis
Abnormal dreams
Angioedema, pruritus, Stevens-Johnson Syndrome, urticaria
- Laboratory abnormalities:
- Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-naïve adult subjects treated with Darunavir/ritonavir 800/100 mg once daily are presented in Table 8.
- Study TMC114-C214
- The safety assessment is based on all safety data from the Phase 3 trial TMC114-C214 comparing Darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-experienced HIV-1-infected adult subjects. The total mean exposure for subjects in the Darunavir/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 80.7 and 76.4 weeks, respectively.
- The majority of the ADRs reported during treatment with Darunavir/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to Darunavir/ritonavir 600/100 mg twice daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the Darunavir/ritonavir arm discontinued treatment due to ADRs.
- ADRs to Darunavir/ritonavir 600/100 mg twice daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table 9 and subsequent text below the table.
- Less Common Adverse Reactions
- Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving Darunavir/ritonavir 600/100 mg twice daily are listed below by body system:
Acute pancreatitis, flatulence
Myalgia
Abnormal dreams
Pruritus, urticaria
- Laboratory abnormalities:
- Selected Grade 2 to 4 laboratory abnormalities that represent a worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with Darunavir/ritonavir 600/100 mg twice daily are presented in Table 10.
- The following serious ADRs of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b studies and Phase 3 studies with Darunavir/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting.
- In subjects co-infected with hepatitis B or hepatitis C virus receiving Darunavir/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving Darunavir/ritonavir who were not co-infected, except for increased hepatic enzymes. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection.
- Darunavir/ritonavir has been studied in combination with other antiretroviral agents in 3 Phase II trials. TMC114-C212, in which 80 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 6 to less than 18 years of age and weighing at least 20 kg were included, TMC114-C228, in which 21 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 6 years of age and weighing at least 10 kg were included, and TMC114-C230 in which 12 antiretroviral treatment-naïve HIV-1 infected pediatric patients aged from 12 to less than 18 years and weighing at least 40 kg were included. The TMC114-C212 and C228 trials evaluated Darunavir/ritonavir twice daily dosing and the TMC114-C230 trial evaluated Darunavir/ritonavir once daily dosing.
- Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults.
- Study TMC114-C212
- Clinical ADRs to Darunavir/ritonavir (all grades, greater than or equal to 3%), were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%) and fatigue (3%).
- Grade 3 or 4 laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%).
- Study TMC114-C228
- Clinical ADRs to Darunavir/ritonavir (all grades, greater than or equal to 5%), were diarrhea (24%), vomiting (19%),rash (19%), abdominal pain (5%) and anorexia (5%).
- There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study.
- Study TMC114-C230
- Clinical ADRs to Darunavir/ritonavir (all grades, greater than or equal to 3%), were vomiting (33%), nausea (25%), diarrhea (16.7%), abdominal pain (8.3%), decreased appetite (8.3%), pruritus (8.3%), and rash (8.3%).
- There were no Grade 3 or 4 laboratory abnormalities considered as ADRs in this study.
## Postmarketing Experience
- The following events have been identified during post approval use of Darunavir. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Redistribution of body fat has been reported.
- Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and Darunavir/ritonavir) has been reported.
- In addition, toxic epidermal necrolysis,acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms have been reported rarely.
# Drug Interactions
- Darunavir co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of Darunavir and ritonavir with drugs that are primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see Table 11).
- Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir (see Table 11).
- Table 11 provides dosing recommendations as a result of drug interactions with Darunavir/ritonavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy.
- In addition to the drugs included in Table 11, the interaction between Darunavir/ritonavir and the following drugs were evaluated in clinical studies and no dose adjustments are needed for either drug: atazanavir, efavirenz, etravirine, nevirapine, omeprazole, ranitidine, rilpivirine, and tenofovir disoproxil fumarate. Using cross-trial comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of darunavir. Darunavir/ritonavir had no clinically significant effect on the pharmacokinetics of dolutegravir.
- Other nucleoside reverse transcriptase inhibitors (NRTIs):
- Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and Darunavir/ritonavir.
- Other PIs:
- The co-administration of Darunavir/ritonavir and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended.
- Integrase strand transfer inhibitors:
- Based on the pharmacokinetic data from literature references, either no clinically significant changes in darunavir concentrations or decreases in darunavir concentrations were observed with concomitant use of raltegravir. The potential decrease in darunavir concentrations does not appear to be clinically relevant. Darunavir/ritonavir and raltegravir can be used without dose adjustments.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- No adequate and well-controlled studies have been conducted in pregnant women. Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice and rats in the presence or absence of ritonavir as well as in rabbits with darunavir alone. In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.
- In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed with darunavir alone or in combination with ritonavir during lactation. This was due to exposure of pups to drug substances via the milk. Sexual development, fertility and mating performance of offspring were not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.
- In the juvenile toxicity study where rats were directly dosed with darunavir, deaths occurred from post-natal day 5 through 11 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma exposure levels.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Darunavir, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Darunavir in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Darunavir during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known whether darunavir is secreted in human milk, darunavir is secreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Darunavir.
### Pediatric Use
- Do not administer Darunavir/ritonavir in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age.
- The safety, pharmacokinetic profile, and virologic and immunologic responses of Darunavir/ritonavir were evaluated in treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighting at least 10 kg. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, 6 to less than 18 years of age) and TMC114-228 (21 subjects, 3 to less than 6 years of age). Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults.
- In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of Darunavir/ritonavir administered once daily were evaluated in treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects). Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults. Once daily dosing recommendations for pediatric patients 3 to less than 12 years of age were derived using population pharmacokinetic modeling and simulation. Although a Darunavir/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted Darunavir exposures for the dosing recommendations in this age group.
### Geriatic Use
- Clinical studies of Darunavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of Darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Darunavir with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Darunavir with respect to specific racial populations.
### Renal Impairment
- Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30–60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis.
### Hepatic Impairment
- No dose adjustment of Darunavir/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of Darunavir/ritonavir in subjects with severe hepatic impairment. Therefore, Darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Darunavir in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Darunavir in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of Darunavir/ritonavir treatment.
# IV Compatibility
There is limited information regarding IV Compatibility of Darunavir in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Human experience of acute overdose with Darunavir/ritonavir is limited. Single doses up to 3200 mg of the oral solution of darunavir alone and up to 1600 mg of the tablet formulation of darunavir in combination with ritonavir have been administered to healthy volunteers without untoward symptomatic effects.
### Management
- No specific antidote is available for overdose with Darunavir. Treatment of overdose with Darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Darunavir in the drug label.
# Pharmacology
## Mechanism of Action
- Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.
## Structure
- Darunavir (darunavir) is an inhibitor of the human immunodeficiency virus (HIV-1) protease.
- Darunavir (darunavir), in the form of darunavir ethanolate, has the following chemical name: [(1S,2R)-3-[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C27H37N3O7S • C2H5OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:
- Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.15 mg/mL in water at 20°C.
- Darunavir 100 mg/mL oral suspension is available as a white to off-white opaque suspension for oral administration.
- Darunavir 75 mg tablets are available as white, caplet-shaped, film-coated tablets for oral administration. Darunavir 150 mg tablets are available as white, oval-shaped, film-coated tablets for oral administration. Darunavir 600 mg tablets are available as orange, oval-shaped, film-coated tablets for oral administration. Darunavir 800 mg tablets are available as dark red, oval-shaped, film-coated tablets for oral administration.
- Each mL of the oral suspension contains darunavir ethanolate equivalent to 100 mg darunavir. In addition, each mL contains the inactive ingredients hydroxypropyl cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, methylparaben sodium, citric acid monohydrate, sucralose, masking flavor, strawberry cream flavor, hydrochloric acid (for pH adjustment) and purified water.
- Each 75 mg tablet contains darunavir ethanolate equivalent to 75 mg of darunavir. Each 150 mg tablet contains darunavir ethanolate equivalent to 150 mg of darunavir. Each 600 mg tablet contains darunavir ethanolate equivalent to 600 mg of darunavir. Each 800 mg tablet contains darunavir ethanolate equivalent to 800 mg of darunavir. During storage, partial conversion from ethanolate to hydrate may occur; however, this does not affect product quality or performance. Each tablet also contains the inactive ingredients colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. The 800 mg tablet also contains hypromellose. The 75 and 150 mg tablet film coating, OPADRY® White, contains polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. The 600 mg tablet film coating, OPADRY® Orange, contains FD&C Yellow No. 6, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. The 800 mg tablet film coating, OPADRY® Dark Red, contains iron oxide red, polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide.
- All dosages for Darunavir are expressed in terms of the free form of darunavir.
## Pharmacodynamics
- In an open-label, randomized, placebo- and active-controlled, four-way crossover trial, 40 healthy subjects were administered supratheraputic doses of darunavir/ritonavir 1600/100 mg once daily and 800/100 mg twice daily for seven days.
- At the mean maximum darunavir concentration of 6599 ng/mL observed in this study, the mean increase in QTcF was 2.2 ms with a 90% two-sided confidence interval (CI) of -2.0 to 6.3 ms. When evaluating the 2-sided 90% CI on the time-matched mean changes in QTcF versus placebo control, the upper bounds of both darunavir/ritonavir groups never exceeded the 10 ms boundary. In the setting of this trial, darunavir/ritonavir did not appear to prolong the QTc interval.
## Pharmacokinetics
- General
- Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of Darunavir 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, Darunavir should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.
- The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 12 displays the population pharmacokinetic estimates of darunavir after oral administration of Darunavir/ritonavir 600/100 mg twice daily [based on sparse sampling in 285 patients in study TMC114-C214, 278 patients in Study TMC114-C229 and 119 patients (integrated data) from Studies TMC114-C202 and TMC114-C213] and Darunavir/ritonavir 800/100 mg once daily [based on sparse sampling in 335 patients in Study TMC114-C211 and 280 patients in Study TMC114-C229] to HIV-1-infected patients.
- Absorption and Bioavailability
- Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5–4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggest that darunavir/ritonavir is an inhibitor of the p-glycoprotein (p-gp) transporters.
- Effects of Food on Oral Absorption
- When Darunavir tablets were administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Therefore, Darunavir tablets, co-administered with ritonavir, should always be taken with food. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).
- Distribution
- Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).
- Metabolism
- In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1.
- Elimination
- A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.
- Special Populations
- Hepatic Impairment
- Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of Darunavir/ritonavir 600/100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated.
- Hepatitis B or Hepatitis C Virus Co-infection
- The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1-infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.
- Renal Impairment
- Results from a mass balance study with 14C-darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1-infected subjects with moderate renal impairment (CrCL between 30–60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1-infected patients with severe renal impairment or end stage renal disease.
- Gender
- Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1-infected females compared to males. This difference is not clinically relevant.
- Race
- Population pharmacokinetic analysis of darunavir in HIV-1-infected subjects indicated that race had no apparent effect on the exposure to darunavir.
- Geriatric Patients
- Population pharmacokinetic analysis in HIV-1-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected subjects (n=12, age greater than or equal to 65).
- Pediatric Patients
- Darunavir/ritonavir administered twice daily:
- The pharmacokinetics of darunavir in combination with ritonavir in 93 antiretroviral treatment-experienced HIV-1-infected pediatric subjects 3 to less than 18 years of age and weighing at least 10 kg showed that the administered weight-based dosages resulted in similar darunavir exposure when compared to the darunavir exposure achieved in treatment-experienced adults receiving Darunavir/ritonavir 600/100 mg twice daily.
- Darunavir/ritonavir administered once daily:
- The pharmacokinetics of darunavir in combination with ritonavir in 12 antiretroviral treatment-naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 40 kg receiving Darunavir/ritonavir 800/100 mg once daily resulted in similar darunavir exposures when compared to the darunavir exposure achieved in treatment-naive adults receiving Darunavir/ritonavir 800/100 mg once daily.
- Based on population pharmacokinetic modeling and simulation, the proposed Darunavir/ritonavir once daily dosing regimens for pediatric patients 3 to less than 12 years of age is predicted to result in similar darunavir exposures when compared to the darunavir exposures achieved in treatment-naïve adults receiving Darunavir/ritonavir 800/100 mg once daily.
- The population pharmacokinetic parameters in pediatric subjects with Darunavir/ritonavir administered once or twice daily are summarized in the table below.
- Drug Interactions
- Darunavir co-administered with ritonavir is an inhibitor of CYP3A and CYP2D6. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A and CYP2D6 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events.
- Darunavir and ritonavir are metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir.
- Drug interaction studies were performed with darunavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir on the AUC, Cmax, and Cmin values are summarized in Table 14 (effect of other drugs on darunavir) and Table 15 (effect of darunavir on other drugs).
- Several interaction studies have been performed with a dose other than the recommended dose of the co-administered drug or darunavir; however, the results are applicable to the recommended dose of the co-administered drug and/or darunavir.
- Mechanism of Action
- Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.
- Antiviral Activity
- Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M (A, B, C, D, E, F, G), and group O primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, rilpivirine, efavirenz, etravirine, or nevirapine, and the fusion inhibitor enfuvirtide.
- Resistance
- Cell Culture: HIV-1 isolates with a decreased susceptibility to darunavir have been selected in cell culture and obtained from subjects treated with darunavir/ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed 2 to 4 of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.
- Clinical studies of Darunavir/ritonavir in treatment-experienced subjects: In a pooled analysis of the 600/100 mg Darunavir/ritonavir twice daily arms of Studies TMC114-C213, TMC114-C202, TMC114-C215, and the control arms of etravirine studies TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or M developed most frequently on Darunavir/ritonavir in 41% and 25%, respectively, of the treatment-experienced subjects who experienced virologic failure, either by rebound or by never being suppressed (less than 50 copies/mL). Other substitutions that developed frequently in Darunavir/ritonavir virologic failure isolates occurred at amino acid positions V11I, I15V, L33F, I47V, I50V, and L89V. These amino acid substitutions were associated with decreased susceptibility to darunavir; 90% of the virologic failure isolates had a greater than 7-fold decrease in susceptibility to darunavir at failure. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 4.3-fold at baseline and 85-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites in the Gag polyprotein of some Darunavir/ritonavir virologic failure isolates. In Study TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M developed most frequently in virologic failures on Darunavir/ritonavir.
- In the 96-week as-treated analysis of the Phase 3 Study TMC114-C214, the percent of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 21% (62/298) in the group of subjects receiving Darunavir/ritonavir 600/100 mg twice daily compared to 32% (96/297) of subjects receiving lopinavir/ritonavir 400/100 mg twice daily. Examination of subjects who failed on Darunavir/ritonavir 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that 7 subjects (7/43; 16%) developed PI substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the 7 had baseline PI resistance-associated substitutions and baseline darunavir phenotypes greater than 7. The most common emerging PI substitutions in these virologic failures were V32I, L33F, M46I or L, I47V, I54L, T74P and L76V. These amino acid substitutions were associated with 59- to 839-fold decreased susceptibility to darunavir at failure. Examination of individual subjects who failed in the comparator arm on lopinavir/ritonavir and had post-baseline genotypes and phenotypes showed that 31 subjects (31/75; 41%) developed substitutions on lopinavir treatment resulting in decreased susceptibility to lopinavir (greater than 10-fold) and the most common substitutions emerging on treatment were L10I or F, M46I or L, I47V or A, I54V and L76V. Of the 31 lopinavir/ritonavir virologic failure subjects, 14 had reduced susceptibility (greater than 10-fold) to lopinavir at baseline.
- In the 48-week analysis of the Phase 3 Study TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving Darunavir/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving Darunavir/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on Darunavir/ritonavir 800/100 mg once daily and had post-baseline genotypes showed that 8 subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to 5 subjects (5/39; 13%) on Darunavir/ritonavir 600/100 mg twice daily. Isolates from 2 subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; 1 subject isolate in the Darunavir/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with a 24-fold decreased susceptibility to darunavir, and 1 subject isolate in the Darunavir/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with a 40-fold decreased susceptibility to darunavir. In the Darunavir/ritonavir 800/100 mg once daily and Darunavir/ritonavir 600/100 mg twice daily groups, isolates from 7 (7/60, 12%) and 4 (4/42, 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.
- Clinical studies of Darunavir/ritonavir in treatment-naive subjects: In the 192-week as-treated analysis censoring those who discontinued before Week 4 of the Phase 3 Study TMC114-C211, the percentage of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 22% (64/288) in the group of subjects receiving Darunavir/ritonavir 800/100 mg once daily compared to 29% (76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the Darunavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 11 of the virologic failures with post-baseline genotypic data (n=43). However, none of the darunavir virologic failures had a decrease in darunavir susceptibility (greater than 7-fold change) at failure. In the comparator lopinavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 17 of the virologic failures with post-baseline genotypic data (n=53), but none of the lopinavir/ritonavir virologic failures had decreased susceptibility to lopinavir (greater than 10-fold change) at failure. The reverse transcriptase M184V substitution and/or resistance to emtricitabine, which was included in the fixed background regimen, was identified in 4 virologic failures from the Darunavir/ritonavir arm and 7 virologic failures in the lopinavir/ritonavir arm.
- Cross-resistance
- Cross-resistance among PIs has been observed. Darunavir has a less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir.
- Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from PI-resistant viruses showed a fold change in EC50 values less than 3 for tipranavir, indicative of limited cross-resistance between darunavir and tipranavir. In Studies TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187) of subjects in the darunavir/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change greater than 3) achieved less than 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses isolated from subjects experiencing virologic failure on Darunavir/ritonavir 600/100 mg twice daily (greater than 7 fold change), 41% were still susceptible to tipranavir and 10% were susceptible to saquinavir while less than 2% were susceptible to the other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir or nelfinavir).
- In Study TMC114-C214, the 7 darunavir/ritonavir virologic failures with reduced susceptibility to darunavir at failure were also resistant to the approved PIs (fos)amprenavir, atazanavir, lopinavir, indinavir, and nelfinavir at failure. Six of these 7 were resistant to saquinavir and 5 were resistant to tipranavir. Four of these virologic failures were already PI-resistant at baseline.
- Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase inhibitors is unlikely because the viral targets are different.
- Baseline Genotype/Phenotype and Virologic Outcome Analyses
- Genotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before initiation of Darunavir/ritonavir 600/100 mg twice daily therapy. The effect of baseline genotype and phenotype on virologic response at 96 weeks was analyzed in as-treated analyses using pooled data from the Phase 2b studies (Studies TMC114-C213, TMC114-C202, and TMC114-C215) (n=439). The findings were confirmed with additional genotypic and phenotypic data from the control arms of etravirine Studies TMC125-C206 and TMC125-C216 at Week 24 (n=591).
- Diminished virologic responses were observed in subjects with 5 or more baseline IAS-defined primary protease inhibitor resistance-associated substitutions (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M) (see Table 16).
- The presence at baseline of two or more of the substitutions V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with a decreased virologic response to Darunavir/ritonavir. In subjects not taking enfuvirtide de novo, the proportion of subjects achieving viral load less than 50 plasma HIV-1 RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0–1, 2 and greater than or equal to 3 of these substitutions, respectively.
- Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be a predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 17. These baseline phenotype groups are based on the select patient populations in the Studies TMC114-C213, TMC114-C202, and TMC114-C215, and are not meant to represent definitive clinical susceptibility breakpoints for Darunavir/ritonavir. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir.
## Nonclinical Toxicology
- Darunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg was administered to rats. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).
- Darunavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays including bacterial reserve mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.
- No effects on fertility or early embryonic development were observed with darunavir in rats and darunavir has shown no teratogenic potential in mice or rats (in the presence or absence of ritonavir), and rabbits.
- In juvenile rats single doses of darunavir (20 mg/kg to 160 mg/kg at ages 5–11 days) or multiple doses of darunavir (40 mg/kg to 1000 mg/kg at age 12 days) caused mortality. The mortalities were associated with convulsions in some of the animals. Within this age range exposures in plasma, liver and brain were dose and age dependent and were considerably greater than those observed in adult rats. These findings were attributed to the ontogeny of the CYP450 liver enzymes involved in the metabolism of darunavir and the immaturity of the blood-brain barrier. No treatment-related mortalities were noted in juvenile rats after a single dose of darunavir at 1000 mg/kg on day 26 of age or after repeat dosing at 500 mg/kg from day 23 to 50 of age. The exposures and toxicity profile in the older animals (day 23 or day 26) were comparable to those observed in adult rats. Due to uncertainties regarding the rate of development of the human blood-brain barrier and liver enzymes, do not administer Darunavir/ritonavir in pediatric patients below 3 years of age.
# Clinical Studies
- The evidence of efficacy of Darunavir/ritonavir is based on the analyses of 192-week data from a randomized, controlled open-label Phase 3 trial in treatment-naïve (TMC114-C211) HIV-1-infected adult subjects and 96-week data from a randomized, controlled, open-label Phase 3 trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data are included from 2 randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.
- Study TMC114-C211
- Study TMC114-C211 is a randomized, controlled, open-label Phase 3 trial comparing Darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as a twice daily or as a once daily regimen) in antiretroviral treatment-naïve HIV-1-infected adult subjects. Both arms used a fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC).
- HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than or equal to 5000 copies/mL. Randomization was stratified by screening plasma viral load (HIV-1 RNA less than 100,000 copies/mL or greater than or equal to 100,000 copies/mL) and screening CD4+ cell count (less than 200 cells/mm3 or greater than or equal to 200 cells/mm3). Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 689 subjects in Study TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier.
- Demographics and baseline characteristics were balanced between the Darunavir/ritonavir arm and the lopinavir/ritonavir arm (see Table 18). Table 18 compares the demographic and baseline characteristics between subjects in the Darunavir/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg per day arm in Study TMC114-C211.
- Week 192 outcomes for subjects on Darunavir/ritonavir 800/100 mg once daily from Study TMC114-C211 are shown inTable 19.
- In Study TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258 cells/mm3 in the Darunavir/ritonavir 800/100 mg once daily arm and 263 cells/mm3 in the lopinavir/ritonavir 800/200 mg per day arm. Of the Darunavir/ritonavir subjects with a confirmed virologic response of < 50 copies/mL at Week 48, 81% remained undetectable at Week 192 versus 68% with lopinavir/ritonavir. In the 192 week analysis, statistical superiority of the Darunavir/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.
- Study TMC114-C229
- Study TMC114-C229 is a randomized, open-label trial comparing Darunavir/ritonavir 800/100 mg once daily to Darunavir/ritonavir 600/100 mg twice daily in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of greater than 1,000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of greater than or equal to 2 NRTIs selected by the investigator.
- HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.
- Table 20 compares the demographic and baseline characteristics between subjects in the Darunavir/ritonavir 800/100 mg once daily arm and subjects in the Darunavir/ritonavir 600/100 mg twice daily arm in Study TMC114-C229. No imbalances between the 2 arms were noted.
- Week 48 outcomes for subjects on Darunavir/ritonavir 800/100 mg once daily from Study TMC114-C229 are shown in Table 21.
- The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm3 and 112 cells/mm3 in the Darunavir/ritonavir 800/100 mg once daily arm and the Darunavir/ritonavir 600/100 mg twice daily arm, respectively).
- Study TMC114-C214
- Study TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing Darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naïve HIV-1-infected adult subjects. Both arms used an optimized background regimen (OBR) consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).
- HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than 1000 copies/mL and were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 400 copies/mL. Analyses included 595 subjects in Study TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier.
- Demographics and baseline characteristics were balanced between the Darunavir/ritonavir arm and the lopinavir/ritonavir arm (see Table 22). Table 22 compares the demographic and baseline characteristics between subjects in the Darunavir/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg twice daily arm in Study TMC114-C214.
- Week 96 outcomes for subjects on Darunavir/ritonavir 600/100 mg twice daily from Study TMC114-C214 are shown inTable 23.
- In Study TMC114-C214 at 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81 cells/mm3 in the Darunavir/ritonavir 600/100 mg twice daily arm and 93 cells/mm3 in the lopinavir/ritonavir 400/100 mg twice daily arm.
- Studies TMC114-C213 and TMC114-C202
- Studies TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to Darunavir/ritonavir received the recommended dose of 600/100 mg twice daily.
- HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA greater than 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide.
- The virologic response rate was evaluated in subjects receiving Darunavir/ritonavir plus an OBR versus a control group receiving an investigator-selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Selected PI(s) in the control arm included: lopinavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received a ritonavir boosted PI regimen out of which 23% of control subjects used dual-boosted PIs. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naïve. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log10 versus baseline.
- In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the Darunavir/ritonavir arm and the comparator PI arm (see Table 24). Table 24 compares the demographic and baseline characteristics between subjects in the Darunavir/ritonavir 600/100 mg twice daily arm and subjects in the comparator PI arm in the pooled analysis of Studies TMC114-C213 and TMC114-C202.
- Week 96 outcomes for subjects on the recommended dose Darunavir/ritonavir 600/100 mg twice daily from the pooled Studies TMC114-C213 and TMC114-C202 are shown inTable 25.
- In the pooled Studies TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA less than 400 copies/mL in the arm receiving Darunavir/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were –1.69 log10 copies/mL in the arm receiving Darunavir/ritonavir 600/100 mg twice daily and –0.37 log10 copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving Darunavir/ritonavir 600/100 mg twice daily (103 cells/mm3) than in the comparator PI arm (17 cells/mm3).
- The pharmacokinetic profile, safety and antiviral activity of Darunavir/ritonavir were evaluated in 3 randomized, open-label, multicenter studies.
- Study TMC114-C212
- Treatment-experienced pediatric subjects between the ages of 6 and less than 18 years and weighing at least 20 kg were stratified according to their weight (greater than or equal to 20 kg to less than 30 kg, greater than or equal to 30 kg to less than 40 kg, greater than or equal to 40 kg) and received Darunavir tablets with either ritonavir capsules or oral solution plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs. Eighty patients were randomized and received at least one dose of Darunavir/ritonavir. Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.
- The 80 randomized pediatric subjects had a median age of 14 (range 6 to less than 18 years), and were 71% male, 54% Caucasian, 30% Black, 9% Hispanic and 8% other. The mean baseline plasma HIV-1 RNA was 4.64 log10 copies/mL, and the median baseline CD4+ cell count was 330 cells/mm3 (range: 6 to 1505 cells/mm3). Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA ≥ 100,000 copies/mL. Most pediatric subjects (79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI.
- Seventy-seven pediatric subjects (96%) completed the 24-week period. Of the patients who discontinued, one patient discontinued treatment due to an adverse event. An additional 2 patients discontinued for other reasons, one patient due to compliance and another patient due to relocation.
- The proportion of pediatric subjects with HIV-1 RNA less than 400 copies/mL and less than 50 copies/mL was 64% and 50%, respectively. The mean increase in CD4+ cell count from baseline was 117 cells/mm3.
- Study TMC114-C228
- Treatment-experienced pediatric subjects between the ages of 3 and less than 6 years and weighing greater than or equal to 10 kg to less than 20 kg received Darunavir oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non-protease inhibitor antiretroviral drugs. Twenty-one subjects received at least one dose of Darunavir/ritonavir.
- The 21 subjects had a median age of 4.4 years (range 3 to less than 6 years), and were 48% male, 57% Black, 29%, Caucasian and 14% other. The mean baseline plasma HIV-1 was 4.34 log10 copies/mL, the median baseline CD4+ cell count was 927 × 106 cells/l (range: 209 to 2,429 × 106 cells/l) and the median baseline CD4+ percentage was 27.7% (range: 15.6% to 51.1%). Overall, 24% of subjects had a baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL. All subjects had used greater than or equal to 2 NRTIs, 62% of subjects had used greater than or equal to 1 NNRTI and 76% had previously used at least one HIV PI.
- Twenty subjects (95%) completed the 48 week period. One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir.
- The proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 48 was 71%.. The mean increase in CD4+ percentage from baseline was 4%. The mean change in CD4+ cell count from baseline was 187 × 106 cells/L.
- Study TMC114-C230
- Treatment-naïve pediatric subjects between the ages of 12 and less than 18 years and weighing at least 40 kg received the adult recommended dose of Darunavir/ritonavir 800/100 mg once daily plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs.
- The 12 randomized pediatric subjects had a median age of 14.4 years (range 12.6 to 17.3 years), and were 33.3% male, 58.3% Caucasian and 41.7% Black. The mean baseline plasma HIV-1 RNA was 4.72 log10 copies/mL, and the median baseline CD4+ cell count was 282 cells/mm3 (range: 204 to 515 cells/mm3). Overall, 41.7% of pediatric subjects had baseline plasma HIV-1 RNA ≥ 100,000 copies/mL.
- All subjects completed the 48 week treatment period.
- The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was 83.3% and 91.7%, respectively. The mean increase in CD4+ cell count from baseline was 221 × 106 cells/L.
# How Supplied
- Darunavir (darunavir) 100 mg/mL oral suspension is a white to off-white opaque liquid supplied in amber-colored multiple-dose bottles containing darunavir ethanolate equivalent to 100 mg of darunavir per mL packaged with a 6 mL oral dosing syringe with 0.2 mL gradations.
- Darunavir (darunavir) 75 mg tablets are supplied as white, caplet-shaped, film-coated tablets containing darunavir ethanolate equivalent to 75 mg of darunavir per tablet. Each tablet is debossed with "75" on one side and "TMC" on the other side.
- Darunavir (darunavir) 150 mg tablets are supplied as white, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 150 mg of darunavir per tablet. Each tablet is debossed with "150" on one side and "TMC" on the other side.
- Darunavir (darunavir) 600 mg tablets are supplied as orange, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 600 mg of darunavir per tablet. Each tablet is debossed with "600MG" on one side and "TMC" on the other side.
- Darunavir (darunavir) 800 mg tablets are supplied as dark red, oval-shaped, film-coated tablets containing darunavir ethanolate equivalent to 800 mg of darunavir per tablet. Each tablet is debossed with "800" on one side and "T" on the other side.
- Darunavir is packaged in bottles in the following configuration:
- 100 mg/mL oral suspension – 200 mL bottles (NDC 59676-565-01)
- 75 mg tablets—bottles of 480 (NDC 59676-563-01)
- 150 mg tablets—bottles of 240 (NDC 59676-564-01)
- 600 mg tablets—bottles of 60 (NDC 59676-562-01)
- 800 mg tablets—bottles of 30 (NDC 59676-566-30)
- Storage:
- Darunavir Oral Suspension
- Store at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F).
- Do not refrigerate or freeze. Avoid exposure to excessive heat.
- Store in the original container.
- Shake well before each usage.
- Darunavir Tablets
- Store at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F).
## Storage
There is limited information regarding Darunavir Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Darunavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PREZISTA®[1]
# Look-Alike Drug Names
There is limited information regarding Darunavir Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Darunavir | |
0c0b2f5d3970271a795423fbe0fd3bb1be129c93 | wikidoc | Darwinism | Darwinism
Darwinism is a term for the underlying concepts in those ideas of Charles Darwin concerning evolution and natural selection. Discussions of Darwinism usually focus on evolution by natural selection, but sometimes Darwinism is taken to mean evolution more broadly, or other ideas not directly associated with the work of Darwin.
# Classical Darwinism
In the 19th century context in which Darwin's On the Origin of Species was first received, "Darwinism" came to stand for an entire range of evolutionary (and often revolutionary) philosophies about both biology and society. One of the more prominent approaches was that summed in the phrase "survival of the fittest" by the philosopher Herbert Spencer, which was later taken to be emblematic of Darwinism even though Spencer's own understanding of evolution was more Lamarckian than Darwinian, and predated the publication of Darwin's theory. What is now called "Social Darwinism" was, in its day, synonymous with "Darwinism" — the application of Darwinian principles of "struggle" to society, usually in support of anti-philanthropic political agendas. Another interpretation, one notably favoured by Darwin's half-cousin Francis Galton, was that Darwinism implied that because natural selection was apparently no longer working on "civilized" people it was possible for "inferior" strains of people (who would normally be filtered out of the gene pool) to overwhelm the "superior" strains, and voluntary corrective measures would be desirable — the foundation of eugenics.
In Darwin's day there was no rigid definition of the term "Darwinism", and it was used by opponents and proponents of Darwin's biological theory alike to mean whatever they wanted it to in a larger context. The ideas had international influence, and Ernst Haeckel developed what was known as Darwinismus in Germany, although, like Spencer Haeckel's "Darwinism" had only a rough resemblance to the theory of Charles Darwin, and was not centered around natural selection at all.
While the reaction against Darwin's ideas is nowadays often thought to have been widespread immediately, in 1886 Wallace went on a lecture tour across the United States, starting in New York and going via Boston, Washington, Kansas, Iowa and Nebraska to California, lecturing on what he called Darwinism without any problems.
# Other uses
The term Darwinism is often used in the United States by promoters of creationism, notably by leading members of the intelligent design movement to describe evolution. In this usage, the term has connotations of atheism. For example, in Charles Hodge's book What Is Darwinism?, Hodge answers the question posed in the book's title by concluding: "It is Atheism." Creationists use the term Darwinism, often pejoratively, to imply that the theory has been held as true only by Darwin and a core group of his followers, whom they cast as dogmatic and inflexible in their belief. Casting evolution as a doctrine or belief bolsters religiously motivated political arguments to mandate equal time for the teaching of creationism in public schools.
However, Darwinism is also used neutrally within the scientific community to distinguish modern evolutionary theories from those first proposed by Darwin, as well as by historians to differentiate it from other evolutionary theories from around the same period. For example, Darwinism may be used to refer to Darwin's proposed mechanism of natural selection, in comparison to more recent mechanisms such as genetic drift and gene flow. It may also refer specifically to the role of Charles Darwin as opposed to others in the history of evolutionary thought — particularly contrasting Darwin's results with those of earlier theories such as Lamarckism or later ones such as the modern synthesis.
A notable example of a scientist who uses the term in a positive sense is Richard Dawkins. | Darwinism
Template:Three other uses
Darwinism is a term for the underlying concepts in those ideas of Charles Darwin concerning evolution and natural selection. Discussions of Darwinism usually focus on evolution by natural selection, but sometimes Darwinism is taken to mean evolution more broadly, or other ideas not directly associated with the work of Darwin.
# Classical Darwinism
Template:Refimprovesect
In the 19th century context in which Darwin's On the Origin of Species was first received, "Darwinism" came to stand for an entire range of evolutionary (and often revolutionary) philosophies about both biology and society. One of the more prominent approaches was that summed in the phrase "survival of the fittest" by the philosopher Herbert Spencer, which was later taken to be emblematic of Darwinism even though Spencer's own understanding of evolution was more Lamarckian than Darwinian, and predated the publication of Darwin's theory. What is now called "Social Darwinism" was, in its day, synonymous with "Darwinism" — the application of Darwinian principles of "struggle" to society, usually in support of anti-philanthropic political agendas. Another interpretation, one notably favoured by Darwin's half-cousin Francis Galton, was that Darwinism implied that because natural selection was apparently no longer working on "civilized" people it was possible for "inferior" strains of people (who would normally be filtered out of the gene pool) to overwhelm the "superior" strains, and voluntary corrective measures would be desirable — the foundation of eugenics.
In Darwin's day there was no rigid definition of the term "Darwinism", and it was used by opponents and proponents of Darwin's biological theory alike to mean whatever they wanted it to in a larger context. The ideas had international influence, and Ernst Haeckel developed what was known as Darwinismus in Germany, although, like Spencer Haeckel's "Darwinism" had only a rough resemblance to the theory of Charles Darwin, and was not centered around natural selection at all.
While the reaction against Darwin's ideas is nowadays often thought to have been widespread immediately, in 1886 Wallace went on a lecture tour across the United States, starting in New York and going via Boston, Washington, Kansas, Iowa and Nebraska to California, lecturing on what he called Darwinism without any problems.[1]
# Other uses
The term Darwinism is often used in the United States by promoters of creationism, notably by leading members of the intelligent design movement to describe evolution. In this usage, the term has connotations of atheism. For example, in Charles Hodge's book What Is Darwinism?, Hodge answers the question posed in the book's title by concluding: "It is Atheism."[2] Creationists use the term Darwinism, often pejoratively, to imply that the theory has been held as true only by Darwin and a core group of his followers, whom they cast as dogmatic and inflexible in their belief.[3] Casting evolution as a doctrine or belief bolsters religiously motivated political arguments to mandate equal time for the teaching of creationism in public schools.
However, Darwinism is also used neutrally within the scientific community to distinguish modern evolutionary theories from those first proposed by Darwin, as well as by historians to differentiate it from other evolutionary theories from around the same period. For example, Darwinism may be used to refer to Darwin's proposed mechanism of natural selection, in comparison to more recent mechanisms such as genetic drift and gene flow. It may also refer specifically to the role of Charles Darwin as opposed to others in the history of evolutionary thought — particularly contrasting Darwin's results with those of earlier theories such as Lamarckism or later ones such as the modern synthesis.
A notable example of a scientist who uses the term in a positive sense is Richard Dawkins.[4] | https://www.wikidoc.org/index.php/Darwinism | |
100994688da6ae373ef3303b1acd9a90c0eff532 | wikidoc | Data mart | Data mart
A data mart (DM) is a specialized version of a data warehouse (DW). Like data warehouses, data marts contain a snapshot of operational data that helps business people to strategize based on analyses of past trends and experiences. The key difference is that the creation of a data mart is predicated on a specific, predefined need for a certain grouping and configuration of select data. A data mart configuration emphasizes easy access to relevant information.
There can be multiple data marts inside a single corporation; each one relevant to one or more business units for which it was designed. DMs may or may not be dependent or related to other data marts in a single corporation. If the data marts are designed using conformed facts and dimensions, then they will be related. In some deployments, each department or business unit is considered the owner of its data mart including all the hardware, software and data. This enables each department to use, manipulate and develop their data any way they see fit; without altering information inside other data marts or the data warehouse. In other deployments where conformed dimensions are used, this business unit ownership will not hold true for shared dimensions like customer, product, etc.
# Design schemas
- star schema or dimensional model is a fairly popular design choice, as it enables a relational database to emulate the analytical functionality of a multidimensional database.
- snowflake schema
# Reasons for creating a data mart
- Ease access to frequently needed data
- Creates collective view by a group of users
- Improves end-user response time
- Ease of creation
- Lower cost than implementing a full Data warehouse
- Potential users are more clearly defined than in a full Data warehouse
# Dependent data mart
According to the Inmon school of data warehousing, a dependent data mart is a logical subset (view) or a physical subset (extract) of a larger data warehouse, isolated for one of the following reasons:
- A need for a special data model or schema: e.g., to restructure for OLAP
- Performance: to offload the data mart to a separate computer for greater efficiency or to obviate the need to manage that workload on the centralized data warehouse.
- Security: to separate an authorized data subset selectively
- Expediency: to bypass the data governance and authorizations required to incorporate a new application on the Enterprise Data Warehouse
- Proving Ground: to demonstrate the viability and ROI (return on investment) potential of an application prior to migrating it to the Enterprise Data Warehouse
- Politics: a coping strategy for IT (Information Technology) in situations where a user group has more influence than funding or is not a good citizen on the centralized data warehouse.
- Politics: a coping strategy for consumers of data in situations where a data warehouse team is unable to create a usable data warehouse.
According to the Inmon school of data warehousing, tradeoffs inherent with data marts include limited scalability, duplication of data, data inconsistency with other silos of information, and inability to leverage enterprise sources of data. | Data mart
Template:POV-check
A data mart (DM) is a specialized version of a data warehouse (DW). Like data warehouses, data marts contain a snapshot of operational data that helps business people to strategize based on analyses of past trends and experiences. The key difference is that the creation of a data mart is predicated on a specific, predefined need for a certain grouping and configuration of select data. A data mart configuration emphasizes easy access to relevant information.
There can be multiple data marts inside a single corporation; each one relevant to one or more business units for which it was designed. DMs may or may not be dependent or related to other data marts in a single corporation. If the data marts are designed using conformed facts and dimensions, then they will be related. In some deployments, each department or business unit is considered the owner of its data mart including all the hardware, software and data.[1] This enables each department to use, manipulate and develop their data any way they see fit; without altering information inside other data marts or the data warehouse. In other deployments where conformed dimensions are used, this business unit ownership will not hold true for shared dimensions like customer, product, etc.
# Design schemas
- star schema or dimensional model is a fairly popular design choice, as it enables a relational database to emulate the analytical functionality of a multidimensional database.
- snowflake schema
# Reasons for creating a data mart
- Ease access to frequently needed data
- Creates collective view by a group of users
- Improves end-user response time
- Ease of creation
- Lower cost than implementing a full Data warehouse
- Potential users are more clearly defined than in a full Data warehouse
# Dependent data mart
According to the Inmon school of data warehousing, a dependent data mart is a logical subset (view) or a physical subset (extract) of a larger data warehouse, isolated for one of the following reasons:
- A need for a special data model or schema: e.g., to restructure for OLAP
- Performance: to offload the data mart to a separate computer for greater efficiency or to obviate the need to manage that workload on the centralized data warehouse.
- Security: to separate an authorized data subset selectively
- Expediency: to bypass the data governance and authorizations required to incorporate a new application on the Enterprise Data Warehouse
- Proving Ground: to demonstrate the viability and ROI (return on investment) potential of an application prior to migrating it to the Enterprise Data Warehouse
- Politics: a coping strategy for IT (Information Technology) in situations where a user group has more influence than funding or is not a good citizen on the centralized data warehouse.
- Politics: a coping strategy for consumers of data in situations where a data warehouse team is unable to create a usable data warehouse.
According to the Inmon school of data warehousing, tradeoffs inherent with data marts include limited scalability, duplication of data, data inconsistency with other silos of information, and inability to leverage enterprise sources of data. | https://www.wikidoc.org/index.php/Data_mart | |
69c98c71918e1a88e6e693a9002198374f49f263 | wikidoc | Oxaprozin | Oxaprozin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Oxaprozin is an analgesic and NSAID that is FDA approved for the treatment of osteoarthritis, rheumathoid arthritis and juvenile rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, constipation, diarrhea, flatulence, indigestion, loss of appetite and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Carefully consider the potential benefits and risks of oxaprozin tablet, USP and other treatment options before deciding to use oxaprozin tablet, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing the response to initial therapy with oxaprozin tablet, USP, the dose and frequency should be adjusted to suit an individual patient's needs.
### Dosage
- Rheumatoid arthritis: For relief of the signs and symptoms of rheumatoid arthritis, the usual recommended dose is 1200 mg (two 600-mg tablets) given orally once a day.
- Osteoarthritis: For relief of the signs and symptoms of osteoarthritis, the usual recommended dose is 1200 mg (two 600-mg tablets) given orally once a day.
- Juvenile rheumatoid arthritis: For the relief of the signs and symptoms of JRA in patients 6-16 years of age, the recommended dose given orally once per day should be based on body weight of the patient as given in Table 3.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxaprozin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxaprozin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Oxaprozin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxaprozin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxaprozin in pediatric patients.
# Contraindications
Oxaprozin tablet, USP is contraindicated in:
- Patients with known hyper-sensitivity to oxaprozin.
- Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
- Peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
- Patients with active gastrointestinal bleeding.
# Warnings
### Cardiovascular Effects
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
- Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- NSAIDs including oxaprozin, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including oxaprozin, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Fluid retention and edema have been observed in some patients taking NSAIDs. oxaprozin should be used with caution in patients with fluid retention or heart failure.
### Gastrointestinal Effects- Risk of Ulceration, Bleeding, and Perforation
- NSAIDs, including oxaprozin, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
- Oxaprozin tablet, USP is contraindicated in patients with active GI bleeding.
### Renal Effects
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
### Advanced renal disease
- No information is available from controlled clinical studies regarding the use of oxaprozin in patients with advanced renal disease. Therefore, treatment with oxaprozin is not recommended in these patients with advanced renal disease. If oxaprozin therapy must be initiated, close monitoring of the patient's renal function is advisable.
### Anaphylactoid reactions
- As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to oxaprozin. Oxaprozin should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
### Skin Reactions
- NSAIDs, including oxaprozin, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
### Pregnancy
- In late pregnancy, as with other NSAIDs, oxaprozin should be avoided because it may cause premature closure of the ductus arteriosus.
# Adverse Reactions
## Clinical Trials Experience
Adverse reaction data were derived from patients who received oxaprozin in multidose, controlled, and open-label clinical trials, and from worldwide marketing experience. Rates for events occurring in more than 1% of patients, and for most of the less common events, are based on 2253 patients who took 1200 to 1800 mg oxaprozin per day in clinical trials. Of these, 1721 were treated for at least 1 month, 971 for at least 3 months, and 366 for more than 1 year. Rates for the rarer events and for events reported from worldwide marketing experience are difficult to estimate accurately and are only listed as less than 1%.
## Incidence Greater Than 1%: In clinical trials of oxaprozin or in patients taking other NSAIDs, the following adverse reactions occurred at an incidence greater than 1%.
- Cardiovascular system: edema.
- Digestive system: abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations, nausea, vomiting.
- Hematologic system: anemia, increased bleeding time.
- Nervous system: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache.
- Skin and appendages: pruritus, rash.
- Special senses: tinnitus.
- Urogenital system: abnormal renal function, dysuria or frequency.
## Incidence Less Than 1%: The following adverse reactions were reported in clinical trials, from worldwide marketing experience (in italics) or in patients taking other NSAIDs.
- Body as a whole: appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis, serum sickness.
- Cardiovascular system: arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis.
- Digestive system: alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, jaundice, liver function abnormalities including hepatitis, liver failure, stomatitis, hemorrhoidal or rectal bleeding, pancreatitis.
- Hematologic system: agranulocytosis, aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, pancytopenia, purpura, thrombocytopenia, leukopenia.
- Metabolic system: hyperglycemia, weight changes.
- Nervous system: anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, weakness.
- Respiratory system: asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression.
- Skin: alopecia, angioedema, urticaria, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, sweat, toxic epidermal necrolysis (Lyell's syndrome).
- Special senses: blurred vision, conjunctivitis, hearing decrease.
- Urogenital: acute interstitial nephritis, cystitis, hematuria, increase in menstrual flow, nephrotic syndrome, oliguria/polyuria, proteinuria, renal insufficiency, acute renal failure, decreased menstrual flow.
## Postmarketing Experience
There is limited information regarding Oxaprozin Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Oxaprozin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratology studies with oxaprozin were performed in mice, rats, and rabbits. In mice and rats, no drug-related developmental abnormalities were observed at 50 to 200 mg/kg/day of oxaprozin (225 to 900 mg/m2). However, in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5 to 30 mg/kg/day of oxaprozin (the usual human dosage range). Animal reproductive studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Oxaprozin should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxaprozin in women who are pregnant.
### Labor and Delivery
- In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of DAYPRO on labor and delivery in pregnant women are unknown.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk; however, oxaprozin was found in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DAYPRO, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N=40) and juvenile rheumatoid arthritis (JRA) patients (≥6 years, N=44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC0-24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships as shown in Table 2. No pharmacokinetic data are available for pediatric patients under 6 years of age
### Geriatic Use
- As with any NSAID, caution should be exercised in treating the elderly (65 years and older). No dosage adjustment is necessary in the elderly for pharmacokinetics reasons, although many elderly may need a reduced dose due to low body weight or disorders associated with aging.
- A multiple dose study comparing the pharmacokinetics of oxaprozin (1200 mg QD) in 20 young (21 -44 years) adults and 20 elderly (64-83 years) adults, did not show any statistically significant differences between age groups.
### Gender
There is no FDA guidance on the use of Oxaprozin with respect to specific gender populations.
### Race
- Pharmacokinetics differences due to race have not been identified.
### Renal Impairment
- The pharmacokinetics of oxaprozin have been investigated in patients with renal insufficiency. Oxaprozin's renal clearance decreased proportionally with creatinine clearance (CrCl), but since only about 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCl. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency
### Hepatic Impairment
There is no FDA guidance on the use of Oxaprozin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxaprozin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxaprozin in patients who are immunocompromised.
### Cardiac Failure
- Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin.
# Administration and Monitoring
### Administration
There is limited information regarding Oxaprozin Administration in the drug label.
### Monitoring
There is limited information regarding Oxaprozin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Oxaprozin and IV administrations.
# Overdosage
- No patient experienced either an accidental or intentional overdosage of oxaprozin in the clinical trials of the drug. Symptoms following acute overdose with other NSAIDs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain and are generally reversible with supportive care. Gastrointestinal bleeding and coma have occurred following NSAID overdose. Hypertension, acute renal failure, and respiratory depression are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
- Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with an osmotic cathartic. Forced diuresis, alkalization of the urine, or hemoperfusion would probably not be useful due to the high degree of protein binding of oxaprozin.
# Pharmacology
## Mechanism of Action
- The mechanism of action of oxaprozin like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
## Structure
## Pharmacodynamics
- Oxaprozin is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in animal models.
## Pharmacokinetics
### Absorption
- Oxaprozin is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of oxaprozin absorption.
### Distribution
- In dose proportionality studies utilizing 600, 1200 and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of the unbound drug. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution and not an increase in the half-life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing.
- The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11-17 L/70 kg. Oxaprozin is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following repetitive once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2-fold and 3-fold greater than in plasma and synovial fluid, respectively. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties, however, the amount of oxaprozin excreted in breast milk has not been evaluated.
### Metabolism
- Several oxaprozin metabolites have been identified in human urine or feces.
- Oxaprozin is primarily metabolized by the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low.
- Oxaprozin's metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (<5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited.
### Excretion
- Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolite. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Upon chronic dosing the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations.
## Nonclinical Toxicology
There is limited information regarding Oxaprozin Nonclinical Toxicology in the drug label.
# Clinical Studies
### Rheumatoid Arthritis
- Oxaprozin was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. Oxaprozin was given in single or divided daily doses of 600 to 1800 mg/day and was found to be comparable to 2600 to 3900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin.
- Oxaprozin was given as a once-a-day dose of 1200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1800 mg/day) were used in selected patients. In some patients, oxaprozin may be better tolerated in divided doses. Due to its long half-life, several days of oxaprozin therapy were needed for the drug to reach its full effect.
### Osteoarthritis
- Oxaprozin was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. Oxaprozin was given both in variable (600 to 1200 mg/day) and in fixed (1200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2600 to 3200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin was effective both in once-daily and in divided dosing schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects.
# How Supplied
- Oxaprozin tablets, USP, 600 mg are available as: white to off-white, capsule shaped film coated tablets with “391” debossed on one side and scored on the other side in the bottles of 100 (NDC 57664-391-08), 500 (NDC 57664-391-13) and 1000 (NDC 57664-391-18).
## Storage
- Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in tight, light-resistant container as defined in the USP, with child resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Oxaprozin Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Oxaprozin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Daypro
# Look-Alike Drug Names
There is limited information regarding Oxaprozin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Oxaprozin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Oxaprozin is an analgesic and NSAID that is FDA approved for the treatment of osteoarthritis, rheumathoid arthritis and juvenile rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, constipation, diarrhea, flatulence, indigestion, loss of appetite and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Carefully consider the potential benefits and risks of oxaprozin tablet, USP and other treatment options before deciding to use oxaprozin tablet, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. After observing the response to initial therapy with oxaprozin tablet, USP, the dose and frequency should be adjusted to suit an individual patient's needs.
### Dosage
- Rheumatoid arthritis: For relief of the signs and symptoms of rheumatoid arthritis, the usual recommended dose is 1200 mg (two 600-mg tablets) given orally once a day.
- Osteoarthritis: For relief of the signs and symptoms of osteoarthritis, the usual recommended dose is 1200 mg (two 600-mg tablets) given orally once a day.
- Juvenile rheumatoid arthritis: For the relief of the signs and symptoms of JRA in patients 6-16 years of age, the recommended dose given orally once per day should be based on body weight of the patient as given in Table 3.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxaprozin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxaprozin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Oxaprozin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oxaprozin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oxaprozin in pediatric patients.
# Contraindications
Oxaprozin tablet, USP is contraindicated in:
- Patients with known hyper-sensitivity to oxaprozin.
- Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
- Peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
- Patients with active gastrointestinal bleeding.
# Warnings
### Cardiovascular Effects
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events.
- Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- NSAIDs including oxaprozin, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including oxaprozin, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Fluid retention and edema have been observed in some patients taking NSAIDs. oxaprozin should be used with caution in patients with fluid retention or heart failure.
### Gastrointestinal Effects- Risk of Ulceration, Bleeding, and Perforation
- NSAIDs, including oxaprozin, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
- Oxaprozin tablet, USP is contraindicated in patients with active GI bleeding.
### Renal Effects
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
### Advanced renal disease
- No information is available from controlled clinical studies regarding the use of oxaprozin in patients with advanced renal disease. Therefore, treatment with oxaprozin is not recommended in these patients with advanced renal disease. If oxaprozin therapy must be initiated, close monitoring of the patient's renal function is advisable.
### Anaphylactoid reactions
- As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to oxaprozin. Oxaprozin should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
### Skin Reactions
- NSAIDs, including oxaprozin, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
### Pregnancy
- In late pregnancy, as with other NSAIDs, oxaprozin should be avoided because it may cause premature closure of the ductus arteriosus.
# Adverse Reactions
## Clinical Trials Experience
Adverse reaction data were derived from patients who received oxaprozin in multidose, controlled, and open-label clinical trials, and from worldwide marketing experience. Rates for events occurring in more than 1% of patients, and for most of the less common events, are based on 2253 patients who took 1200 to 1800 mg oxaprozin per day in clinical trials. Of these, 1721 were treated for at least 1 month, 971 for at least 3 months, and 366 for more than 1 year. Rates for the rarer events and for events reported from worldwide marketing experience are difficult to estimate accurately and are only listed as less than 1%.
## Incidence Greater Than 1%: In clinical trials of oxaprozin or in patients taking other NSAIDs, the following adverse reactions occurred at an incidence greater than 1%.
- Cardiovascular system: edema.
- Digestive system: abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations, nausea, vomiting.
- Hematologic system: anemia, increased bleeding time.
- Nervous system: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache.
- Skin and appendages: pruritus, rash.
- Special senses: tinnitus.
- Urogenital system: abnormal renal function, dysuria or frequency.
## Incidence Less Than 1%: The following adverse reactions were reported in clinical trials, from worldwide marketing experience (in italics) or in patients taking other NSAIDs.
- Body as a whole: appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis, serum sickness.
- Cardiovascular system: arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis.
- Digestive system: alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, jaundice, liver function abnormalities including hepatitis, liver failure, stomatitis, hemorrhoidal or rectal bleeding, pancreatitis.
- Hematologic system: agranulocytosis, aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, pancytopenia, purpura, thrombocytopenia, leukopenia.
- Metabolic system: hyperglycemia, weight changes.
- Nervous system: anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, weakness.
- Respiratory system: asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression.
- Skin: alopecia, angioedema, urticaria, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, sweat, toxic epidermal necrolysis (Lyell's syndrome).
- Special senses: blurred vision, conjunctivitis, hearing decrease.
- Urogenital: acute interstitial nephritis, cystitis, hematuria, increase in menstrual flow, nephrotic syndrome, oliguria/polyuria, proteinuria, renal insufficiency, acute renal failure, decreased menstrual flow.
## Postmarketing Experience
There is limited information regarding Oxaprozin Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Oxaprozin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Teratology studies with oxaprozin were performed in mice, rats, and rabbits. In mice and rats, no drug-related developmental abnormalities were observed at 50 to 200 mg/kg/day of oxaprozin (225 to 900 mg/m2). However, in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5 to 30 mg/kg/day of oxaprozin (the usual human dosage range). Animal reproductive studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Oxaprozin should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxaprozin in women who are pregnant.
### Labor and Delivery
- In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of DAYPRO on labor and delivery in pregnant women are unknown.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk; however, oxaprozin was found in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DAYPRO, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N=40) and juvenile rheumatoid arthritis (JRA) patients (≥6 years, N=44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC0-24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships as shown in Table 2. No pharmacokinetic data are available for pediatric patients under 6 years of age
### Geriatic Use
- As with any NSAID, caution should be exercised in treating the elderly (65 years and older). No dosage adjustment is necessary in the elderly for pharmacokinetics reasons, although many elderly may need a reduced dose due to low body weight or disorders associated with aging.
- A multiple dose study comparing the pharmacokinetics of oxaprozin (1200 mg QD) in 20 young (21 -44 years) adults and 20 elderly (64-83 years) adults, did not show any statistically significant differences between age groups.
### Gender
There is no FDA guidance on the use of Oxaprozin with respect to specific gender populations.
### Race
- Pharmacokinetics differences due to race have not been identified.
### Renal Impairment
- The pharmacokinetics of oxaprozin have been investigated in patients with renal insufficiency. Oxaprozin's renal clearance decreased proportionally with creatinine clearance (CrCl), but since only about 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCl. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency
### Hepatic Impairment
There is no FDA guidance on the use of Oxaprozin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxaprozin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxaprozin in patients who are immunocompromised.
### Cardiac Failure
- Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin.
# Administration and Monitoring
### Administration
There is limited information regarding Oxaprozin Administration in the drug label.
### Monitoring
There is limited information regarding Oxaprozin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Oxaprozin and IV administrations.
# Overdosage
- No patient experienced either an accidental or intentional overdosage of oxaprozin in the clinical trials of the drug. Symptoms following acute overdose with other NSAIDs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain and are generally reversible with supportive care. Gastrointestinal bleeding and coma have occurred following NSAID overdose. Hypertension, acute renal failure, and respiratory depression are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
- Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with an osmotic cathartic. Forced diuresis, alkalization of the urine, or hemoperfusion would probably not be useful due to the high degree of protein binding of oxaprozin.
# Pharmacology
## Mechanism of Action
- The mechanism of action of oxaprozin like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
## Structure
## Pharmacodynamics
- Oxaprozin is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in animal models.
## Pharmacokinetics
### Absorption
- Oxaprozin is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of oxaprozin absorption.
### Distribution
- In dose proportionality studies utilizing 600, 1200 and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of the unbound drug. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution and not an increase in the half-life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing.
- The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11-17 L/70 kg. Oxaprozin is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following repetitive once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2-fold and 3-fold greater than in plasma and synovial fluid, respectively. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties, however, the amount of oxaprozin excreted in breast milk has not been evaluated.
### Metabolism
- Several oxaprozin metabolites have been identified in human urine or feces.
- Oxaprozin is primarily metabolized by the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low.
- Oxaprozin's metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (<5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited.
### Excretion
- Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolite. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Upon chronic dosing the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations.
## Nonclinical Toxicology
There is limited information regarding Oxaprozin Nonclinical Toxicology in the drug label.
# Clinical Studies
### Rheumatoid Arthritis
- Oxaprozin was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. Oxaprozin was given in single or divided daily doses of 600 to 1800 mg/day and was found to be comparable to 2600 to 3900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin.
- Oxaprozin was given as a once-a-day dose of 1200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1800 mg/day) were used in selected patients. In some patients, oxaprozin may be better tolerated in divided doses. Due to its long half-life, several days of oxaprozin therapy were needed for the drug to reach its full effect.
### Osteoarthritis
- Oxaprozin was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. Oxaprozin was given both in variable (600 to 1200 mg/day) and in fixed (1200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2600 to 3200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin was effective both in once-daily and in divided dosing schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects.
# How Supplied
- Oxaprozin tablets, USP, 600 mg are available as: white to off-white, capsule shaped film coated tablets with “391” debossed on one side and scored on the other side in the bottles of 100 (NDC 57664-391-08), 500 (NDC 57664-391-13) and 1000 (NDC 57664-391-18).
## Storage
- Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in tight, light-resistant container as defined in the USP, with child resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Oxaprozin Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Oxaprozin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Daypro
# Look-Alike Drug Names
There is limited information regarding Oxaprozin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Daypro | |
4a574fd6a71d8ebb1de84e099a08066b7e2647f2 | wikidoc | Oxycodone | Oxycodone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Oxycodone is an analgesic opioid that is FDA approved for the {{{indicationType}}} of pain, chronic (severe), in patients requiring a long-term daily around-the-clock opioid analgesic, pain (moderate to severe). Common adverse reactions include dermatologic: pruritus (controlled-release, 13% ; immediate-release, 3% or greater ), sweating (controlled-release, 5% ; immediate-release, less than 3% ), gastrointestinal: abdominal pain (up to 5% ), constipation (controlled-release, 23% ; immediate-release, 3% or greater ), nausea (controlled-release, 23% ; immediate-release, 3% or greater ), vomiting (controlled-release, 12% ; immediate-release, 3% or greater ), xerostomia (controlled-release, 6% ; immediate-release, less than 3% ), neurologic: Asthenia (controlled-release, 6% ; immediate-release, 3% or greater ), dizziness (controlled-release, 13% ; immediate-release, 3% or greater ), headache (controlled-release, 7% ; immediate-release, 3% or greater ), somnolence (controlled-release, 23% ; immediate-release, 3% or greater ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Reserve use of single doses greater than 40 mg, total daily doses greater than 80 mg , oral solution concentration of 100 mg per 5 mL (20 mg per mL), and controlled-release 60 mg or 80 mg tablets, for opioid-tolerant patients only (oral solution) to avoid dosing errors include total dose in mg and mL when prescribing, administering, and dispensing
- Do not discontinue abruptly in physically dependent patient; taper gradually to prevent withdrawal.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: individualize dose; initial dose selection must take into account patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse; due to substantial inter-patient variability in relative potency of different opioid products, when converting it is recommended to underestimate a patient's 24-hour oral oxycodone requirements and provide rescue mediation as needed.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: (as first opioid and for patients who are not opioid-tolerant) initial, 10 mg or every 12 hours; titrate by 25% to 50% of the current dose every 1 to 2 days based on analgesic requirement and tolerance.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: (conversion from other oral oxycodone formulations) initial, one-half of total daily oxycodone requirement orally every 12 hours; titrate by 25% to 50% of the current dose every 1 to 2 days based on analgesic requirement and tolerance.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: (conversion from other opioids) initial, 10 mg orally every 12 hours; titrate by 25% to 50% of the current dose every 1 to 2 days based on analgesic requirement and tolerance.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: (conversion from transdermal fentanyl) 18 hours following patch removal initiate 10 mg orally every 12 hours for every 25 mcg/hr of transdermal fentanyl; titrate by 25% to 50% of the current dose every 1 to 2 days based on analgesic requirement and tolerance.
- Pain (Moderate to Severe): (immediate-release capsules, tablets, or oral solution 5 mg/5 mL) opioid-naive patients; initial, 5 to 15 mg orally every 4 to 6 hours as needed for pain; titrate based on pain severity and patient response.
- Pain (Moderate to Severe): (oral solution 100 mg/5 mL) reserve for opioid-tolerant patients who have been titrated to a stable analgesic regimen with lower doses of oxycodone and can benefit from use of a smaller volume of oral solution; always use the enclosed oral syringe to measure dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Oxycodone in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Oxycodone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Oxycodone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Oxycodone in pediatric patients.
# Contraindications
- Oxycodone hydrochloride tablets are contraindicated in patients with known hypersensitivity to oxycodone, or in any situation where opioids are contraindicated. This includes patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone hydrochloride tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.
# Warnings
- Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depression occurs most frequently in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.
- Oxycodone hydrochloride tablets should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of oxycodone hydrochloride tablets may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.
- Oxycodone hydrochloride tablets, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Oxycodone hydrochloride tablets may produce orthostatic hypotension in ambulatory patients. Oxycodone hydrochloride tablets, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure.
- The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.
# Adverse Reactions
## Clinical Trials Experience
- Oxycodone hydrochloride tablets have been evaluated in open label clinical trials in patients with cancer and nonmalignant pain. Oxycodone hydrochloride tablets are associated with adverse experiences similar to those seen with other opioids.
- Serious adverse reactions that may be associated with oxycodone hydrochloride tablets therapy in clinical use are those observed with other opioid analgesics and include: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock (see overdosage, warnings).
- The less severe adverse events seen on initiation of therapy with oxycodone hydrochloride tablets are also typical opioid side effects. These events are dose dependent, and their frequency depends on the clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid analgesia. The most frequent of these include nausea, constipation, vomiting, headache, and pruritus.
- In many cases the frequency of adverse events during initiation of opioid therapy may be minimized by careful individualization of starting dosage, slow titration and the avoidance of large rapid swings in plasma concentration of the opioid. Many of these adverse events will abate as therapy is continued and some degree of tolerance is developed, but others may be expected to remain throughout therapy.
- In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving oxycodone hydrochloride tablets, the following adverse events were recorded in oxycodone hydrochloride tablets treated patients with an incidence ≥ 3%. In descending order of frequency they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.
- The following adverse experiences occurred in less than 3% of patients involved in clinical trials with oxycodone:
- Abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis.
- Deep thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia.
- Anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting.
- Anemia and leukopenia.
- Edema, gout, hyperglycemia, iron deficiency anemia and peripheral edema.
- Arthralgia, arthritis, bone pain, myalgia and pathological fracture.
- Agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation.
- Bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis.
- Herpes simplex, rash, sweating, and urticaria.
- Amblyopia.
- Urinary tract infection.
### Drug Abuse and Dependence
- Oxycodone Hydrochloride Tablets contain Oxycodone, a mu-agonist opioid if the morphine type and is a Schedule II controlled substance.
- Oxycodone hydrochloride, like other opioids used in analgesia, can be abused and is subject to criminal diversion.
- Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.
- “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
- Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
- Oxycodone hydrochloride is intended for oral use only. Abuse of oxycodone hydrochloride tablets poses a risk of overdose and death. The risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
- Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispening and storage are appropriate measures that help to limit abuse of opioid drugs.
- Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.
- Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.
- The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued.
## Postmarketing Experience
There is limited information regarding Oxycodone Postmarketing Experience in the drug label.
# Drug Interactions
- Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent. However, clinicians should be aware of this possible interaction.
- Neuromuscular Blocking Agents: Oxycodone, as well as other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
- Patients receiving narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with oxycodone hydrochloride tablets may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dosage of oxycodone hydrochloride tablets. When such combined therapy is contemplated, the dose of one or both agents should be reduced.
- Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone hydrochloride tablets. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms in these patients.
- MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies in Sprague-Dawley rats and New Zealand rabbits revealed that when oxycodone was administered orally at doses up to 16 mg/kg (approximately 2 times the daily oral dose of 90 mg for adults on a mg/m2 basis) and 25 mg/kg (approximately 5 times the daily oral dose of 90 mg on a mg/m2 basis), respectively was not teratogenic or embryo-fetal toxic. There are no adequate and well controlled studies of oxycodone in pregnant women. Because animal reproductive studies are not always predictive of human responses, oxycodone hydrochloride tablets should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.
- Neonates whose mothers have taken oxycodone chronically may exhibit respiratory depression and/or withdrawal symptoms, either at birth and/or in the nursery.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxycodone in women who are pregnant.
### Labor and Delivery
- Oxycodone hydrochloride tablets are not recommended for use in women during or immediately prior to labor. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. Neonates, whose mothers received opioid analgesics during labor, should be observed closely for signs of respiratory depression. A specific narcotic antagonist, naloxone, should be available for reversal of narcotic-induced respiratory depression in the neonate.
### Nursing Mothers
- Oxycodone has been detected in breast milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of an opioid analgesic is stopped. Ordinarily, nursing should not be undertaken while a patient is receiving oxycodone hydrochloride tablets since oxycodone may be excreted in milk.
### Pediatric Use
- The safety and efficacy of oxycodone in pediatric patients have not been evaluated.
### Geriatic Use
- Population pharmacokinetic studies conducted with oxycodone hydrochloride tablets indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.
### Gender
- Population pharmacokinetic analyses performed in the clinical study support the lack of gender effect on the pharmacokinetics of oxycodone from oxycodone hydrochloride tablets.
### Race
- Population pharmacokinetic analyses support the lack of race effect on oxycodone pharmacokinetics after administration of oxycodone hydrochloride tablets, but these data should be interpreted conservatively, since the majority of patients enrolled into the studies were Caucasians (94%).
### Renal Impairment
- In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased renal function were evaluated to study these potential differences. In previous studies, patients with renal impairment (defined as a creatinine clearance < 60 mL/min) had concentrations of oxycodone in the plasma that were higher than in subjects with normal renal function. Based on information available on the metabolism and excretion of oxycodone, dose initiation in patients with renal impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
### Hepatic Impairment
- In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, since oxycodone is extensively metabolized, its clearance may decrease in hepatic failure patients. Dose initiation in patients with hepatic impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxycodone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxycodone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Oxycodone Administration in the drug label.
### Monitoring
There is limited information regarding Oxycodone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Oxycodone and IV administrations.
# Overdosage
- Acute overdose with oxycodone hydrochloride tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.
- To treat oxycodone hydrochloride tablets overdose, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
- The narcotic antagonists, naloxone or nalmefene, are specific antidotes for opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone hydrochloride tablets overdose. If needed the appropriate dose of naloxone hydrochloride or nalmefene should be administered simultaneously with efforts at respiratory resuscitation (see package insert for each drug for the details). Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Gastric emptying may be useful in removing unabsorbed drug.
- Opioid antagonists should be administered cautiously to persons who are suspected to be physically dependent on any opioid agonist, including Oxycodone. (see Opioid-Tolerant Individuals.)
- Opioid-Tolerant Individuals:In an individual physically dependent on opioids, administration of a usual dose of antagonist will precipitate an acute withdrawal. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Use of an opioid antagonist should be reserved for cases where such treatment is clearly needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses.
# Pharmacology
## Mechanism of Action
- The analgesic ingredient, oxycodone, is a semi-synthetic narcotic with multiple actions qualitatively similar to those of morphine; the most prominent of these involves the central nervous system and organs composed of smooth muscle.
- Oxycodone, as the hydrochloride salt, is a pure agonist opioid whose principal therapeutic action is analgesia and has been in clinical use since 1917. Like all pure opioid agonists, there is no ceiling effect to analgesia, such as is seen with partial agonists or non-opioid analgesics. Based upon a single-dose, relative-potency study conducted in humans with cancer pain, 10 to 15 mg of oxycodone given intramuscularly produced an analgesic effect similar to 10 mg of morphine given intramuscularly. Both drugs have a 3 to 4 hour duration of action. Oxycodone retains approximately one half of its analgesic activity when administered orally
- The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. A significant feature of opioid-induced analgesia is that it occurs without loss of consciousness. The relief of pain by morphine-like opioids is relatively selective, in that other sensory modalities, (e.g., touch, vibrations, vision, hearing, etc.) are not obtunded.
- Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.
- Oxycodone depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
- Oxycodone, like other opioid analgesics, produces some degree of nausea and vomiting which is caused by direct stimulation of the chemoreceptor trigger zone (CTZ) located in the medulla. The frequency and severity of emesis gradually diminishes with time.
- Oxycodone may cause a decrease in the secretion of hydrochloric acid in the stomach that reduces motility while increasing the tone of the antrum, stomach, and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
- Oxycodone, in therapeutic doses, produces peripheral vasodilatation (arteriolar and venous), decreased peripheral resistance, and inhibits baroreceptor reflexes. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
- Caution should be used in hypovolemic patients, such as those suffering acute myocardial infarction, because oxycodone may cause or further aggravate their hypotension. Caution should also be used in patients with cor pulmonale who have received therapeutic doses of opioids.
## Structure
- Oxycodone hydrochloride tablets USP is an opioid analgesic.
- Each tablet for oral administration contains 5 mg, 10 mg, 15 mg, 20 mg or 30 mg of oxycodone hydrochloride USP.
- Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7).
- Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula:
- The tablets contain the following inactive ingredients: corn starch; lactose monohydrate; microcrystalline cellulose; silicon dioxide; sodium starch glycolate; and stearic acid. The 10 mg tablet also contains D&C Red No. 27 aluminum lake. The 15 mg tablet also contains D&C Yellow No. 10 aluminum lake and FD&C Blue No. 2 aluminum lake. The 20 mg tablet also contains FD&C Blue No. 2 aluminum lake; FD&C Red No. 40 aluminum lake; and FD&C Yellow No. 6 aluminum lake. The 30 mg tablet also contains FD&C Blue No. 2 aluminum lake.
- The 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg tablets contain the equivalent of 4.5 mg, 9 mg, 13.5 mg, 18 mg, and 27 mg, respectively, of oxycodone free base.
## Pharmacodynamics
- The relationship between the plasma level of oxycodone and the analgesic response will depend on the patient's age, state of health, medical condition and extent of previous opioid treatment.
- The minimum effective plasma concentration of oxycodone to achieve analgesia will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. Thus, patients need to be treated with individualized titration of dosage to the desired effect. The minimum effective analgesic concentration of oxycodone for any individual patient may increase with repeated dosing due to an increase in pain and/or development of tolerance.
## Pharmacokinetics
- The activity of oxycodone hydrochloride tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to provide immediate release of oxycodone.
- About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone. The relative oral bioavailability of oxycodone hydrochloride 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablets, is 96% and 101% respectively. Oxycodone hydrochloride 15 mg tablets and 30 mg tablets are bioequivalent to the 5 mg oxycodone hydrochloride tablets (see Table 1 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride 5 mg tablets at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride tablets.
- A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution. (see Table 1). In addition, food caused a delay in Tmax (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets.
- Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk. (See PRECAUTIONS-Nursing Mothers.)
- Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present.
- The formation of oxymorphone, but not noroxycodone, is mediated by CYP2D6 and as such its formation can, in theory, be affected by other drugs. (See Precautions-Drug Interactions.)
- Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone hydrochloride tablets was 3.5 to 4 hours.
- Population pharmacokinetic studies conducted with oxycodone hydrochloride tablets indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.
- Population pharmacokinetic analyses performed in the clinical study support the lack of gender effect on the pharmacokinetics of oxycodone from oxycodone hydrochloride tablets.
- Population pharmacokinetic analyses support the lack of race effect on oxycodone pharmacokinetics after administration of oxycodone hydrochloride tablets, but these data should be interpreted conservatively, since the majority of patients enrolled into the studies were Caucasians (94%).
- In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased renal function were evaluated to study these potential differences. In previous studies, patients with renal impairment (defined as a creatinine clearance < 60 mL/min) had concentrations of oxycodone in the plasma that were higher than in subjects with normal renal function. Based on information available on the metabolism and excretion of oxycodone, dose initiation in patients with renal impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
- In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, since oxycodone is extensively metabolized, its clearance may decrease in hepatic failure patients. Dose initiation in patients with hepatic impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
## Nonclinical Toxicology
There is limited information regarding Oxycodone Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Oxycodone Clinical Studies in the drug label.
# How Supplied
- Oxycodone hydrochloride tablets, USP are available as follows:
- Oxycodone hydrochloride tablets, USP 5 mg are supplied as white round biconvex tablets debossed “K” on left and “18” on right of the bisect on one side and plain on the other side.
- NDC 10702-018-01 Bottles of 100 tablets
- NDC 10702-018-50 Bottles of 500 tablets
- Oxycodone hydrochloride tablets, USP 10 mg are supplied as pink round biconvex tablets debossed “K” on left and “56” on right of the bisect on one side and plain on the other side.
- NDC 10702-056-01 Bottles of 100 tablets
- NDC 10702-056-50 Bottles of 500 tablets
- Oxycodone hydrochloride tablets, USP 15 mg are supplied as green round biconvex tablets debossed “K” on left and “8” on right of the bisect on one side and plain on the other side.
- NDC 10702-008-01 Bottles of 100 tablets
- NDC 10702-008-50 Bottles of 500 tablets
- Oxycodone hydrochloride tablets, USP 20 mg are supplied as gray round biconvex tablets debossed “K” on left and “57” on right of the bisect on one side and plain on the other side.
- NDC 10702-057-01 Bottles of 100 tablets
- NDC 10702-057-50 Bottles of 500 tablets
- Oxycodone hydrochloride tablets, USP 30 mg are supplied as blue round biconvex tablets debossed “K” on left and “9” on right of the bisect on one side and plain on the other side.
- NDC 10702-009-01 Bottles of 100 tablets
- NDC 10702-009-50 Bottles of 500 tablets
- DEA Order Form Required
## Storage
- Dispense in a tight, light-resistant and child-resistant container as defined in the USP. Protect from moisture.
- Store at 20° to 25°C (68° to 77°F) with excursions permitted between 15° to 30°C (59° to 86°F) .
- Manufactured by:
KVK-TECH, INC.
110 Terry Dr. Suite 200
Newtown, PA 18940-1850
Item ID # 6102/03 10/13
Manufacturer’s Code: 10702
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Oxycodone Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Oxycodone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Oxycodone Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Oxycodone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Oxycodone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
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# Overview
Oxycodone is an analgesic opioid that is FDA approved for the {{{indicationType}}} of pain, chronic (severe), in patients requiring a long-term daily around-the-clock opioid analgesic, pain (moderate to severe). Common adverse reactions include dermatologic: pruritus (controlled-release, 13% ; immediate-release, 3% or greater ), sweating (controlled-release, 5% ; immediate-release, less than 3% ), gastrointestinal: abdominal pain (up to 5% ), constipation (controlled-release, 23% ; immediate-release, 3% or greater ), nausea (controlled-release, 23% ; immediate-release, 3% or greater ), vomiting (controlled-release, 12% ; immediate-release, 3% or greater ), xerostomia (controlled-release, 6% ; immediate-release, less than 3% ), neurologic: Asthenia (controlled-release, 6% ; immediate-release, 3% or greater ), dizziness (controlled-release, 13% ; immediate-release, 3% or greater ), headache (controlled-release, 7% ; immediate-release, 3% or greater ), somnolence (controlled-release, 23% ; immediate-release, 3% or greater ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Reserve use of single doses greater than 40 mg, total daily doses greater than 80 mg , oral solution concentration of 100 mg per 5 mL (20 mg per mL), and controlled-release 60 mg or 80 mg tablets, for opioid-tolerant patients only (oral solution) to avoid dosing errors include total dose in mg and mL when prescribing, administering, and dispensing
- Do not discontinue abruptly in physically dependent patient; taper gradually to prevent withdrawal.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: individualize dose; initial dose selection must take into account patient's prior analgesic treatment experience and risk factors for addiction, abuse, and misuse; due to substantial inter-patient variability in relative potency of different opioid products, when converting it is recommended to underestimate a patient's 24-hour oral oxycodone requirements and provide rescue mediation as needed.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: (as first opioid and for patients who are not opioid-tolerant) initial, 10 mg or every 12 hours; titrate by 25% to 50% of the current dose every 1 to 2 days based on analgesic requirement and tolerance.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: (conversion from other oral oxycodone formulations) initial, one-half of total daily oxycodone requirement orally every 12 hours; titrate by 25% to 50% of the current dose every 1 to 2 days based on analgesic requirement and tolerance.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: (conversion from other opioids) initial, 10 mg orally every 12 hours; titrate by 25% to 50% of the current dose every 1 to 2 days based on analgesic requirement and tolerance.
- Pain, chronic (Severe), in patients requiring a long-term daily around-the-clock opioid analgesic: (conversion from transdermal fentanyl) 18 hours following patch removal initiate 10 mg orally every 12 hours for every 25 mcg/hr of transdermal fentanyl; titrate by 25% to 50% of the current dose every 1 to 2 days based on analgesic requirement and tolerance.
- Pain (Moderate to Severe): (immediate-release capsules, tablets, or oral solution 5 mg/5 mL) opioid-naive patients; initial, 5 to 15 mg orally every 4 to 6 hours as needed for pain; titrate based on pain severity and patient response.
- Pain (Moderate to Severe): (oral solution 100 mg/5 mL) reserve for opioid-tolerant patients who have been titrated to a stable analgesic regimen with lower doses of oxycodone and can benefit from use of a smaller volume of oral solution; always use the enclosed oral syringe to measure dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Oxycodone in adult patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Oxycodone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
safety and efficacy not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Oxycodone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Oxycodone in pediatric patients.
# Contraindications
- Oxycodone hydrochloride tablets are contraindicated in patients with known hypersensitivity to oxycodone, or in any situation where opioids are contraindicated. This includes patients with significant respiratory depression (in unmonitored settings or the absence of resuscitative equipment) and patients with acute or severe bronchial asthma or hypercarbia. Oxycodone hydrochloride tablets are contraindicated in any patient who has or is suspected of having paralytic ileus.
# Warnings
- Respiratory depression is the chief hazard from all opioid agonist preparations. Respiratory depression occurs most frequently in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other agents that depress respiration.
- Oxycodone hydrochloride tablets should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of oxycodone hydrochloride tablets may decrease respiratory drive to the point of apnea. In these patients alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.
- Oxycodone hydrochloride tablets, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Oxycodone hydrochloride tablets may produce orthostatic hypotension in ambulatory patients. Oxycodone hydrochloride tablets, like all opioid analgesics, should be administered with caution to patients in circulatory shock, since vasodilatation produced by the drug may further reduce cardiac output and blood pressure.
- The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries.
# Adverse Reactions
## Clinical Trials Experience
- Oxycodone hydrochloride tablets have been evaluated in open label clinical trials in patients with cancer and nonmalignant pain. Oxycodone hydrochloride tablets are associated with adverse experiences similar to those seen with other opioids.
- Serious adverse reactions that may be associated with oxycodone hydrochloride tablets therapy in clinical use are those observed with other opioid analgesics and include: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock (see overdosage, warnings).
- The less severe adverse events seen on initiation of therapy with oxycodone hydrochloride tablets are also typical opioid side effects. These events are dose dependent, and their frequency depends on the clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. They should be expected and managed as a part of opioid analgesia. The most frequent of these include nausea, constipation, vomiting, headache, and pruritus.
- In many cases the frequency of adverse events during initiation of opioid therapy may be minimized by careful individualization of starting dosage, slow titration and the avoidance of large rapid swings in plasma concentration of the opioid. Many of these adverse events will abate as therapy is continued and some degree of tolerance is developed, but others may be expected to remain throughout therapy.
- In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving oxycodone hydrochloride tablets, the following adverse events were recorded in oxycodone hydrochloride tablets treated patients with an incidence ≥ 3%. In descending order of frequency they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.
- The following adverse experiences occurred in less than 3% of patients involved in clinical trials with oxycodone:
- Abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis.
- Deep thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia.
- Anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting.
- Anemia and leukopenia.
- Edema, gout, hyperglycemia, iron deficiency anemia and peripheral edema.
- Arthralgia, arthritis, bone pain, myalgia and pathological fracture.
- Agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation.
- Bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis.
- Herpes simplex, rash, sweating, and urticaria.
- Amblyopia.
- Urinary tract infection.
### Drug Abuse and Dependence
- Oxycodone Hydrochloride Tablets contain Oxycodone, a mu-agonist opioid if the morphine type and is a Schedule II controlled substance.
- Oxycodone hydrochloride, like other opioids used in analgesia, can be abused and is subject to criminal diversion.
- Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk of harm. Drug addiction is a treatable disease, utilizing a multi-disciplinary approach, but relapse is common.
- “Drug-seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction.
- Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.
- Oxycodone hydrochloride is intended for oral use only. Abuse of oxycodone hydrochloride tablets poses a risk of overdose and death. The risk is increased with concurrent abuse of alcohol and other substances. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.
- Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispening and storage are appropriate measures that help to limit abuse of opioid drugs.
- Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.
- Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Physical dependence is manifested by withdrawal symptoms after abrupt discontinuation of a drug or upon administration of an antagonist. Physical dependence and tolerance are not unusual during chronic opioid therapy.
- The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued.
## Postmarketing Experience
There is limited information regarding Oxycodone Postmarketing Experience in the drug label.
# Drug Interactions
- Oxycodone is metabolized in part to oxymorphone via the cytochrome p450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent. However, clinicians should be aware of this possible interaction.
- Neuromuscular Blocking Agents: Oxycodone, as well as other opioid analgesics, may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
- Patients receiving narcotic analgesics, general anesthetics, phenothiazines, other tranquilizers, sedative-hypnotics or other CNS depressants (including alcohol) concomitantly with oxycodone hydrochloride tablets may exhibit an additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual dosage of oxycodone hydrochloride tablets. When such combined therapy is contemplated, the dose of one or both agents should be reduced.
- Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol and buprenorphine) should be administered with caution to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic such as oxycodone hydrochloride tablets. In this situation, mixed agonist/antagonist analgesics may reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms in these patients.
- MAOIs have been reported to intensify the effects of at least one opioid drug causing anxiety, confusion and significant depression of respiration or coma. The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies in Sprague-Dawley rats and New Zealand rabbits revealed that when oxycodone was administered orally at doses up to 16 mg/kg (approximately 2 times the daily oral dose of 90 mg for adults on a mg/m2 basis) and 25 mg/kg (approximately 5 times the daily oral dose of 90 mg on a mg/m2 basis), respectively was not teratogenic or embryo-fetal toxic. There are no adequate and well controlled studies of oxycodone in pregnant women. Because animal reproductive studies are not always predictive of human responses, oxycodone hydrochloride tablets should be used during pregnancy only if potential benefit justifies the potential risk to the fetus.
- Neonates whose mothers have taken oxycodone chronically may exhibit respiratory depression and/or withdrawal symptoms, either at birth and/or in the nursery.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oxycodone in women who are pregnant.
### Labor and Delivery
- Oxycodone hydrochloride tablets are not recommended for use in women during or immediately prior to labor. Occasionally, opioid analgesics may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. Neonates, whose mothers received opioid analgesics during labor, should be observed closely for signs of respiratory depression. A specific narcotic antagonist, naloxone, should be available for reversal of narcotic-induced respiratory depression in the neonate.
### Nursing Mothers
- Oxycodone has been detected in breast milk. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of an opioid analgesic is stopped. Ordinarily, nursing should not be undertaken while a patient is receiving oxycodone hydrochloride tablets since oxycodone may be excreted in milk.
### Pediatric Use
- The safety and efficacy of oxycodone in pediatric patients have not been evaluated.
### Geriatic Use
- Population pharmacokinetic studies conducted with oxycodone hydrochloride tablets indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.
### Gender
- Population pharmacokinetic analyses performed in the clinical study support the lack of gender effect on the pharmacokinetics of oxycodone from oxycodone hydrochloride tablets.
### Race
- Population pharmacokinetic analyses support the lack of race effect on oxycodone pharmacokinetics after administration of oxycodone hydrochloride tablets, but these data should be interpreted conservatively, since the majority of patients enrolled into the studies were Caucasians (94%).
### Renal Impairment
- In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased renal function were evaluated to study these potential differences. In previous studies, patients with renal impairment (defined as a creatinine clearance < 60 mL/min) had concentrations of oxycodone in the plasma that were higher than in subjects with normal renal function. Based on information available on the metabolism and excretion of oxycodone, dose initiation in patients with renal impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
### Hepatic Impairment
- In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, since oxycodone is extensively metabolized, its clearance may decrease in hepatic failure patients. Dose initiation in patients with hepatic impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oxycodone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Oxycodone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Oxycodone Administration in the drug label.
### Monitoring
There is limited information regarding Oxycodone Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Oxycodone and IV administrations.
# Overdosage
- Acute overdose with oxycodone hydrochloride tablets can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.
- To treat oxycodone hydrochloride tablets overdose, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
- The narcotic antagonists, naloxone or nalmefene, are specific antidotes for opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone hydrochloride tablets overdose. If needed the appropriate dose of naloxone hydrochloride or nalmefene should be administered simultaneously with efforts at respiratory resuscitation (see package insert for each drug for the details). Since the duration of action of oxycodone may exceed that of the antagonist, the patient should be kept under continued surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. Gastric emptying may be useful in removing unabsorbed drug.
- Opioid antagonists should be administered cautiously to persons who are suspected to be physically dependent on any opioid agonist, including Oxycodone. (see Opioid-Tolerant Individuals.)
- Opioid-Tolerant Individuals:In an individual physically dependent on opioids, administration of a usual dose of antagonist will precipitate an acute withdrawal. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Use of an opioid antagonist should be reserved for cases where such treatment is clearly needed. If it is necessary to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses.
# Pharmacology
## Mechanism of Action
- The analgesic ingredient, oxycodone, is a semi-synthetic narcotic with multiple actions qualitatively similar to those of morphine; the most prominent of these involves the central nervous system and organs composed of smooth muscle.
- Oxycodone, as the hydrochloride salt, is a pure agonist opioid whose principal therapeutic action is analgesia and has been in clinical use since 1917. Like all pure opioid agonists, there is no ceiling effect to analgesia, such as is seen with partial agonists or non-opioid analgesics. Based upon a single-dose, relative-potency study conducted in humans with cancer pain, 10 to 15 mg of oxycodone given intramuscularly produced an analgesic effect similar to 10 mg of morphine given intramuscularly. Both drugs have a 3 to 4 hour duration of action. Oxycodone retains approximately one half of its analgesic activity when administered orally
- The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug. A significant feature of opioid-induced analgesia is that it occurs without loss of consciousness. The relief of pain by morphine-like opioids is relatively selective, in that other sensory modalities, (e.g., touch, vibrations, vision, hearing, etc.) are not obtunded.
- Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves both a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.
- Oxycodone depresses the cough reflex by direct effect on the cough center in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
- Oxycodone, like other opioid analgesics, produces some degree of nausea and vomiting which is caused by direct stimulation of the chemoreceptor trigger zone (CTZ) located in the medulla. The frequency and severity of emesis gradually diminishes with time.
- Oxycodone may cause a decrease in the secretion of hydrochloric acid in the stomach that reduces motility while increasing the tone of the antrum, stomach, and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
- Oxycodone, in therapeutic doses, produces peripheral vasodilatation (arteriolar and venous), decreased peripheral resistance, and inhibits baroreceptor reflexes. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
- Caution should be used in hypovolemic patients, such as those suffering acute myocardial infarction, because oxycodone may cause or further aggravate their hypotension. Caution should also be used in patients with cor pulmonale who have received therapeutic doses of opioids.
## Structure
- Oxycodone hydrochloride tablets USP is an opioid analgesic.
- Each tablet for oral administration contains 5 mg, 10 mg, 15 mg, 20 mg or 30 mg of oxycodone hydrochloride USP.
- Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7).
- Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula:
- The tablets contain the following inactive ingredients: corn starch; lactose monohydrate; microcrystalline cellulose; silicon dioxide; sodium starch glycolate; and stearic acid. The 10 mg tablet also contains D&C Red No. 27 aluminum lake. The 15 mg tablet also contains D&C Yellow No. 10 aluminum lake and FD&C Blue No. 2 aluminum lake. The 20 mg tablet also contains FD&C Blue No. 2 aluminum lake; FD&C Red No. 40 aluminum lake; and FD&C Yellow No. 6 aluminum lake. The 30 mg tablet also contains FD&C Blue No. 2 aluminum lake.
- The 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg tablets contain the equivalent of 4.5 mg, 9 mg, 13.5 mg, 18 mg, and 27 mg, respectively, of oxycodone free base.
## Pharmacodynamics
- The relationship between the plasma level of oxycodone and the analgesic response will depend on the patient's age, state of health, medical condition and extent of previous opioid treatment.
- The minimum effective plasma concentration of oxycodone to achieve analgesia will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. Thus, patients need to be treated with individualized titration of dosage to the desired effect. The minimum effective analgesic concentration of oxycodone for any individual patient may increase with repeated dosing due to an increase in pain and/or development of tolerance.
## Pharmacokinetics
- The activity of oxycodone hydrochloride tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to provide immediate release of oxycodone.
- About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone. The relative oral bioavailability of oxycodone hydrochloride 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablets, is 96% and 101% respectively. Oxycodone hydrochloride 15 mg tablets and 30 mg tablets are bioequivalent to the 5 mg oxycodone hydrochloride tablets (see Table 1 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride 5 mg tablets at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride tablets.
- A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution. (see Table 1). In addition, food caused a delay in Tmax (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets.
- Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk. (See PRECAUTIONS-Nursing Mothers.)
- Oxycodone hydrochloride is extensively metabolized to noroxycodone, oxymorphone, and their glucuronides. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present.
- The formation of oxymorphone, but not noroxycodone, is mediated by CYP2D6 and as such its formation can, in theory, be affected by other drugs. (See Precautions-Drug Interactions.)
- Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone hydrochloride tablets was 3.5 to 4 hours.
- Population pharmacokinetic studies conducted with oxycodone hydrochloride tablets indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.
- Population pharmacokinetic analyses performed in the clinical study support the lack of gender effect on the pharmacokinetics of oxycodone from oxycodone hydrochloride tablets.
- Population pharmacokinetic analyses support the lack of race effect on oxycodone pharmacokinetics after administration of oxycodone hydrochloride tablets, but these data should be interpreted conservatively, since the majority of patients enrolled into the studies were Caucasians (94%).
- In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased renal function were evaluated to study these potential differences. In previous studies, patients with renal impairment (defined as a creatinine clearance < 60 mL/min) had concentrations of oxycodone in the plasma that were higher than in subjects with normal renal function. Based on information available on the metabolism and excretion of oxycodone, dose initiation in patients with renal impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
- In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, since oxycodone is extensively metabolized, its clearance may decrease in hepatic failure patients. Dose initiation in patients with hepatic impairment should follow a conservative approach. Dosages should be adjusted according to the clinical situation.
## Nonclinical Toxicology
There is limited information regarding Oxycodone Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Oxycodone Clinical Studies in the drug label.
# How Supplied
- Oxycodone hydrochloride tablets, USP are available as follows:
- Oxycodone hydrochloride tablets, USP 5 mg are supplied as white round biconvex tablets debossed “K” on left and “18” on right of the bisect on one side and plain on the other side.
- NDC 10702-018-01 Bottles of 100 tablets
- NDC 10702-018-50 Bottles of 500 tablets
- Oxycodone hydrochloride tablets, USP 10 mg are supplied as pink round biconvex tablets debossed “K” on left and “56” on right of the bisect on one side and plain on the other side.
- NDC 10702-056-01 Bottles of 100 tablets
- NDC 10702-056-50 Bottles of 500 tablets
- Oxycodone hydrochloride tablets, USP 15 mg are supplied as green round biconvex tablets debossed “K” on left and “8” on right of the bisect on one side and plain on the other side.
- NDC 10702-008-01 Bottles of 100 tablets
- NDC 10702-008-50 Bottles of 500 tablets
- Oxycodone hydrochloride tablets, USP 20 mg are supplied as gray round biconvex tablets debossed “K” on left and “57” on right of the bisect on one side and plain on the other side.
- NDC 10702-057-01 Bottles of 100 tablets
- NDC 10702-057-50 Bottles of 500 tablets
- Oxycodone hydrochloride tablets, USP 30 mg are supplied as blue round biconvex tablets debossed “K” on left and “9” on right of the bisect on one side and plain on the other side.
- NDC 10702-009-01 Bottles of 100 tablets
- NDC 10702-009-50 Bottles of 500 tablets
- DEA Order Form Required
## Storage
- Dispense in a tight, light-resistant and child-resistant container as defined in the USP. Protect from moisture.
- Store at 20° to 25°C (68° to 77°F) with excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
- Manufactured by:
KVK-TECH, INC.
110 Terry Dr. Suite 200
Newtown, PA 18940-1850
Item ID # 6102/03 10/13
Manufacturer’s Code: 10702
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Oxycodone Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Oxycodone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Oxycodone Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Oxycodone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dazidox | |
6866bf7d523ce80482dcf9928344e778b64c9945 | wikidoc | Glossitis | Glossitis
Glossitis is inflammation or infection of the tongue. It causes the tongue to swell and change color. Finger-like projections on the surface of the tongue (papillae) may be lost, causing the tongue to appear smooth.
Glossitis usually responds well to treatment if the cause of inflammation is removed. This disorder may be painless, or it may cause tongue and mouth discomfort. In some cases, glossitis may result in severe tongue swelling that blocks the airway, a medical emergency that needs immediate attention.
# Causes
## Common Causes
- Alcohol
- Benign migratory glossitis
- Deserpidine
- Erythema multiforme
- Folate deficiency
- Glucagonoma
- Iron deficiency
- Lichen planus
- Malnutrition
- Pellagra
- Pernicious anemia
- Reserpine
- Spices
- Xerostemia
## Causes by Organ System
## Causes in Alphabetical Order
- Aids
- Albuterol
- Alcohol
- Alcoholism
- Allergic reaction
- Anemia
- Angular cheilitis
- Aphthous ulcer
- Ariboflavinosis
- Benign migratory glossitis
- Candidiasis
- Carcinoid syndrome
- Celiac disease
- Cheilosis
- Cowden disease
- Crohn’s disease
- Dana syndrome
- Dehydration
- Deserpidine
- Doxycycline
- Erythema multiforme
- Folate deficiency
- Glucagonoma
- Herpes simplex
- Immunocompromise
- Iron deficiency
- Iron deficiency anemia
- Kawasaki disease
- Kwashiorkor amyloidosis
- Lichen planus
- Lincomycin hydrochloride
- Malnutrition
- Mecamylamine
- Median rhomboid glossitis
- Meropenem
- Mouthwash
- Niacin deficiency
- Pellagra
- Pemphigus vulgaris
- Peripheral neuropathy
- Pernicious anemia
- Persistent tuberculum impar
- Plummer-vinson disease
- Poor oral hygiene
- Psoriasis
- Pyridoxine deficiency
- Reserpine
- Riboflavin deficiency
- Scarlet fever
- Sideropenic dysphagia
- Smoking
- Spices
- Syphilis
- Tetracycline
- Thiamine deficiency
- Tobacco
- Toxic shock syndrome
- Trauma
- Tubocurarine
- Whipple disease
- Xerostemia
- Zinc deficiency
# Symptoms
- Tongue swelling.
- Smooth appearance to the tongue.
- Tongue color changes (usually dark "beefy" red).
Pale, if caused by pernicious anemia.
Fiery red, if caused by deficiency of B vitamins.
- Pale, if caused by pernicious anemia.
- Fiery red, if caused by deficiency of B vitamins.
- Sore and tender tongue.
- Difficulty with chewing, swallowing, or speaking.
A health care provider should be contacted if symptoms of glossitis persist for longer than 10 days, if tongue swelling is severe, or if breathing, speaking, chewing, or swallowing become difficult.
# Causes, incidence, and risk factors
- Bacterial or viral infections (including oral herpes simplex).
- Poor hydration and low saliva in the mouth may allow bacteria to grow more readily.
- Mechanical irritation or injury from burns, rough edges of teeth or dental appliances, or other trauma
- Exposure to irritants such as tobacco, alcohol, hot foods, or spices.
- Allergic reaction to toothpaste, mouthwash, breath fresheners, dyes in candy, plastic in dentures or retainers, or certain blood-pressure medications (ACE inhibitors).
- Disorders such as iron deficiency anemia, pernicious anemia and other B-vitamin deficiencies, oral lichen planus, erythema multiforme, aphthous ulcer, pemphigus vulgaris, syphilis, and others.
- Occasionally, glossitis can be inherited.
- Drugs such as doxycycline, Lincomycin Hydrochloride, Meropenem and tetracycline.
A painful tongue may be an indication of several underlying serious medical conditions and nearly always merits assessment by a doctor or dentist
# Treatment
The goal of treatment is to reduce inflammation. Treatment usually does not require hospitalization unless tongue swelling is severe. Good oral hygiene is necessary, including thorough tooth brushing at least twice a day, and flossing at least daily. Corticosteroids such as prednisone may be given to reduce the inflammation of glossitis. For mild cases, topical applications (such as a prednisone mouth rinse that is not swallowed) may be recommended to avoid the side effects of swallowed or injected corticosteroids. Antibiotics, antifungal medications, or other antimicrobials may be prescribed if the cause of glossitis is an infection. Anemia and nutritional deficiencies must be treated, often by dietary changes or other supplements. Avoid irritants (such as hot or spicy foods, alcohol, and tobacco) to minimize the discomfort.
# Prevention
Good oral hygiene (thorough tooth brushing and flossing and regular professional cleaning and examination) may be helpful to prevent these disorders. Drinking plenty of water and the production of enough saliva, aid in the reduction of bacterial growth. Minimize irritants or injury in the mouth when possible. Avoid excessive use of any food or substance that irritates the mouth or tongue. | Glossitis
Template:DiseaseDisorder infobox
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.
Glossitis is inflammation or infection of the tongue. It causes the tongue to swell and change color. Finger-like projections on the surface of the tongue (papillae) may be lost, causing the tongue to appear smooth.
Glossitis usually responds well to treatment if the cause of inflammation is removed. This disorder may be painless, or it may cause tongue and mouth discomfort. In some cases, glossitis may result in severe tongue swelling that blocks the airway, a medical emergency that needs immediate attention.
# Causes
## Common Causes
- Alcohol
- Benign migratory glossitis
- Deserpidine
- Erythema multiforme
- Folate deficiency
- Glucagonoma
- Iron deficiency
- Lichen planus
- Malnutrition
- Pellagra
- Pernicious anemia
- Reserpine
- Spices
- Xerostemia
## Causes by Organ System
## Causes in Alphabetical Order
- Aids
- Albuterol
- Alcohol
- Alcoholism
- Allergic reaction
- Anemia
- Angular cheilitis
- Aphthous ulcer
- Ariboflavinosis
- Benign migratory glossitis
- Candidiasis
- Carcinoid syndrome
- Celiac disease
- Cheilosis
- Cowden disease
- Crohn’s disease
- Dana syndrome
- Dehydration
- Deserpidine
- Doxycycline
- Erythema multiforme
- Folate deficiency
- Glucagonoma
- Herpes simplex
- Immunocompromise
- Iron deficiency
- Iron deficiency anemia
- Kawasaki disease
- Kwashiorkor amyloidosis
- Lichen planus
- Lincomycin hydrochloride
- Malnutrition
- Mecamylamine
- Median rhomboid glossitis
- Meropenem
- Mouthwash
- Niacin deficiency
- Pellagra
- Pemphigus vulgaris
- Peripheral neuropathy
- Pernicious anemia
- Persistent tuberculum impar
- Plummer-vinson disease
- Poor oral hygiene
- Psoriasis
- Pyridoxine deficiency
- Reserpine
- Riboflavin deficiency
- Scarlet fever
- Sideropenic dysphagia
- Smoking
- Spices
- Syphilis
- Tetracycline
- Thiamine deficiency
- Tobacco
- Toxic shock syndrome
- Trauma
- Tubocurarine
- Whipple disease
- Xerostemia
- Zinc deficiency
# Symptoms
- Tongue swelling.
- Smooth appearance to the tongue.
- Tongue color changes (usually dark "beefy" red).
Pale, if caused by pernicious anemia.
Fiery red, if caused by deficiency of B vitamins.
- Pale, if caused by pernicious anemia.
- Fiery red, if caused by deficiency of B vitamins.
- Sore and tender tongue.
- Difficulty with chewing, swallowing, or speaking.
A health care provider should be contacted if symptoms of glossitis persist for longer than 10 days, if tongue swelling is severe, or if breathing, speaking, chewing, or swallowing become difficult.
# Causes, incidence, and risk factors
- Bacterial or viral infections (including oral herpes simplex).
- Poor hydration and low saliva in the mouth may allow bacteria to grow more readily.
- Mechanical irritation or injury from burns, rough edges of teeth or dental appliances, or other trauma
- Exposure to irritants such as tobacco, alcohol, hot foods, or spices.
- Allergic reaction to toothpaste, mouthwash, breath fresheners, dyes in candy, plastic in dentures or retainers, or certain blood-pressure medications (ACE inhibitors).
- Disorders such as iron deficiency anemia, pernicious anemia and other B-vitamin deficiencies, oral lichen planus, erythema multiforme, aphthous ulcer, pemphigus vulgaris, syphilis, and others.
- Occasionally, glossitis can be inherited.
- Drugs such as doxycycline, Lincomycin Hydrochloride, Meropenem and tetracycline.
A painful tongue may be an indication of several underlying serious medical conditions and nearly always merits assessment by a doctor or dentist [1]
# Treatment
The goal of treatment is to reduce inflammation. Treatment usually does not require hospitalization unless tongue swelling is severe. Good oral hygiene is necessary, including thorough tooth brushing at least twice a day, and flossing at least daily. Corticosteroids such as prednisone may be given to reduce the inflammation of glossitis. For mild cases, topical applications (such as a prednisone mouth rinse that is not swallowed) may be recommended to avoid the side effects of swallowed or injected corticosteroids. Antibiotics, antifungal medications, or other antimicrobials may be prescribed if the cause of glossitis is an infection. Anemia and nutritional deficiencies must be treated, often by dietary changes or other supplements. Avoid irritants (such as hot or spicy foods, alcohol, and tobacco) to minimize the discomfort.
# Prevention
Good oral hygiene (thorough tooth brushing and flossing and regular professional cleaning and examination) may be helpful to prevent these disorders. Drinking plenty of water and the production of enough saliva, aid in the reduction of bacterial growth. Minimize irritants or injury in the mouth when possible. Avoid excessive use of any food or substance that irritates the mouth or tongue. | https://www.wikidoc.org/index.php/Ddx:Glossitis | |
e2d5b49cef10acf72f66142cd647fbbb625aefea | wikidoc | Dysphonia | Dysphonia
Synonyms and keywords: hoarseness
# Overview
Dysphonia is the medical term for hoarseness or other phonation disorders. It is considered much less severe than aphonia. Hoarseness can be a change in pitch, a rough sound of the voice, or an increased effort in speaking.
# Classificaiton of Dysphonia
## Based Upon Chronicity
- Acute hoarseness has a sudden onset and lasts fewer than 2 weeks
- Chronic hoarseness lasts longer than 2 weeks
## Based Upon Pathophysiology
- Organic dysphonia
- Functional dysphonia
- Spasmodic dysphonia
# Causes
## Common Causes
- Aging
- Cold
- Foreign body in respiratory tract
- Hypothyroidism
- Laryngitis
- Laryngeal cancer
- Overstress of vocal cords (speaking, shouting, singing and crying)
- Sinusitis
- Tracheitis
## Causes by Organ System
## Causes in Alphabetical Order
In alphabetical order.
## Acute
- Acute viral laryngitis
- Aortic aneurysm
- Aortic dissection
- Anaphylaxis
- Bacterial tracheitis / laryngitis
- Cerebrovascular accident (CVA)
- Chorditis
- Croup
- Deep space face and neck infection
- Epiglottitis
- Foreign body
- Head injury
- Laryngitis
- Laryngotracheobronchitis
- Overstress of vocal cords (speaking, shouting, singing, crying)
- Sinusitis
- Smoke irritation
- Surgery
- Trauma
- Upper Respiratory Infection
## Chronic
- Aging
- Allergic Rhinitis
- Amyloidosis
- Amyotrophic Lateral Sclerosis
- Aortic aneurysm
- Bronchial carcinoma
- Bronchogenic tumor
- Chondromas
- Chronic cough, severe cold
- Chronic inhalation of chemical irritant agents (professional activity)
- Chronic sinusitis
- Drugs
- Edema of vocal cords
- Esophageal tumor
- Excessively dry and warm room coupled with low water intake
- Foreign body
- Gastroesophageal Reflux Disease (GERD)
- Glomus jugulare tumor
- Guillain-Barre Syndrome
- Habitual aphonia
- Hemangioma
- Hemorrhage into vocal folds
- Hypothyroidism
- Juvenile dermatomyositis
- Laryngeal papillomatosis
- Laryngocelesventricular prolapse
- Laryngeal carcinoma
- Left atrial enlargement
- Lipoma
- Lung cancer
- Menopause
- Multiple Sclerosis
- Muscular Dystrophy
- Myasthenia Gravis
- Neural tumor
- Neurofibroma
- Papillomas
- Parkinson's Disease
- Postsurgical
- Psychogenic aphonia
- Puberty
- Reinke's Edema
- Retention cysts
- Rheumatoid Arthritis
- Sarcoidosis
- Spastic dysphonia
- Squamous Cell Carcinoma
- Systemic Lupus Erythematosus
- Thyroid tumor
- Ventricular dysphonias
- Virilization
- Vocal cord nodules
- Vocal fold cyst
- Vocal cord paralysis
- Vocal cord polyps
- Wegener's Granulotomosis
# Diagnosis
# History and Symptoms
The following should be characterized as part of a full history:
- Onset
- Duration
- Prior history
- Exposure
- Medications
- Voice use
- Associated symptoms
- Medical history
- Surgical history
- Trauma
# Physical Examination
- Focus on neck, head, lung, thyroid and cardiac exams
- Evaluate voice quality
# Laboratory Findings
- Thyroid function tests to rule out hypothyroidism
## X-Ray
- Chest X-ray
- Lateral neck X-ray
## MRI and CT
- CT scan of sinuses
- CT scan of head and neck
## Other Diagnostic Studies
- Upper gastrointestinal (GI) endoscopy
- Direct or fiber optic nasolaryngoscopy
- Biopsy
# Treatment
- Airway, breathing and circulation
- Voice rest
- Diet modification (GERD)
- Stop smoking
- Wear protective clothing or masks (if hoarseness is due to exposure)
- Treat underlying etiologies
- Voice therapy
# Pharmacotherapy
## Acute Pharmacotherapies
- Antibiotics
- Oral steroids
- H2 blocker
- Proton pump inhibitors
- Intranasal steroids
- Antihistamines
# Surgery and Device Based Therapy
- Surgical intervention for abscesses, masses
- Cricothyrotomy or tracheostomy (to establish airway) | Dysphonia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: hoarseness
# Overview
Dysphonia is the medical term for hoarseness or other phonation disorders. It is considered much less severe than aphonia. Hoarseness can be a change in pitch, a rough sound of the voice, or an increased effort in speaking.
# Classificaiton of Dysphonia
## Based Upon Chronicity
- Acute hoarseness has a sudden onset and lasts fewer than 2 weeks
- Chronic hoarseness lasts longer than 2 weeks
## Based Upon Pathophysiology
- Organic dysphonia
- Functional dysphonia
- Spasmodic dysphonia
# Causes
## Common Causes
- Aging
- Cold
- Foreign body in respiratory tract
- Hypothyroidism
- Laryngitis
- Laryngeal cancer
- Overstress of vocal cords (speaking, shouting, singing and crying)
- Sinusitis
- Tracheitis
## Causes by Organ System
## Causes in Alphabetical Order
In alphabetical order. [1] [2]
## Acute
- Acute viral laryngitis
- Aortic aneurysm
- Aortic dissection
- Anaphylaxis
- Bacterial tracheitis / laryngitis
- Cerebrovascular accident (CVA)
- Chorditis
- Croup
- Deep space face and neck infection
- Epiglottitis
- Foreign body
- Head injury
- Laryngitis
- Laryngotracheobronchitis
- Overstress of vocal cords (speaking, shouting, singing, crying)
- Sinusitis
- Smoke irritation
- Surgery
- Trauma
- Upper Respiratory Infection
## Chronic
- Aging
- Allergic Rhinitis
- Amyloidosis
- Amyotrophic Lateral Sclerosis
- Aortic aneurysm
- Bronchial carcinoma
- Bronchogenic tumor
- Chondromas
- Chronic cough, severe cold
- Chronic inhalation of chemical irritant agents (professional activity)
- Chronic sinusitis
- Drugs
- Edema of vocal cords
- Esophageal tumor
- Excessively dry and warm room coupled with low water intake
- Foreign body
- Gastroesophageal Reflux Disease (GERD)
- Glomus jugulare tumor
- Guillain-Barre Syndrome
- Habitual aphonia
- Hemangioma
- Hemorrhage into vocal folds
- Hypothyroidism
- Juvenile dermatomyositis
- Laryngeal papillomatosis
- Laryngocelesventricular prolapse
- Laryngeal carcinoma
- Left atrial enlargement
- Lipoma
- Lung cancer
- Menopause
- Multiple Sclerosis
- Muscular Dystrophy
- Myasthenia Gravis
- Neural tumor
- Neurofibroma
- Papillomas
- Parkinson's Disease
- Postsurgical
- Psychogenic aphonia
- Puberty
- Reinke's Edema
- Retention cysts
- Rheumatoid Arthritis
- Sarcoidosis
- Spastic dysphonia
- Squamous Cell Carcinoma
- Systemic Lupus Erythematosus
- Thyroid tumor
- Ventricular dysphonias
- Virilization
- Vocal cord nodules
- Vocal fold cyst
- Vocal cord paralysis
- Vocal cord polyps
- Wegener's Granulotomosis
# Diagnosis
# History and Symptoms
The following should be characterized as part of a full history:
- Onset
- Duration
- Prior history
- Exposure
- Medications
- Voice use
- Associated symptoms
- Medical history
- Surgical history
- Trauma
# Physical Examination
- Focus on neck, head, lung, thyroid and cardiac exams
- Evaluate voice quality
# Laboratory Findings
- Thyroid function tests to rule out hypothyroidism
## X-Ray
- Chest X-ray
- Lateral neck X-ray
## MRI and CT
- CT scan of sinuses
- CT scan of head and neck
## Other Diagnostic Studies
- Upper gastrointestinal (GI) endoscopy
- Direct or fiber optic nasolaryngoscopy
- Biopsy
# Treatment
- Airway, breathing and circulation
- Voice rest
- Diet modification (GERD)
- Stop smoking
- Wear protective clothing or masks (if hoarseness is due to exposure)
- Treat underlying etiologies
- Voice therapy
# Pharmacotherapy
## Acute Pharmacotherapies
- Antibiotics
- Oral steroids
- H2 blocker
- Proton pump inhibitors
- Intranasal steroids
- Antihistamines
# Surgery and Device Based Therapy
- Surgical intervention for abscesses, masses
- Cricothyrotomy or tracheostomy (to establish airway) | https://www.wikidoc.org/index.php/Ddx:Hoarseness |
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