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1e2e00466fa1a2739603d62d9e3009b5f44bf9a2 | wikidoc | Castor oil | Castor oil
Castor oil is a vegetable oil obtained from the castor bean (technically castor seed as the castor plant, Ricinus communis, is not a member of the bean family). Castor oil (CAS number 8001-79-4) is a colorless to very pale yellow liquid with mild or no odor or taste. Its boiling point is 313°C and its density is 961 kg·m-3. It is a triglyceride in which approximately ninety percent of fatty acid chains are ricinoleic acid. Oleic and linoleic acids are the other significant components.
The structure of the major component fo castor oil is shown below:
# Background
Ricinoleic acid, a monounsaturated, 18-carbon fatty acid, is unusual in that it has a hydroxyl functional group on the twelfth carbon. This functional group causes ricinoleic acid (and castor oil) to be unusually polar, and also allows chemical derivatization that is not practical with most other seed oils. It is the hydroxyl group which makes castor oil and ricinoleic acid valuable as chemical feedstocks. Compared to other seed oils which lack the hydroxyl group, castor oil demands a higher price. As an example, in July 2007 Indian castor oil sold for about US$0.90 per kilogram (US$0.41 per pound) while US soybean, sunflower and canola oil sold for about US$0.30 per kilogram (US$0.14 per pound)
Castor oil and its derivatives have applications in the manufacturing of soaps, lubricants, hydraulic and brake fluids, paints, dyes, coatings, inks, cold resistant plastics, waxes and polishes, nylon, pharmaceuticals and perfumes.
The castor seed contains ricin, a toxic protein removed by cold pressing and filtering. However, harvesting castor beans is not without risk,
allergenic compounds found on the plant surface can cause permanent nerve damage, making the harvest of castor beans a human health risk. India, Brazil and China are the major crop producers and the workers suffer harmful side effects from working with these plants. These health issues, in addition to concerns about the toxic byproduct (ricin) from castor oil production, have encouraged the quest for alternative, domestic sources for hydroxy fatty acids. Alternatively, some researchers are trying to genetically modify the castor plant to prevent the synthesis of ricin.
# Castor oil fatty acids
# Uses
## Castor oil in food
In the food industry, castor oil (food grade) is used in food additives , flavorings, candy (i.e., chocolate) , as a mold inhibitor, and in packaging. Polyoxyethylated castor oil (eg. Cremophor EL) is also used in the foodstuff industries.
## Medicinal use of castor oil
The United States Food and Drug Administration (FDA) has categorized castor oil as "generally recognized as safe and effective" (GRASE) for over-the-counter use as a laxative. However, it is not a preferred treatment for constipation.
Undecylenic acid, a castor oil derivative, is also FDA-approved for over-the-counter use on skin disorders or skin problems.
Ricinoleic acid is the main component of castor oil and it exerts anti-inflammatory effects.
One study has found that castor oil decreased pain more than ultrasound gel or Vaseline during extracorporeal shock wave application.
Therapeutically, modern drugs are rarely given in a pure chemical state, so most active ingredients are combined with excipients or additives. Castor oil, or a castor oil derivative such as Cremophor EL (polyethoxylated castor oil, a nonionic surfactant), is added to many modern drugs, including:
- Miconazole, an anti-fungal agent;
- Paclitaxel, a mitotic inhibitor used in cancer chemotherapy;
- Sandimmune (cyclosporine injection, USP), an immunosuppressant drug widely used in connection with organ transplant to reduce the activity of the patient's immune system;
- Nelfinavir mesylate, an HIV protease inhibitor;
- Saperconazole, a triazole antifungal agent (contains Emulphor EL -719P, a castor oil derivative);
- Prograf, an immunosuppressive drug (contains HCO-60, polyoxyl 60 hydrogenated Castor oil);
- Balsam Peru - Castor oil - and Trypsin Topical (contains castor oil);
- Aci-Jel, a gel used to create or maintain the acidity of the vagina (comprises acetic acid/oxyquinoline/ricinoleic acid - vaginal);
### Traditional or folk medicines
The use of cold pressed castor oil in folk medicine predates government regulations. Cold pressed castor oil is tasteless and odorless when pure. Uses include skin problems, burns, sunburns, skin disorders, skin cuts, abrasions, etc.
The oil is also used as a rub or pack for various ailments, including abdominal complaints, headaches, muscle pains, inflammatory conditions, skin eruptions, lesions, and sinusitis. A castor oil pack is made by soaking a piece of flannel in castor oil, then putting it on the area of complaint and placing a heat source, such as a hot water bottle, on top of it. This remedy was often suggested by the American Healing Psychic, Edgar Cayce, given in many healing readings in the early to mid-1900s.
## Industrial castor oil
Castor oil has numerous applications in transportation, cosmetics and pharmaceutical, and manufacturing industries, for example: adhesives, brake fluids , caulks, dyes, electrical liquid dielectrics, humectants, hydraulic fluids, inks, lacquers, leather treatments, lubricating greases, machining oils, paints, pigments, polyurethane adhesives
, refrigeration lubricants, rubbers, sealants, textiles, washing powders, and waxes.
Vegetable oils, due to their good lubricity and biodegradability are attractive alternatives to petroleum-derived lubricants, but oxidative stability and low temperature performance limit their widespread use. Castor oil has better low temperature viscosity properties and high temperature lubrication than most vegetable oils, making it useful as a lubricant in jet, diesel, and race-car engines. However, castor oil tends to form gums in a short time, and its use is therefore restricted to engines that are regularly rebuilt, such as motorcycle race engines. Biodegradability results in decreased persistance in the environment (relative to petroleum-based lubricants) in case of an accidental release. The lubricants company Castrol took its name from castor oil.
Since it is has a relatively high dielectric constant (4.7), highly refined and dried castor oil is sometimes used as a dielectric fluid within high performance high voltage capacitors.
Castor oil is the raw material for the production of a number of chemicals, notably sebacic acid, undecylenic acid, nylon-11. A review listing numerous chemicals derived from castor oil is available.
Castor oil is the preferred lubricant for bicycle pumps, most likely because it doesn't dissolve natural-rubber seals.
# Castor oil: Use as a means of intimidation in Fascist Italy
In Fascist Italy under the regime of Benito Mussolini, castor oil was one of the tools of the blackshirts
Political dissidents were force-fed large quantities of castor oil by Fascist paramilitary groups. This technique was said to have been originated by Gabriele D'Annunzio. Victims of this treatment would experience severe diarrhea and dehydration, often resulting in death
Sometimes when the blackshirts wished to make sure that the victim would die rather than simply be badly disabled, they would mix gasoline with the castor oil.
It is said that Mussolini's power was backed by "the bludgeon and castor oil." In lesser quantities, castor oil was also used as an instrument of intimidation, for example to discourage civilians or soldiers who would call in sick either in the factory or in the military. Since its healing properties were widely exaggerated, abuse could be easily masked under pretense of a doctor's prescription. It took decades after Mussolini's death before the myth of castor oil as a panacea for a wide range of diseases and medical conditions was totally demystified, as it was also widely administered to pregnant women, elderly or mentally-ill patients in hospitals in the false belief that it had no negative side effects.
## Linguistic connotations
Today the Italian terms manganello and olio di ricino, even used separately, still carry strong political connotations and if these words are still used to satirize patronizing politicians or the authors of unpopular legislation, they should be used with caution when engaging in a common conversation. Usare l'olio di ricino, ("to use castor oil") o usare il manganello ("use the bludgeon"), means to coerce or abuse and can be misunderstood in the absence of a proper context. | Castor oil
Castor oil is a vegetable oil obtained from the castor bean (technically castor seed as the castor plant, Ricinus communis, is not a member of the bean family). Castor oil (CAS number 8001-79-4) is a colorless to very pale yellow liquid with mild or no odor or taste. Its boiling point is 313°C and its density is 961 kg·m-3.[1] It is a triglyceride in which approximately ninety percent of fatty acid chains are ricinoleic acid. Oleic and linoleic acids are the other significant components.[2]
The structure of the major component fo castor oil is shown below:
# Background
Ricinoleic acid, a monounsaturated, 18-carbon fatty acid, is unusual in that it has a hydroxyl functional group on the twelfth carbon. This functional group causes ricinoleic acid (and castor oil) to be unusually polar, and also allows chemical derivatization that is not practical with most other seed oils. It is the hydroxyl group which makes castor oil and ricinoleic acid valuable as chemical feedstocks. Compared to other seed oils which lack the hydroxyl group, castor oil demands a higher price. As an example, in July 2007 Indian castor oil sold for about US$0.90 per kilogram (US$0.41 per pound)[3] while US soybean, sunflower and canola oil sold for about US$0.30 per kilogram (US$0.14 per pound)[4]
Castor oil and its derivatives have applications in the manufacturing of soaps, lubricants, hydraulic and brake fluids, paints, dyes, coatings, inks, cold resistant plastics, waxes and polishes, nylon, pharmaceuticals and perfumes.
The castor seed contains ricin, a toxic protein removed by cold pressing and filtering.[5] However, harvesting castor beans is not without risk, [6]
allergenic compounds found on the plant surface can cause permanent nerve damage, making the harvest of castor beans a human health risk. India, Brazil and China are the major crop producers and the workers suffer harmful side effects from working with these plants.[7] These health issues, in addition to concerns about the toxic byproduct (ricin) from castor oil production, have encouraged the quest for alternative, domestic sources for hydroxy fatty acids.[8][9] Alternatively, some researchers are trying to genetically modify the castor plant to prevent the synthesis of ricin.[10]
# Castor oil fatty acids
# Uses
## Castor oil in food
In the food industry, castor oil (food grade) is used in food additives [3], flavorings, candy (i.e., chocolate) [11], as a mold inhibitor, and in packaging. Polyoxyethylated castor oil (eg. Cremophor EL)[12] is also used in the foodstuff industries.[13]
## Medicinal use of castor oil
The United States Food and Drug Administration (FDA) has categorized castor oil as "generally recognized as safe and effective" (GRASE) for over-the-counter use as a laxative.[14] However, it is not a preferred treatment for constipation.[15]
Undecylenic acid, a castor oil derivative, is also FDA-approved for over-the-counter use on skin disorders or skin problems.[16]
Ricinoleic acid is the main component of castor oil and it exerts anti-inflammatory effects.[17]
One study has found that castor oil decreased pain more than ultrasound gel or Vaseline during extracorporeal shock wave application.[18]
Therapeutically, modern drugs are rarely given in a pure chemical state, so most active ingredients are combined with excipients or additives. Castor oil, or a castor oil derivative such as Cremophor EL (polyethoxylated castor oil, a nonionic surfactant), is added to many modern drugs, including:
- Miconazole, an anti-fungal agent;[19][20]
- Paclitaxel, a mitotic inhibitor used in cancer chemotherapy;[21]
- Sandimmune (cyclosporine injection, USP), an immunosuppressant drug widely used in connection with organ transplant to reduce the activity of the patient's immune system;[22]
- Nelfinavir mesylate, an HIV protease inhibitor;[23]
- Saperconazole, a triazole antifungal agent (contains Emulphor EL -719P, a castor oil derivative);[24]
- Prograf, an immunosuppressive drug (contains HCO-60, polyoxyl 60 hydrogenated Castor oil);[citation needed]
- Balsam Peru - Castor oil - and Trypsin Topical (contains castor oil);[25]
- Aci-Jel, a gel used to create or maintain the acidity of the vagina (comprises acetic acid/oxyquinoline/ricinoleic acid - vaginal);[citation needed]
### Traditional or folk medicines
The use of cold pressed castor oil in folk medicine predates government regulations. Cold pressed castor oil is tasteless and odorless when pure. Uses include skin problems, burns, sunburns, skin disorders, skin cuts, abrasions, etc.
The oil is also used as a rub or pack for various ailments, including abdominal complaints, headaches, muscle pains, inflammatory conditions, skin eruptions, lesions, and sinusitis. A castor oil pack is made by soaking a piece of flannel in castor oil, then putting it on the area of complaint and placing a heat source, such as a hot water bottle, on top of it. This remedy was often suggested by the American Healing Psychic, Edgar Cayce, given in many healing readings in the early to mid-1900s.[26]
## Industrial castor oil
Castor oil has numerous applications in transportation, cosmetics and pharmaceutical, and manufacturing industries, for example: adhesives[27], brake fluids [28], caulks, dyes[27], electrical liquid dielectrics, humectants,[27] hydraulic fluids, inks[27], lacquers, leather treatments,[27] lubricating greases, machining oils, paints[27], pigments, polyurethane adhesives [29]
, refrigeration lubricants, rubbers[27], sealants, textiles[27], washing powders, and waxes.
Vegetable oils, due to their good lubricity and biodegradability are attractive alternatives to petroleum-derived lubricants, but oxidative stability and low temperature performance limit their widespread use.[30] Castor oil has better low temperature viscosity properties and high temperature lubrication than most vegetable oils, making it useful as a lubricant in jet, diesel, and race-car engines.[31] However, castor oil tends to form gums in a short time, and its use is therefore restricted to engines that are regularly rebuilt, such as motorcycle race engines. Biodegradability results in decreased persistance in the environment (relative to petroleum-based lubricants[32]) in case of an accidental release. The lubricants company Castrol took its name from castor oil.
Since it is has a relatively high dielectric constant (4.7), highly refined and dried castor oil is sometimes used as a dielectric fluid within high performance high voltage capacitors.
Castor oil is the raw material for the production of a number of chemicals, notably sebacic acid, undecylenic acid, nylon-11. A review listing numerous chemicals derived from castor oil is available.[33]
Castor oil is the preferred lubricant for bicycle pumps, most likely because it doesn't dissolve natural-rubber seals.[34]
# Castor oil: Use as a means of intimidation in Fascist Italy
In Fascist Italy under the regime of Benito Mussolini, castor oil was one of the tools of the blackshirts[35]
[36]
[37] Political dissidents were force-fed large quantities of castor oil by Fascist paramilitary groups. This technique was said to have been originated by Gabriele D'Annunzio. Victims of this treatment would experience severe diarrhea and dehydration, often resulting in death [38]
Sometimes when the blackshirts wished to make sure that the victim would die rather than simply be badly disabled, they would mix gasoline with the castor oil.
It is said that Mussolini's power was backed by "the bludgeon and castor oil." In lesser quantities, castor oil was also used as an instrument of intimidation, for example to discourage civilians or soldiers who would call in sick either in the factory or in the military. Since its healing properties were widely exaggerated, abuse could be easily masked under pretense of a doctor's prescription. It took decades after Mussolini's death before the myth of castor oil as a panacea for a wide range of diseases and medical conditions was totally demystified, as it was also widely administered to pregnant women, elderly or mentally-ill patients in hospitals in the false belief that it had no negative side effects.
## Linguistic connotations
Today the Italian terms manganello and olio di ricino, even used separately, still carry strong political connotations and if these words are still used to satirize patronizing politicians or the authors of unpopular legislation, they should be used with caution when engaging in a common conversation. Usare l'olio di ricino, ("to use castor oil") o usare il manganello ("use the bludgeon"), means to coerce or abuse and can be misunderstood in the absence of a proper context. | https://www.wikidoc.org/index.php/Castor_oil | |
7988f026884d24856ae9a26981284ebc2ed8d32d | wikidoc | Castration | Castration
# Overview
Castration is any action, surgical, chemical, or otherwise, by which a male loses the functions of the testes or a female loses the functions of the ovaries. In common usage the term is usually applied to males, although as a medical term it is applied to both males and females. For more information about female castration, see oophorectomy.
# Castration in Medicine
Testicular cancer is generally treated by surgical removal of the cancerous testicle(s) (orchiectomy), often followed by radiation or chemotherapy. Unless both testicles are cancerous, only one is removed.
Either surgical removal of both testicles or chemical castration may be carried out in the case of prostate cancer , as hormone testosterone-depletion treatment to slow down the cancer. Similarly, testosterone-depletion treatment (either surgical removal of both testicles or chemical castration) is used to greatly reduce sexual drive or interest in those with sexual drives, obsessions, or behaviors, or any combination of those that may be considered deviant. Castration in humans has been proposed, and sometimes used, as a method of birth control in certain poorer regions.
Orchiectomy may be performed as a part of sex reassignment surgery.
### Chemical Castration
Chemical castration is a form of temporary castration caused by hormonal medication. In the case of chemical castration, ongoing regular injections of anti-androgens are administered.
Chemical castration seems to have a greater effect on bone density than physical castration. Since the development of teriparatide, this severe bone loss has been able to be reversed in nearly every case. At this time there is a limitation on the use of this medication to 24 months until the long-term use is better evaluated.
## Medical consequences
A subject of castration who is castrated before the onset of puberty will retain a high voice, non-muscular build, and small genitals. They may well be taller than average, as the production of sex hormones in puberty—particularly testosterone—stops long bone growth. The person may not develop pubic hair and will have a small sex drive or none at all. Castrations after the onset of puberty will typically reduce the sex drive considerably or eliminate it altogether. Also castrated people are automatically sterile, because the testes (for males) and ovaries (for females) produce sex cells needed for sexual reproduction. Once removed the subject is infertile. The voice does not change. Some castrates report mood changes, such as depression or a more serene outlook on life. Body strength and muscle mass can decrease somewhat. Body hair sometimes may decrease. Castration prevents male pattern baldness if it is done before hair is lost; however, castration will not restore hair growth after hair has already been lost due to male pattern baldness. Castration eliminates the risk of testicular cancer.
Without Hormone Replacement Therapy (HRT), typical symptoms (similar to those experienced by menopausal women) include hot flashes; gradual bone-density loss, resulting in osteopenia or osteoporosis; potential weight gain or redistribution of body fat to the hips/chest. Replacement of testosterone in the form of gel, patches, or injections can largely reverse these effects, although breast enlargement has also been reported as a possible side effect of testosterone usage . | Castration
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Castration is any action, surgical, chemical, or otherwise, by which a male loses the functions of the testes or a female loses the functions of the ovaries. In common usage the term is usually applied to males, although as a medical term it is applied to both males and females. For more information about female castration, see oophorectomy.
# Castration in Medicine
Testicular cancer is generally treated by surgical removal of the cancerous testicle(s) (orchiectomy), often followed by radiation or chemotherapy. Unless both testicles are cancerous, only one is removed.
Either surgical removal of both testicles or chemical castration may be carried out in the case of prostate cancer [1], as hormone testosterone-depletion treatment to slow down the cancer. Similarly, testosterone-depletion treatment (either surgical removal of both testicles or chemical castration) is used to greatly reduce sexual drive or interest in those with sexual drives, obsessions, or behaviors, or any combination of those that may be considered deviant. Castration in humans has been proposed, and sometimes used, as a method of birth control in certain poorer regions.
Orchiectomy may be performed as a part of sex reassignment surgery.
### Chemical Castration
Chemical castration is a form of temporary castration caused by hormonal medication. In the case of chemical castration, ongoing regular injections of anti-androgens are administered.
Chemical castration seems to have a greater effect on bone density than physical castration. Since the development of teriparatide, this severe bone loss has been able to be reversed in nearly every case. At this time there is a limitation on the use of this medication to 24 months until the long-term use is better evaluated.
## Medical consequences
A subject of castration who is castrated before the onset of puberty will retain a high voice, non-muscular build, and small genitals. They may well be taller than average, as the production of sex hormones in puberty—particularly testosterone—stops long bone growth. The person may not develop pubic hair and will have a small sex drive or none at all. Castrations after the onset of puberty will typically reduce the sex drive considerably or eliminate it altogether. Also castrated people are automatically sterile, because the testes (for males) and ovaries (for females) produce sex cells needed for sexual reproduction. Once removed the subject is infertile. The voice does not change. Some castrates report mood changes, such as depression or a more serene outlook on life. Body strength and muscle mass can decrease somewhat. Body hair sometimes may decrease. Castration prevents male pattern baldness if it is done before hair is lost; however, castration will not restore hair growth after hair has already been lost due to male pattern baldness. [2] Castration eliminates the risk of testicular cancer.
Without Hormone Replacement Therapy (HRT), typical symptoms (similar to those experienced by menopausal women) include hot flashes; gradual bone-density loss, resulting in osteopenia or osteoporosis; potential weight gain or redistribution of body fat to the hips/chest. Replacement of testosterone in the form of gel, patches, or injections can largely reverse these effects, although breast enlargement has also been reported as a possible side effect of testosterone usage [3]. | https://www.wikidoc.org/index.php/Castration | |
3f21b6c2eaca04085d2ce04cfb1da66abb72adca | wikidoc | Catabiosis | Catabiosis
Catabiosis - the process of growing older, aging and physical degradation.
The word comes from Greek 'kata' - down, against, reverse and 'biosis' - way of life and is generally used to describe senscence and degeneration in living organisms and biophysics of aging in general.
One of the popular catabiotic theories is the entropy theory of aging, where aging is characterized by thermodynamically favourable increase in structural disorder. Living organisms are not closed systems that take free energy from the environment and offload their entropy as waste. However, basic components of living systems: DNA, proteins, lipids and sugars tend towards the state of maximum entropy while continuously accumulating damages causing catabiosis of the living structure.
Catabiotic force on the contrary is the influence exerted by living structures on adjoining cells, by which the latter are developed in harmony with the primary structures. | Catabiosis
Template:AB
Catabiosis - the process of growing older, aging and physical degradation.
The word comes from Greek 'kata' - down, against, reverse and 'biosis' - way of life and is generally used to describe senscence and degeneration in living organisms and biophysics of aging in general.
One of the popular catabiotic theories is the entropy theory of aging, where aging is characterized by thermodynamically favourable increase in structural disorder. Living organisms are not closed systems that take free energy from the environment and offload their entropy as waste. However, basic components of living systems: DNA, proteins, lipids and sugars tend towards the state of maximum entropy while continuously accumulating damages causing catabiosis of the living structure.
Catabiotic force on the contrary is the influence exerted by living structures on adjoining cells, by which the latter are developed in harmony with the primary structures. | https://www.wikidoc.org/index.php/Catabiosis | |
106ca6d7f1be8e07a30496c64ba0478afc8ee7e1 | wikidoc | Catabolism | Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, fatty acids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides and amino acids, respectively. As molecules such as polysaccharides, proteins and nucleic acids are made from long chains of these small monomer units, the large molecules are called polymers.
Cells use the monomers released from breaking down polymers to either construct new polymer molecules, or degrade the monomers further to simple waste products, releasing energy. Cellular wastes include lactic acid, acetic acid, carbon dioxide, ammonia, and urea. The creation of these wastes is usually an oxidation process involving a release of chemical free energy, some of which is lost as heat, but the rest is used to drive the synthesis of adenosine triphosphate (ATP). This molecule acts as a way for the cell to transfer the energy released by catabolism to the energy-requiring reactions that make up anabolism. Catabolism therefore provides the chemical energy necessary for the maintenance and growth of cells. Examples of catabolic processes include glycolysis, the citric acid cycle, the breakdown of muscle protein in order to use amino acids as substrates for gluconeogenesis and breakdown of fat in adipose tissue to fatty acids.
There are many signals that control catabolism. Most of the known signals are hormones and the molecules involved in metabolism itself. Endocrinologists have traditionally classified many of the hormones as anabolic or catabolic, depending on which part of metabolism they stimulate. The "classic" catabolic hormones known since the early 20th century are cortisol, glucagon, and adrenaline (and other catecholamines). In recent decades, many more hormones with at least some catabolic effects have been discovered, including cytokines, orexin and hypocretin (a hormone pair), and melatonin. | Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, fatty acids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides and amino acids, respectively. As molecules such as polysaccharides, proteins and nucleic acids are made from long chains of these small monomer units, the large molecules are called polymers.
Cells use the monomers released from breaking down polymers to either construct new polymer molecules, or degrade the monomers further to simple waste products, releasing energy. Cellular wastes include lactic acid, acetic acid, carbon dioxide, ammonia, and urea. The creation of these wastes is usually an oxidation process involving a release of chemical free energy, some of which is lost as heat, but the rest is used to drive the synthesis of adenosine triphosphate (ATP). This molecule acts as a way for the cell to transfer the energy released by catabolism to the energy-requiring reactions that make up anabolism. Catabolism therefore provides the chemical energy necessary for the maintenance and growth of cells. Examples of catabolic processes include glycolysis, the citric acid cycle, the breakdown of muscle protein in order to use amino acids as substrates for gluconeogenesis and breakdown of fat in adipose tissue to fatty acids.
There are many signals that control catabolism. Most of the known signals are hormones and the molecules involved in metabolism itself. Endocrinologists have traditionally classified many of the hormones as anabolic or catabolic, depending on which part of metabolism they stimulate. The "classic" catabolic hormones known since the early 20th century are cortisol, glucagon, and adrenaline (and other catecholamines). In recent decades, many more hormones with at least some catabolic effects have been discovered, including cytokines, orexin and hypocretin (a hormone pair), and melatonin. | https://www.wikidoc.org/index.php/Catabolic | |
99dcaa67f4ef8d42e1dcb3d32674ef2d18518ee6 | wikidoc | Categories | Categories
# Why put an article in a category?
- At some point it becomes useful to classify the information according to categories. For instance, you might want to add an article on acute MI to the category of cardiology. Acute MI would then be included with all the other articles related to the subject of cardiology in this category. All the articles in a category can come together to forming a living textbook of a given topic.
- Categories are also used to list all the articles that need work for instance, like the addition of an overview statement.
# How to put an article in a category
To add an article to a category, simply add (for each category) a line as follows:
Note (1): The absent space between the colon (:) and the words before it and after it
Note (2): Only the letter in "Category" and the first letter in the category name are capitalized
Typing this:
Note: Only the first letter in the first word is capitalized , but the first letter in the second word is not capitalized
Adds the page to the Category of Cardiology chapters and Vascular medicine chapters, respectively.
It is convention to insert these lines near the bottom of the wiki page. Once your edit is saved, the category will exist and add the article you just edited will be added to it.
# Approved Categories for Tagging Chapter Pages | Categories
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Why put an article in a category?
- At some point it becomes useful to classify the information according to categories. For instance, you might want to add an article on acute MI to the category of cardiology. Acute MI would then be included with all the other articles related to the subject of cardiology in this category. All the articles in a category can come together to forming a living textbook of a given topic.
- Categories are also used to list all the articles that need work for instance, like the addition of an overview statement.
# How to put an article in a category
To add an article to a category, simply add (for each category) a line as follows:
[[Category:Name of category]]
Note (1): The absent space between the colon (:) and the words before it and after it
Note (2): Only the letter [C] in "Category" and the first letter in the category name are capitalized
Typing this:
[[Category:Cardiology]]
[[Category:Vascular medicine]]
Note: Only the first letter in the first word is capitalized [V], but the first letter in the second word is not capitalized [m]
Adds the page to the Category of Cardiology chapters and Vascular medicine chapters, respectively.
It is convention to insert these lines near the bottom of the wiki page. Once your edit is saved, the category will exist and add the article you just edited will be added to it.
# Approved Categories for Tagging Chapter Pages
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Categories | |
77f1f8f704170b3c274e7b99f5521bfb28fb93d2 | wikidoc | Causticity | Causticity
A corrosive substance is one that will destroy or irreversibly damage another substance with which it comes in contact. The main hazards to people include damage to eyes, skin and tissue under the skin, but inhalation or ingestion of a corrosive substance can damage the respiratory and gastrointestinal tracts.
A low concentration of a corrosive substance is usually an irritant. Corrosion of non-living surfaces such as metals is a distinct process. For example, a water/air electrochemical cell corrodes iron to rust. In the Globally Harmonized System, both rapid corrosion of metals and chemical corrosion of skin qualify for the "corrosive" symbol.
Common corrosives are strong acids and strong bases, or concentrated solutions of certain weak acids and weak bases. Their action on living tissue is based on acid-base catalysis of ester and amide hydrolysis. Both corrosive acids and corrosive bases are able to defat skin by catalyzing the hydrolysis of fats, which are chemically esters). Proteins are chemically amides, which can also be hydrolyzed by acid-base catalysis. Strong acids and bases denature proteins and also hydrate easily. Hydration removes water from the tissue and is significantly exothermic. For example, concentrated sulfuric acid causes thermal burns in addition to chemical burns.
There are also more specific corrosives. Hydrofluoric acid, for example, is initially painless but easily permeates tissue to selectively attack bone. Although zinc chloride solutions are also regularly acidic (by the Brønsted definition), the zinc cation also specifically attacks hydroxyl groups as a Lewis acid. This explains the ability of zinc chloride solutions to react with cellulose and corrode through paper and silk.
The word 'corrosion' is derived from the latin verb corrode which means 'to gnaw' indicating how these substance seem to 'gnaw' their way through the flesh.
# Corrosive substances
Common corrosive chemicals are classified into:
- Acids
- Strong acids — the most common are sulfuric acid, nitric acid and hydrochloric acid (H2SO4, HNO3 and HCl, respectively).
- Some concentrated weak acids, for example acetic acid
- Solutions of Lewis acids with specific reactivity, e.g. solutions of zinc chloride
- Bases
- Caustics or alkalis, such as sodium hydroxide (NaOH) and potassium hydroxide (KOH); also, alkali metals in the metallic form hydrate to give caustics
- Some concentrated weak bases, such as ammonia when anhydrous or in a concentrated solution
- Dehydrating agents such as phosphorus pentoxide, calcium oxide, anhydrous zinc chloride, also elemental alkali metals
- Electrophilic halogens: elemental fluorine, chlorine, bromine and iodine, and electrophilic salts such as sodium hypochlorite or N-chloro compounds such as chloramine-T; anionic halogens as in chlorides are not corrosive
- Organic halides and organic acid halides such as acetyl chloride and benzyl chloroformate
- Acid anhydrides
- Some organic materials such as phenol ("carbolic acid")
- Extremely electrophilic reagents such as dimethyl sulfate | Causticity
A corrosive substance is one that will destroy or irreversibly damage another substance with which it comes in contact. The main hazards to people include damage to eyes, skin and tissue under the skin, but inhalation or ingestion of a corrosive substance can damage the respiratory and gastrointestinal tracts.
A low concentration of a corrosive substance is usually an irritant. Corrosion of non-living surfaces such as metals is a distinct process. For example, a water/air electrochemical cell corrodes iron to rust. In the Globally Harmonized System, both rapid corrosion of metals and chemical corrosion of skin qualify for the "corrosive" symbol.
Common corrosives are strong acids and strong bases, or concentrated solutions of certain weak acids and weak bases. Their action on living tissue is based on acid-base catalysis of ester and amide hydrolysis. Both corrosive acids and corrosive bases are able to defat skin by catalyzing the hydrolysis of fats, which are chemically esters). Proteins are chemically amides, which can also be hydrolyzed by acid-base catalysis. Strong acids and bases denature proteins and also hydrate easily. Hydration removes water from the tissue and is significantly exothermic. For example, concentrated sulfuric acid causes thermal burns in addition to chemical burns.
There are also more specific corrosives. Hydrofluoric acid, for example, is initially painless but easily permeates tissue to selectively attack bone. Although zinc chloride solutions are also regularly acidic (by the Brønsted definition), the zinc cation also specifically attacks hydroxyl groups as a Lewis acid. This explains the ability of zinc chloride solutions to react with cellulose and corrode through paper and silk.
The word 'corrosion' is derived from the latin verb corrode which means 'to gnaw' indicating how these substance seem to 'gnaw' their way through the flesh.
# Corrosive substances
Common corrosive chemicals are classified into:
- Acids
- Strong acids — the most common are sulfuric acid, nitric acid and hydrochloric acid (H2SO4, HNO3 and HCl, respectively).
- Some concentrated weak acids, for example acetic acid
- Solutions of Lewis acids with specific reactivity, e.g. solutions of zinc chloride
- Bases
- Caustics or alkalis, such as sodium hydroxide (NaOH) and potassium hydroxide (KOH); also, alkali metals in the metallic form hydrate to give caustics
- Some concentrated weak bases, such as ammonia when anhydrous or in a concentrated solution
- Dehydrating agents such as phosphorus pentoxide, calcium oxide, anhydrous zinc chloride, also elemental alkali metals
- Electrophilic halogens: elemental fluorine, chlorine, bromine and iodine, and electrophilic salts such as sodium hypochlorite or N-chloro compounds such as chloramine-T[1]; anionic halogens as in chlorides are not corrosive
- Organic halides and organic acid halides such as acetyl chloride and benzyl chloroformate
- Acid anhydrides
- Some organic materials such as phenol ("carbolic acid")
- Extremely electrophilic reagents such as dimethyl sulfate | https://www.wikidoc.org/index.php/Caustic | |
92bd54d7064633198c3b408712c825790db294ca | wikidoc | Caveolin 2 | Caveolin 2
Caveolin-2 is a protein that in humans is encoded by the CAV2 gene.
The protein encoded by this gene is a major component of the inner surface of caveolae, small invaginations of the plasma membrane, and is involved in essential cellular functions, including signal transduction, lipid metabolism, cellular growth control and apoptosis. This protein may function as a tumor suppressor. CAV1 and CAV2 are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex. Two transcript variants encoding distinct isoforms have been identified for this gene. By using alternative initiation codons in the same reading frame, two isoforms (alpha and beta) are encoded by one transcript.
# Interactions
Caveolin 2 has been shown to interact with Caveolin 1 and RAS p21 protein activator 1. | Caveolin 2
Caveolin-2 is a protein that in humans is encoded by the CAV2 gene.[1][2][3]
The protein encoded by this gene is a major component of the inner surface of caveolae, small invaginations of the plasma membrane, and is involved in essential cellular functions, including signal transduction, lipid metabolism, cellular growth control and apoptosis. This protein may function as a tumor suppressor. CAV1 and CAV2 are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex. Two transcript variants encoding distinct isoforms have been identified for this gene. By using alternative initiation codons in the same reading frame, two isoforms (alpha and beta) are encoded by one transcript.[3]
# Interactions
Caveolin 2 has been shown to interact with Caveolin 1[4][5] and RAS p21 protein activator 1.[6] | https://www.wikidoc.org/index.php/Caveolin_2 | |
92fe810ce4402f806a97dd332bdeeeca26c447ca | wikidoc | Caveolin 3 | Caveolin 3
Caveolin-3 is a protein that in humans is encoded by the CAV3 gene. Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites.
# Function
This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules.
# Clinical significance
Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), HyperCKemia, distal myopathy or rippling muscle disease (RMD). Other mutations in Caveolin causes Long QT Syndrome or familial hypertrophic cardiomyopathy, although the role of Cav3 in Long QT syndrome has recently been disputed.
# Interactions
Caveolin 3 has been shown to interact with a range of different proteins, including, but not limited to:
- DAG1,
- DYSF,
- EGFR, and
- RYR1.
# Structure
Using transmission electron microscopy and single particle analysis methods, it has been shown that nine Caveolin-3 monomers assemble to form a complex that is toroidal in shape, ∼16.5 nm in diameter and ∼5.5 nm in height.
# Cardiac physiology
Caveolin-3 is one of three isoforms of the protein caveolin. Caveolin-3 is concentrated in the caveolae of myocytes, and modulates numerous metabolic processes including: nitric oxide synthesis, cholesterol metabolism, and cardiac myocytes contraction. There are many proteins that associate with caveolin-3, including ion channels and exchangers.
## Associations with ion channels
### ATP-dependent potassium channels
In cardiac myocytes, caveolin-3 negatively regulates ATP-dependent potassium channels (KATP) localized in caveolae. KATP channel opening decreases significantly when interacting with caveolin-3; other isoforms of caveolin do not show this type of effect on KATP channels. The amount of KATP activation during times of biological stress influences the amount of cellular damage that will occur, thus regulation of caveolin-3 expression during these times influences the amount of cellular damage.
### Sodium-calcium exchanger
Caveolin-3 associates with the cardiac sodium-calcium exchanger (NCX) in caveolae of cardiac myocytes. This association occurs predominately in areas proximate to the peripheral membrane of cardiac myocytes. Interactions between caveolin-3 and cardiac NCX influence NCX-regulation of cellular signaling factors and excitation of cardiac myocytes.
### L-Type calcium channel
Caveolin-3 influences the opening of L-Type calcium channels (LTCC) which play a role in cardiac myocyte contraction. Disruption of interactions between caveolin-3 and its associated binding proteins has been shown to affect LTCC. Specifically, disruption of caveolin-3 decreases the basal and b2-adrenergic-stimulated opening probabilities of LTCC. This occurs by changing the PKA-mediated phosphorylation of caveolin-3-associated binding proteins, causing negative down-stream effects on LTCC activity.
## Implications in disease
Alterations in caveolin-3 expression have been implicated in the altered expression and regulation of numerous signaling molecules involved in cardiomyopathies. Disruption of caveolin-3 disturbs the structure of cardiac caveolae and blocks atrial natriuretic peptide (ANP) expression, a cardiac-related hormone involved in many functions including maintaining cellular homeostasis. Normal caveolin-3 expression under conditions of stress increases cardiac cellular levels of ANP, maintaining cardiac homeostasis. Mutations have been identified in the caveolin-3 gene that result in cardiomyopathies. Several of these mutations influence caveolin-3 function by reducing the expression of its cell-surface domains. Mutations resulting in loss-of-function of caveolin-3 cause cardiac myocyte hypertrophy, dilation of the heart, and depression of fractional shortening. Knockout of caveolin-3 genes are sufficient to induce these manifestations. Similarly, dominant-negative genotypes for caveolin-3 increase cardiac hypertrophy, whereas increased expression of caveolin-3 inhibits the ability of the heart to hypertrophy, implicating caveolin-3 as a negative regulator of cardiac hypertrophy. Overexpression of caveolin-3 leads to the development of cardiomyopathy, resulting in degeneration of cardiac tissue and manifesting pathologies due to the associated degeneration. | Caveolin 3
Caveolin-3 is a protein that in humans is encoded by the CAV3 gene.[1][2][3] Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites.
# Function
This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules.[3]
# Clinical significance
Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), HyperCKemia, distal myopathy or rippling muscle disease (RMD). Other mutations in Caveolin causes Long QT Syndrome or familial hypertrophic cardiomyopathy, although the role of Cav3 in Long QT syndrome has recently been disputed.[3][4]
# Interactions
Caveolin 3 has been shown to interact with a range of different proteins, including, but not limited to:
- DAG1,[5]
- DYSF,[6]
- EGFR,[7] and
- RYR1.[8]
# Structure
Using transmission electron microscopy and single particle analysis methods, it has been shown that nine Caveolin-3 monomers assemble to form a complex that is toroidal in shape, ∼16.5 nm in diameter and ∼5.5 nm in height.[9]
# Cardiac physiology
Caveolin-3 is one of three isoforms of the protein caveolin.[10] Caveolin-3 is concentrated in the caveolae of myocytes, and modulates numerous metabolic processes including: nitric oxide synthesis, cholesterol metabolism, and cardiac myocytes contraction.[10][11][12] There are many proteins that associate with caveolin-3, including ion channels and exchangers.[10][13][14][15][16][17][18][19]
## Associations with ion channels
### ATP-dependent potassium channels
In cardiac myocytes, caveolin-3 negatively regulates ATP-dependent potassium channels (KATP) localized in caveolae.[14] KATP channel opening decreases significantly when interacting with caveolin-3; other isoforms of caveolin do not show this type of effect on KATP channels. The amount of KATP activation during times of biological stress influences the amount of cellular damage that will occur, thus regulation of caveolin-3 expression during these times influences the amount of cellular damage.[14]
### Sodium-calcium exchanger
Caveolin-3 associates with the cardiac sodium-calcium exchanger (NCX) in caveolae of cardiac myocytes.[10][20] This association occurs predominately in areas proximate to the peripheral membrane of cardiac myocytes.[20] Interactions between caveolin-3 and cardiac NCX influence NCX-regulation of cellular signaling factors and excitation of cardiac myocytes.[10]
### L-Type calcium channel
Caveolin-3 influences the opening of L-Type calcium channels (LTCC) which play a role in cardiac myocyte contraction.[13] Disruption of interactions between caveolin-3 and its associated binding proteins has been shown to affect LTCC.[13] Specifically, disruption of caveolin-3 decreases the basal and b2-adrenergic-stimulated opening probabilities of LTCC.[13] This occurs by changing the PKA-mediated phosphorylation of caveolin-3-associated binding proteins, causing negative down-stream effects on LTCC activity.[13]
## Implications in disease
Alterations in caveolin-3 expression have been implicated in the altered expression and regulation of numerous signaling molecules involved in cardiomyopathies.[17] Disruption of caveolin-3 disturbs the structure of cardiac caveolae and blocks atrial natriuretic peptide (ANP) expression, a cardiac-related hormone involved in many functions including maintaining cellular homeostasis.[17][21] Normal caveolin-3 expression under conditions of stress increases cardiac cellular levels of ANP, maintaining cardiac homeostasis.[17] Mutations have been identified in the caveolin-3 gene that result in cardiomyopathies.[16] Several of these mutations influence caveolin-3 function by reducing the expression of its cell-surface domains.[15] Mutations resulting in loss-of-function of caveolin-3 cause cardiac myocyte hypertrophy, dilation of the heart, and depression of fractional shortening.[18][19] Knockout of caveolin-3 genes are sufficient to induce these manifestations.[21] Similarly, dominant-negative genotypes for caveolin-3 increase cardiac hypertrophy, whereas increased expression of caveolin-3 inhibits the ability of the heart to hypertrophy, implicating caveolin-3 as a negative regulator of cardiac hypertrophy.[18][19] Overexpression of caveolin-3 leads to the development of cardiomyopathy, resulting in degeneration of cardiac tissue and manifesting pathologies due to the associated degeneration.[15] | https://www.wikidoc.org/index.php/Caveolin_3 | |
dcc2e9062c763a6d5e799a698a5f994ce3eb66ea | wikidoc | Cavitation | Cavitation
Cavitation is a general term used to describe the behavior of voids or bubbles in a liquid. Cavitation is usually divided into two classes of behavior: inertial (or transient) cavitation and non-inertial cavitation. Inertial cavitation is the process where a void or bubble in a liquid rapidly collapses, producing a shock wave. Such cavitation often occurs in pumps, propellers, impellers, and in the vascular tissues of plants. Non-inertial cavitation is the process where a bubble in a fluid is forced to oscillate in size or shape due to some form of energy input, such as an acoustic field. Such cavitation is often employed in ultrasonic cleaning baths and can also be observed in pumps, propellers etc.
# Inertial cavitation
Inertial cavitation was first studied by Lord Rayleigh in the late 19th century when he considered the collapse of a spherical void within a liquid.
When a volume of liquid is subjected to a sufficiently low pressure it may rupture and form a cavity. This phenomenon is termed cavitation inception and may occur behind the blade of a rapidly rotating propeller or on any surface vibrating underwater with sufficient amplitude and acceleration. Other ways of generating cavitation voids involve the local deposition of energy such as an intense focussed laser pulse (optic cavitation) or with an electrical discharge through a spark. Vapor gasses evaporate into the cavity from the surrounding medium, thus the cavity is not a perfect vacuum but has a relatively low gas pressure. Such a low pressure cavitation bubble in a liquid will begin to collapse due to the higher pressure of the surrounding medium. As the bubble collapses, the pressure and temperature of the vapor within will increase. The bubble will eventually collapse to a minute fraction of its original size, at which point the gas within dissipates into the surrounding liquid via a rather violent mechanism, which releases a significant amount of energy in the form of an acoustic shock-wave and as visible light. At the point of total collapse, the temperature of the vapor within the bubble may be several thousand kelvin, and the pressure several hundred atmospheres.
Inertial cavitation can also occur in the presence of an acoustic field. Microscopic gas bubbles which are generally present in a liquid will be forced to oscillate due to an applied acoustic field. If the acoustic intensity is sufficiently high, the bubbles will first grow in size, and then rapidly collapse. Hence, inertial cavitation can occur even if the rarefaction in the liquid is insufficient for a Rayleigh-like void to occur. High power ultrasonics usually utilize the inertial cavitation of microscopic vacuum bubbles for treatment of surfaces, liquids and slurries.
The physical process of cavitation inception is similar to boiling. The major difference between the two is the thermodynamic paths which precede the formation of the vapor. Boiling occurs when the local vapor pressure of the liquid rises above its local ambient pressure and sufficient energy is present to cause the phase change to a gas. Cavitation inception occurs when the local pressure falls sufficiently far below the saturated vapor pressure, a value given by the tensile strength of the liquid.
In order for cavitation inception to occur, the cavitation "bubbles" generally need a surface on which they can nucleate. This surface can be provided by the sides of a container or by impurities in the liquid or by small undissolved microbubble within the liquid. It is generally accepted that hydrophobic surfaces stabilize small bubbles. These pre-existing bubbles start to grow unbounded when they are exposed to a pressure below the threshold pressure, termed Blake's threshold.
# Non-inertial cavitation
Non-inertial cavitation is the process where small bubbles in a liquid are forced to oscillate in the presence of an acoustic field, when the intensity of the acoustic field is insufficient to cause total bubble collapse. This form of cavitation causes significantly less erosion than inertial cavitation, and is often used for the cleaning of delicate materials, such as silicon wafers.
# Problems
Cavitation is, in many cases, an undesirable occurrence. In devices such as propellers and pumps, cavitation causes a great deal of noise, damage to components, vibrations, and a loss of efficiency.
When the cavitation bubbles collapse, they force liquid energy to very small volumes, thereby creating spots of high temperature and emitting shock waves, the latter of which a source of noise. The noise created by cavitation is a particular problem for military submarines, as it increases the chances of being detected by sonar.
Although the collapse of a cavity is a relatively low energy event, highly localized collapses can erode metals, such as steel, over time. The pitting caused by the collapse of cavities produces great wear on components and can dramatically shorten a propeller or pump's lifetime.
In industry, cavitation is often used to homogenize, or mix and break down suspended particles in a colloidal liquid compound, such as paint mixtures, or milk. Many industrial mixing machines are based upon this design principle. It is usually achieved through impeller design, or by forcing the mixture through an annular opening that has a narrow entrance orifice with a much larger exit orifice. In the latter case, the drastic decrease in pressure as the liquid accelerates into a larger volume induces cavitation. This method can be controlled with hydraulic devices that control inlet orifice size, allowing for dynamic adjustment during the process, or modification for different substances. The outer surface of this type of mixing valve, upon which the cavitation bubbles are driven against to cause their implosion, undergoes tremendous stress, and is often constructed of super-hard or tough materials such as stainless steel, Stellite, or even polycrystalline diamond (PCD).
Cavitating water purification devices have also been designed, in which the extreme conditions of cavitation can break down pollutants and organic molecules. Spectral analysis of light emitted in sonochemical reactions reveal chemical and plasma based mechanisms of energy transfer. The light emitted from cavitation bubbles is termed sonoluminesence.
Hydrophobic chemicals are attracted underwater by cavitation as the pressure difference between the bubbles and the liquid water forces them to join together. This effect may assist in protein folding.
# Biomedical application
Cavitation plays an important role for the destruction of kidney stones in shock wave lithotripsy. Currently it is tested if cavitation can be used to transfer large molecules into biological cells (sonoporation). Nitrogen cavitation is a method used in research to lyse cell membranes while leaving organelles intact.
Cavitation also probably plays a role in HIFU, a non-invasive treatment methodology for cancer.
# Pumps and propellers
Major places where cavitation occurs are in pumps, on propellers, or at restrictions in a flowing liquid.
As an impeller's (in a pump), or propeller's (as in the case of a ship or submarine) blades move through a fluid, low pressure areas are formed as the fluid accelerates around and moves past the blades. The faster the blades move, the lower the pressure around it can become. As it reaches vapor pressure, the fluid vaporizes and forms small bubbles of gas. This is cavitation. When the bubbles collapse later, they typically cause very strong local shockwaves in the fluid, which may be audible and may even damage the blades.
Cavitation in pumps may occur in two different forms:
## Suction cavitation
Suction cavitation occurs when the pump suction is under a low pressure/high vacuum condition where the liquid turns into a vapor at the eye of the pump impeller. This vapor is carried over to the discharge side of the pump where it no longer sees vacuum and is compressed back into a liquid by the discharge pressure. This imploding action occurs violently and attacks the face of the impeller. An impeller that has been operating under a suction cavitation condition can have large chunks of material removed from its face or very small bits of material removed causing the impeller to look sponge like. Both cases will cause premature failure of the pump often due to bearing failure. Suction cavitation is often identified by a sound like gravel or marbles in the pump casing.
## Discharge cavitation
Discharge cavitation occurs when the pump discharge pressure is extremely high, normally occurring in a pump that is running at less than 10% of its best efficiency point. The high discharge pressure causes the majority of the fluid to circulate inside the pump instead of being allowed to flow out the discharge. As the liquid flows around the impeller it must pass through the small clearance between the impeller and the pump cutwater at extremely high velocity. This velocity causes a vacuum to develop at the cutwater (similar to what occurs in a venturi) which turns the liquid into a vapor. A pump that has been operating under these conditions shows premature wear of the impeller vane tips and the pump cutwater. In addition, due to the high pressure conditions, premature failure of the pump's mechanical seal and bearings can be expected. Under extreme conditions, this can break the impeller shaft.
Discharge cavitation is believed to be the cause of the cracking of joints.
# Cavitation in engines
Some bigger diesel engines suffer from cavitation due to high compression and undersized cylinder walls. Vibrations of the cylinder wall induce alternating low and high pressure in the coolant against the cylinder wall. The result is pitting of the cylinder wall that will eventually let cooling fluid leak into the cylinder and combustion gases to leak into the coolant.
It is possible to prevent this from happening with chemical additives in the cooling fluid that form a protecting layer on the cylinder wall. This layer will be exposed to the same cavitation, but rebuilds itself.
# Vascular plants
Cavitation occurs in the xylem of vascular plants when the water potential becomes so great that dissolved air within the water expands to fill the plant cell - either vessel elements or tracheids. Plants are generally able to repair cavitated xylem, for example with root pressure, but for others such as vines, cavitation often leads to mortality. In some trees, the sound of the cavitation is clearly audible.
In the autumn the dropping temperature increases the formation of air bubbles in the tracheids of some plant species, causing them to drop their leaves.
# Marine Life
Just as cavitation bubbles form on a fast spinning boat propeller, they may also form on the tails and fins of aquatic animals. The effects of cavitation are especially important near the surface of the ocean where the ambient water pressure is relatively low and cavitation is more likely to occur.
For powerful swimming animals like dolphins and tuna, cavitation may be detrimental because it limits their maximum swimming speed. Even if they have the power to swim faster, dolphins may have to restrict their speed because collapsing cavitation bubbles on their tail are too painful. Cavitation also slows tuna, but for a different reason. Unlike dolphins, these fish do not feel the painful bubbles because they have bony fins without nerve endings. Nevertheless they cannot swim faster because the cavitation bubbles create an air film around their fins that limits their speed. Lesions have been found on tuna that are consistent with cavitation damage.
Cavitation is not always a limitation for sea life. Some animals have found ways to use it to their advantage when hunting prey. The pistol shrimp snaps a specialized claw to create cavitation, which can kill small fish. The mantis shrimp (type smasher) uses cavitation as well in order to stun, smash open, or kill the shellfish that it feasts upon.
# Coastal erosion
In the last half a decade, coastal erosion in the form of inertial cavitation has been generally accepted. Air pockets in an incoming wave are forced into cracks in the cliff being eroded, the force of the wave then compresses the air pockets until the bubble implodes, becoming liquid, giving off various forms of energy which blast apart the rock.
# List of cavitation tunnels
## Canada
- National Research Council - Institute for Ocean Technology Cavitation Tunnel, , St. Johns, Newfoundland, Canada
## France
- "Tunnel de Cavitation" Ecole Navale , Lanveoc
- "Grand Tunnel Hydrodynamique" Bassin d'Essais des Carènes , Val de Reuil
## Germany
- Multiple cavitation tunnels at the Versuchsanstalt für Wasserbau und Schiffbau , Berlin
- Large Cavitation tunnel at Hamburg Ship Model Basin ,Hamburg
## Iran
- Applied Hydrodynamics Laboratory, Iran University of Science and Technology, , Narmak, Tehran, Iran.
## Netherlands
- Large Cavitation Tunnel and High Speed Cavitation Tunnel at the Maritime Research Institute, Wageningen.
## Norway
- "Cavitation Lab" NTNU, The Norwegian University of Science and Technology , Trondheim
## Poland
- Ship Design and Research Centre (CTO S.A.) Centrum Techniki Okrętowej S.A., , Gdansk, Poland.
## South Korea
- Samsung Ship Model Basin (SSMB), Samsung Heavy Industries, , Daejeon, South Korea.
## Sweden
- SSPA
## Taiwan
- The Large Cavitation Tunnel at National Taiwan Ocean University, Keelung, Taiwan
## United Kingdom
- "Emerson Cavitation Tunnel," University of Newcastle upon Tyne.
## United States
- The Garfield Thomas Water Tunnel The Pennsylvania State University , State College, PA
- The William B. Morgan Large Cavitation Channel , Memphis, TN
- MIT's variable pressure water tunnel | Cavitation
Cavitation is a general term used to describe the behavior of voids or bubbles in a liquid. Cavitation is usually divided into two classes of behavior: inertial (or transient) cavitation and non-inertial cavitation. Inertial cavitation is the process where a void or bubble in a liquid rapidly collapses, producing a shock wave. Such cavitation often occurs in pumps, propellers, impellers, and in the vascular tissues of plants. Non-inertial cavitation is the process where a bubble in a fluid is forced to oscillate in size or shape due to some form of energy input, such as an acoustic field. Such cavitation is often employed in ultrasonic cleaning baths and can also be observed in pumps, propellers etc.
# Inertial cavitation
Inertial cavitation was first studied by Lord Rayleigh in the late 19th century when he considered the collapse of a spherical void within a liquid.
When a volume of liquid is subjected to a sufficiently low pressure it may rupture and form a cavity. This phenomenon is termed cavitation inception and may occur behind the blade of a rapidly rotating propeller or on any surface vibrating underwater with sufficient amplitude and acceleration. Other ways of generating cavitation voids involve the local deposition of energy such as an intense focussed laser pulse (optic cavitation) or with an electrical discharge through a spark. Vapor gasses evaporate into the cavity from the surrounding medium, thus the cavity is not a perfect vacuum but has a relatively low gas pressure. Such a low pressure cavitation bubble in a liquid will begin to collapse due to the higher pressure of the surrounding medium. As the bubble collapses, the pressure and temperature of the vapor within will increase. The bubble will eventually collapse to a minute fraction of its original size, at which point the gas within dissipates into the surrounding liquid via a rather violent mechanism, which releases a significant amount of energy in the form of an acoustic shock-wave and as visible light. At the point of total collapse, the temperature of the vapor within the bubble may be several thousand kelvin, and the pressure several hundred atmospheres.
Inertial cavitation can also occur in the presence of an acoustic field. Microscopic gas bubbles which are generally present in a liquid will be forced to oscillate due to an applied acoustic field. If the acoustic intensity is sufficiently high, the bubbles will first grow in size, and then rapidly collapse. Hence, inertial cavitation can occur even if the rarefaction in the liquid is insufficient for a Rayleigh-like void to occur. High power ultrasonics usually utilize the inertial cavitation of microscopic vacuum bubbles for treatment of surfaces, liquids and slurries.
The physical process of cavitation inception is similar to boiling. The major difference between the two is the thermodynamic paths which precede the formation of the vapor. Boiling occurs when the local vapor pressure of the liquid rises above its local ambient pressure and sufficient energy is present to cause the phase change to a gas. Cavitation inception occurs when the local pressure falls sufficiently far below the saturated vapor pressure, a value given by the tensile strength of the liquid.
In order for cavitation inception to occur, the cavitation "bubbles" generally need a surface on which they can nucleate. This surface can be provided by the sides of a container or by impurities in the liquid or by small undissolved microbubble within the liquid. It is generally accepted that hydrophobic surfaces stabilize small bubbles. These pre-existing bubbles start to grow unbounded when they are exposed to a pressure below the threshold pressure, termed Blake's threshold.
# Non-inertial cavitation
Non-inertial cavitation is the process where small bubbles in a liquid are forced to oscillate in the presence of an acoustic field, when the intensity of the acoustic field is insufficient to cause total bubble collapse. This form of cavitation causes significantly less erosion than inertial cavitation, and is often used for the cleaning of delicate materials, such as silicon wafers.
# Problems
Cavitation is, in many cases, an undesirable occurrence. In devices such as propellers and pumps, cavitation causes a great deal of noise, damage to components, vibrations, and a loss of efficiency.
When the cavitation bubbles collapse, they force liquid energy to very small volumes, thereby creating spots of high temperature and emitting shock waves, the latter of which a source of noise. The noise created by cavitation is a particular problem for military submarines, as it increases the chances of being detected by sonar.
Although the collapse of a cavity is a relatively low energy event, highly localized collapses can erode metals, such as steel, over time. The pitting caused by the collapse of cavities produces great wear on components and can dramatically shorten a propeller or pump's lifetime.
In industry, cavitation is often used to homogenize, or mix and break down suspended particles in a colloidal liquid compound, such as paint mixtures, or milk. Many industrial mixing machines are based upon this design principle. It is usually achieved through impeller design, or by forcing the mixture through an annular opening that has a narrow entrance orifice with a much larger exit orifice. In the latter case, the drastic decrease in pressure as the liquid accelerates into a larger volume induces cavitation. This method can be controlled with hydraulic devices that control inlet orifice size, allowing for dynamic adjustment during the process, or modification for different substances. The outer surface of this type of mixing valve, upon which the cavitation bubbles are driven against to cause their implosion, undergoes tremendous stress, and is often constructed of super-hard or tough materials such as stainless steel, Stellite, or even polycrystalline diamond (PCD).
Cavitating water purification devices have also been designed, in which the extreme conditions of cavitation can break down pollutants and organic molecules. Spectral analysis of light emitted in sonochemical reactions reveal chemical and plasma based mechanisms of energy transfer. The light emitted from cavitation bubbles is termed sonoluminesence.
Hydrophobic chemicals are attracted underwater by cavitation as the pressure difference between the bubbles and the liquid water forces them to join together. This effect may assist in protein folding.[1]
# Biomedical application
Cavitation plays an important role for the destruction of kidney stones in shock wave lithotripsy. Currently it is tested if cavitation can be used to transfer large molecules into biological cells (sonoporation). Nitrogen cavitation is a method used in research to lyse cell membranes while leaving organelles intact.
Cavitation also probably plays a role in HIFU, a non-invasive treatment methodology for cancer.
# Pumps and propellers
Major places where cavitation occurs are in pumps, on propellers, or at restrictions in a flowing liquid.
As an impeller's (in a pump), or propeller's (as in the case of a ship or submarine) blades move through a fluid, low pressure areas are formed as the fluid accelerates around and moves past the blades. The faster the blades move, the lower the pressure around it can become. As it reaches vapor pressure, the fluid vaporizes and forms small bubbles of gas. This is cavitation. When the bubbles collapse later, they typically cause very strong local shockwaves in the fluid, which may be audible and may even damage the blades.
Cavitation in pumps may occur in two different forms:
## Suction cavitation
Suction cavitation occurs when the pump suction is under a low pressure/high vacuum condition where the liquid turns into a vapor at the eye of the pump impeller. This vapor is carried over to the discharge side of the pump where it no longer sees vacuum and is compressed back into a liquid by the discharge pressure. This imploding action occurs violently and attacks the face of the impeller. An impeller that has been operating under a suction cavitation condition can have large chunks of material removed from its face or very small bits of material removed causing the impeller to look sponge like. Both cases will cause premature failure of the pump often due to bearing failure. Suction cavitation is often identified by a sound like gravel or marbles in the pump casing.
## Discharge cavitation
Discharge cavitation occurs when the pump discharge pressure is extremely high, normally occurring in a pump that is running at less than 10% of its best efficiency point. The high discharge pressure causes the majority of the fluid to circulate inside the pump instead of being allowed to flow out the discharge. As the liquid flows around the impeller it must pass through the small clearance between the impeller and the pump cutwater at extremely high velocity. This velocity causes a vacuum to develop at the cutwater (similar to what occurs in a venturi) which turns the liquid into a vapor. A pump that has been operating under these conditions shows premature wear of the impeller vane tips and the pump cutwater. In addition, due to the high pressure conditions, premature failure of the pump's mechanical seal and bearings can be expected. Under extreme conditions, this can break the impeller shaft.
Discharge cavitation is believed to be the cause of the cracking of joints.
# Cavitation in engines
Some bigger diesel engines suffer from cavitation due to high compression and undersized cylinder walls. Vibrations of the cylinder wall induce alternating low and high pressure in the coolant against the cylinder wall. The result is pitting of the cylinder wall that will eventually let cooling fluid leak into the cylinder and combustion gases to leak into the coolant.
It is possible to prevent this from happening with chemical additives in the cooling fluid that form a protecting layer on the cylinder wall. This layer will be exposed to the same cavitation, but rebuilds itself.
# Vascular plants
Cavitation occurs in the xylem of vascular plants when the water potential becomes so great that dissolved air within the water expands to fill the plant cell - either vessel elements or tracheids. Plants are generally able to repair cavitated xylem, for example with root pressure, but for others such as vines, cavitation often leads to mortality. In some trees, the sound of the cavitation is clearly audible.
In the autumn the dropping temperature increases the formation of air bubbles in the tracheids of some plant species, causing them to drop their leaves.
# Marine Life
Just as cavitation bubbles form on a fast spinning boat propeller, they may also form on the tails and fins of aquatic animals. The effects of cavitation are especially important near the surface of the ocean where the ambient water pressure is relatively low and cavitation is more likely to occur.
For powerful swimming animals like dolphins and tuna, cavitation may be detrimental because it limits their maximum swimming speed.[2] Even if they have the power to swim faster, dolphins may have to restrict their speed because collapsing cavitation bubbles on their tail are too painful. Cavitation also slows tuna, but for a different reason. Unlike dolphins, these fish do not feel the painful bubbles because they have bony fins without nerve endings. Nevertheless they cannot swim faster because the cavitation bubbles create an air film around their fins that limits their speed. Lesions have been found on tuna that are consistent with cavitation damage.
Cavitation is not always a limitation for sea life. Some animals have found ways to use it to their advantage when hunting prey. The pistol shrimp snaps a specialized claw to create cavitation, which can kill small fish. The mantis shrimp (type smasher) uses cavitation as well in order to stun, smash open, or kill the shellfish that it feasts upon.
# Coastal erosion
In the last half a decade, coastal erosion in the form of inertial cavitation has been generally accepted.[3] Air pockets in an incoming wave are forced into cracks in the cliff being eroded, the force of the wave then compresses the air pockets until the bubble implodes, becoming liquid, giving off various forms of energy which blast apart the rock.
# List of cavitation tunnels
## Canada
- National Research Council - Institute for Ocean Technology Cavitation Tunnel, [1], St. Johns, Newfoundland, Canada
## France
- "Tunnel de Cavitation" Ecole Navale [2], Lanveoc
- "Grand Tunnel Hydrodynamique" Bassin d'Essais des Carènes [3], Val de Reuil
## Germany
- Multiple cavitation tunnels at the Versuchsanstalt für Wasserbau und Schiffbau [4], Berlin
- Large Cavitation tunnel at Hamburg Ship Model Basin [5],Hamburg
## Iran
- Applied Hydrodynamics Laboratory, Iran University of Science and Technology, [6], Narmak, Tehran, Iran.
## Netherlands
- Large Cavitation Tunnel and High Speed Cavitation Tunnel [7] at the Maritime Research Institute, Wageningen.
## Norway
- "Cavitation Lab" NTNU, The Norwegian University of Science and Technology [8], Trondheim
## Poland
- Ship Design and Research Centre (CTO S.A.) Centrum Techniki Okrętowej S.A., [9], Gdansk, Poland.
## South Korea
- Samsung Ship Model Basin (SSMB), Samsung Heavy Industries, [10], Daejeon, South Korea.
## Sweden
- SSPA [11]
## Taiwan
- The Large Cavitation Tunnel at National Taiwan Ocean University, Keelung, Taiwan
## United Kingdom
- "Emerson Cavitation Tunnel," University of Newcastle upon Tyne. [12]
## United States
- The Garfield Thomas Water Tunnel The Pennsylvania State University [13], State College, PA
- The William B. Morgan Large Cavitation Channel [14], Memphis, TN
- MIT's variable pressure water tunnel [15] | https://www.wikidoc.org/index.php/Cavitation | |
028e4ab1fd8cb2591bdc742b4e9fed41e5273bed | wikidoc | Cefadroxil | Cefadroxil
# 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
Cefadroxil is a cephalosporin that is FDA approved for the treatment of urinary tract infections caused by E. coli, P. mirabilis, and Klebsiella species, skin and skin structure infections caused by staphylococci and/or 4streptococci, pharyngitis and/or tonsillitis caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci). Common adverse reactions include GI upset, nausea, vomiting, diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For uncomplicated lower urinary tract infections (i.e., cystitis) the usual dosage is 1 or 2 g per day in a single (q.d.) or divided doses (b.i.d.).
- For all other urinary tract infections the usual dosage is 2 g per day in divided doses (b.i.d.).
- For skin and skin structure infections the usual dosage is 1 g per day in single (q.d.) or divided doses (b.i.d.).
- Treatment of Group A beta-hemolytic streptococci pharyngitis and tonsillitis-1 g per day in single (q.d.) or divided doses (b.i.d.) for 10 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefadroxil in adult patients.
### Non–Guideline-Supported Use
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- For urinary tract infections, the recommended daily dosage for children is 30 mg/kg/day in divided doses every 12 hours. For pharyngitis, tonsillitis, and impetigo, the recommended daily dosage for children is 30 mg/kg/day in a single dose or in equally divided doses every 12 hours. For other skin and skin structure infections, the recommended daily dosage is 30 mg/kg/day in equally divided doses every 12 hours. In the treatment of Group A beta-hemolytic streptococci infections, a therapeutic dosage of Cefadroxil should be administered for at least 10 days.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefadroxil in pediatric patients.
### Non–Guideline-Supported Use
# Contraindications
- Cefadroxil monohydrate is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
# Warnings
- Before therapy with Cefadroxil monohydrate is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefadroxil, cephalosporins, penicillins, or other drugs. if this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-sensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefadroxil monohydrate occurs, discontinue the drug. serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
- Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefadroxil, and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicated that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis’’. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug effective against Clostridium difficile.
# Adverse Reactions
## Clinical Trials Experience
- Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. Dyspepsia, nausea and vomiting have been reported rarely. Diarrhea has also occurred.
- Allergies (in the form of rash, urticaria, angioedema, and pruritus) have been observed. These reactions usually subsided upon discontinuation of the drug. Anaphylaxis has also been reported.
- Other reactions have included hepatic dysfunction including cholestasis and elevations in serum transaminase, genital pruritus, genital moniliasis, vaginitis, moderate transient neutropenia, fever, agranulocytosis, thrombocytopenia, idiosyncratic hepatic failure, erythema multiforme, Stevens-Johnson syndrome, serum sickness, and arthralgia have been rarely reported.
- In addition to the adverse reactions listed above which have been observed in patients treated with cefadroxil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:
- Toxic epidermal necrolysis, abdominal pain, superinfection, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, prolonged prothrombin time, positive Coombs’ test, increased BUN, increased creatinine, elevated alkaline phosphatase, elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT), elevated bilirubin, elevated LDH, eosinophilia, pancytopenia, neutropenia.
- Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment, when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
## Postmarketing Experience
There is limited information regarding Cefadroxil Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Cefadroxil Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in mice and rats at doses up to 11 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefadroxil monohydrate. There are, however, no adequate and well controlled studies in pregnant 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 Cefadroxil in women who are pregnant.
### Labor and Delivery
Cefadroxil monohydrate has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.
### Nursing Mothers
Caution should be exercised when cefadroxil monohydrate is administered to a nursing mother.
### Pediatric Use
There is no FDA guidance on the use of Cefadroxil in pediatric settings.
### Geriatic Use
- Of approximately 650 patients who received cefadroxil for the treatment of urinary tract infections in three clinical trials, 28% were 60 years and older, while 16% were 70 years and older. Of approximately 1000 patients who received cefadroxil for the treatment of skin and skin structure infection in 14 clinical trials, 12% were 60 years and older while 4% were 70 years and over. No overall differences in safety were observed between the elderly patients in these studies and younger patients. Clinical studies of cefadroxil for the treatment of pharyngitis or tonsillitis did not include sufficient numbers of patients 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience with cefadroxil has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Cefadroxil is substantially excreted by the kidney, and dosage adjustment is indicated for patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Cefadroxil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefadroxil with respect to specific racial populations.
### Renal Impairment
- In patients with renal impairment, the dosage of cefadroxil monohydrate should be adjusted according to creatinine clearance rates to prevent drug accumulation. The following schedule is suggested. In adults, the initial dose is 1000 mg of cefadroxil monohydrate and the maintenance dose (based on the creatinine clearance rate ) is 500 mg at the time intervals listed below.
- Patients with creatinine clearance rates over 50 mL/min may be treated as if they were patients having normal renal function.
### Hepatic Impairment
There is no FDA guidance on the use of Cefadroxil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefadroxil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefadroxil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Cefadroxil Administration in the drug label.
### Monitoring
There is limited information regarding Cefadroxil Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Cefadroxil and IV administrations.
# Overdosage
- A study of children under six years of age suggested that ingestion of less than 250 mg/kg of cephalosporins is not associated with significant outcomes. No action is required other than general support and observation. For amounts greater than 250 mg/kg, induce gastric emptying.
- In five anuric patients, it was demonstrated that an average of 63% of a 1 g oral dose is extracted from the body during a 6 to 8 hour hemodialysis session.
# Pharmacology
## Mechanism of Action
There is limited information regarding Cefadroxil Mechanism of Action in the drug label.
## Structure
- It is chemically designated as 5-Thia-1-azabicyclo oct-2-ene-2-carboxylic acid, 7- amino]-3-methyl-8-oxo-, monohydrate, ]-. It has the molecular formula C16H17N3O5SH2O and the molecular weight of 381.40. It has the following structural formula:
## Pharmacodynamics
There is limited information regarding Cefadroxil Pharmacodynamics in the drug label.
## Pharmacokinetics
- Cefadroxil monohydrate is rapidly absorbed after oral administration. Following single doses of 500 mg and 1000 mg, average peak serum concentrations were approximately 16 and 28 mcg/mL, respectively. Measurable levels were present 12 hours after administration. Over 90% of the drug is excreted unchanged in the urine within 24 hours. Peak urine concentrations are approximately 1800 mcg/mL during the period following a single 500 mg oral dose. Increases in dosage generally produce a proportionate increase in cefadroxil urinary concentration. The urine antibiotic concentration, following a 1 g dose, was maintained well above the MIC of susceptible urinary pathogens for 20 to 22 hours.
## Nonclinical Toxicology
There is limited information regarding Cefadroxil Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Cefadroxil Clinical Studies in the drug label.
# How Supplied
Cefadroxil Tablets, USP 1 gram: White to off-white, film-coated, oval shaped tablets with ‘416’ and ‘par’ on either side of the breakline on one side and plain on the other side. Tablets are supplied as follows:
- NDC 49884-416-03: Bottle of 50
- NDC 49884-416-01: Bottle of 100
- NDC 49884-416-05: Bottle of 500
- NDC 49884-416-74: Carton of 100
## Storage
Store at 20° – 25° C (68° – 77° F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cefadroxil Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Cefadroxil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Duricef
# Look-Alike Drug Names
There is limited information regarding Cefadroxil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cefadroxil
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.
# Overview
Cefadroxil is a cephalosporin that is FDA approved for the treatment of urinary tract infections caused by E. coli, P. mirabilis, and Klebsiella species, skin and skin structure infections caused by staphylococci and/or 4streptococci, pharyngitis and/or tonsillitis caused by Streptococcus pyogenes (Group A beta-hemolytic streptococci). Common adverse reactions include GI upset, nausea, vomiting, diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For uncomplicated lower urinary tract infections (i.e., cystitis) the usual dosage is 1 or 2 g per day in a single (q.d.) or divided doses (b.i.d.).
- For all other urinary tract infections the usual dosage is 2 g per day in divided doses (b.i.d.).
- For skin and skin structure infections the usual dosage is 1 g per day in single (q.d.) or divided doses (b.i.d.).
- Treatment of Group A beta-hemolytic streptococci pharyngitis and tonsillitis-1 g per day in single (q.d.) or divided doses (b.i.d.) for 10 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefadroxil in adult patients.
### Non–Guideline-Supported Use
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- For urinary tract infections, the recommended daily dosage for children is 30 mg/kg/day in divided doses every 12 hours. For pharyngitis, tonsillitis, and impetigo, the recommended daily dosage for children is 30 mg/kg/day in a single dose or in equally divided doses every 12 hours. For other skin and skin structure infections, the recommended daily dosage is 30 mg/kg/day in equally divided doses every 12 hours. In the treatment of Group A beta-hemolytic streptococci infections, a therapeutic dosage of Cefadroxil should be administered for at least 10 days.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefadroxil in pediatric patients.
### Non–Guideline-Supported Use
# Contraindications
- Cefadroxil monohydrate is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
# Warnings
- Before therapy with Cefadroxil monohydrate is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefadroxil, cephalosporins, penicillins, or other drugs. if this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-sensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to Cefadroxil monohydrate occurs, discontinue the drug. serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
- Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefadroxil, and may range from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicated that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis’’. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug effective against Clostridium difficile.
# Adverse Reactions
## Clinical Trials Experience
- Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. Dyspepsia, nausea and vomiting have been reported rarely. Diarrhea has also occurred.
- Allergies (in the form of rash, urticaria, angioedema, and pruritus) have been observed. These reactions usually subsided upon discontinuation of the drug. Anaphylaxis has also been reported.
- Other reactions have included hepatic dysfunction including cholestasis and elevations in serum transaminase, genital pruritus, genital moniliasis, vaginitis, moderate transient neutropenia, fever, agranulocytosis, thrombocytopenia, idiosyncratic hepatic failure, erythema multiforme, Stevens-Johnson syndrome, serum sickness, and arthralgia have been rarely reported.
- In addition to the adverse reactions listed above which have been observed in patients treated with cefadroxil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics:
- Toxic epidermal necrolysis, abdominal pain, superinfection, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, prolonged prothrombin time, positive Coombs’ test, increased BUN, increased creatinine, elevated alkaline phosphatase, elevated aspartate aminotransferase (AST), elevated alanine aminotransferase (ALT), elevated bilirubin, elevated LDH, eosinophilia, pancytopenia, neutropenia.
- Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment, when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
## Postmarketing Experience
There is limited information regarding Cefadroxil Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Cefadroxil Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction studies have been performed in mice and rats at doses up to 11 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cefadroxil monohydrate. There are, however, no adequate and well controlled studies in pregnant 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 Cefadroxil in women who are pregnant.
### Labor and Delivery
Cefadroxil monohydrate has not been studied for use during labor and delivery. Treatment should only be given if clearly needed.
### Nursing Mothers
Caution should be exercised when cefadroxil monohydrate is administered to a nursing mother.
### Pediatric Use
There is no FDA guidance on the use of Cefadroxil in pediatric settings.
### Geriatic Use
- Of approximately 650 patients who received cefadroxil for the treatment of urinary tract infections in three clinical trials, 28% were 60 years and older, while 16% were 70 years and older. Of approximately 1000 patients who received cefadroxil for the treatment of skin and skin structure infection in 14 clinical trials, 12% were 60 years and older while 4% were 70 years and over. No overall differences in safety were observed between the elderly patients in these studies and younger patients. Clinical studies of cefadroxil for the treatment of pharyngitis or tonsillitis did not include sufficient numbers of patients 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience with cefadroxil has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Cefadroxil is substantially excreted by the kidney, and dosage adjustment is indicated for patients with renal impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Cefadroxil with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefadroxil with respect to specific racial populations.
### Renal Impairment
- In patients with renal impairment, the dosage of cefadroxil monohydrate should be adjusted according to creatinine clearance rates to prevent drug accumulation. The following schedule is suggested. In adults, the initial dose is 1000 mg of cefadroxil monohydrate and the maintenance dose (based on the creatinine clearance rate [mL/min/1.73 m2]) is 500 mg at the time intervals listed below.
- Patients with creatinine clearance rates over 50 mL/min may be treated as if they were patients having normal renal function.
### Hepatic Impairment
There is no FDA guidance on the use of Cefadroxil in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefadroxil in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefadroxil in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Cefadroxil Administration in the drug label.
### Monitoring
There is limited information regarding Cefadroxil Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Cefadroxil and IV administrations.
# Overdosage
- A study of children under six years of age suggested that ingestion of less than 250 mg/kg of cephalosporins is not associated with significant outcomes. No action is required other than general support and observation. For amounts greater than 250 mg/kg, induce gastric emptying.
- In five anuric patients, it was demonstrated that an average of 63% of a 1 g oral dose is extracted from the body during a 6 to 8 hour hemodialysis session.
# Pharmacology
## Mechanism of Action
There is limited information regarding Cefadroxil Mechanism of Action in the drug label.
## Structure
- It is chemically designated as 5-Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 7-[[amino (4-hydroxyphenyl) acetyl] amino]-3-methyl-8-oxo-, monohydrate, [6R-[6α, 7β(R*)]]-. It has the molecular formula C16H17N3O5S•H2O and the molecular weight of 381.40. It has the following structural formula:
## Pharmacodynamics
There is limited information regarding Cefadroxil Pharmacodynamics in the drug label.
## Pharmacokinetics
- Cefadroxil monohydrate is rapidly absorbed after oral administration. Following single doses of 500 mg and 1000 mg, average peak serum concentrations were approximately 16 and 28 mcg/mL, respectively. Measurable levels were present 12 hours after administration. Over 90% of the drug is excreted unchanged in the urine within 24 hours. Peak urine concentrations are approximately 1800 mcg/mL during the period following a single 500 mg oral dose. Increases in dosage generally produce a proportionate increase in cefadroxil urinary concentration. The urine antibiotic concentration, following a 1 g dose, was maintained well above the MIC of susceptible urinary pathogens for 20 to 22 hours.
## Nonclinical Toxicology
There is limited information regarding Cefadroxil Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Cefadroxil Clinical Studies in the drug label.
# How Supplied
Cefadroxil Tablets, USP 1 gram: White to off-white, film-coated, oval shaped tablets with ‘416’ and ‘par’ on either side of the breakline on one side and plain on the other side. Tablets are supplied as follows:
- NDC 49884-416-03: Bottle of 50
- NDC 49884-416-01: Bottle of 100
- NDC 49884-416-05: Bottle of 500
- NDC 49884-416-74: Carton of 100 [10 x 10s (2 x 5 cards)]
## Storage
Store at 20° – 25° C (68° – 77° F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cefadroxil Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Cefadroxil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Duricef
# Look-Alike Drug Names
There is limited information regarding Cefadroxil Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cefadroxil | |
8e3b35a97b8c682118ea9921f4e68296a9c93d31 | wikidoc | Cefditoren | Cefditoren
# 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
Cefditoren is a 3rd generation cephalosporin that is FDA approved for the treatment of acute bacterial exacerbation of chronic bronchitis, community acquired pneumonia, infection of skin and/or subcutaneous tissue, and pharyngitis/tonsillitis. Common adverse reactions include diarrhea, nausea and candida vaginitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Caused by Haemophilus influenzae (including ß-lactamase-producing strains), Haemophilus parainfluenzae (including ß-lactamase producing strains), Streptococcus pneumoniae (penicillin susceptible strains only), or Moraxella catarrhalis (including ß-lactamase-producing strains).
- Caused by Haemophilus influenzae (including ß-lactamase-producing strains), Haemophilus parainfluenzae (including ß-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including ß-lactamase producing strains).
- Caused by Streptococcus pyogenes. NOTE: Cefditoren Pivoxil is effective in the eradication of Streptococcus pyogenes from the oropharynx. Cefditoren Pivoxil Tablets has not been studied for the prevention of rheumatic fever following Streptococcus pyogenes pharyngitis/tonsillitis. Only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever.
- Caused by Staphylococcus aureus (including ß-lactamase-producing strains) or Streptococcus pyogenes.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefditoren in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefditoren in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Use of cefditoren pivoxil is not recommended for pediatric patients less than 12 years of age. The safety and efficacy of cefditoren pivoxil tablets in this population, including any effects of altered carnitine concentration, have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefditoren in pediatric patients.
### Non–Guideline-Supported Use
- Cefditoren pivoxil 9 milligrams/kilogram (mg/kg) daily.
# Contraindications
- Cefditoren Pivoxil is contraindicated in patients with known allergy to the cephalosporin class of antibiotics or any of its components.
- Cefditoren Pivoxil is contraindicated in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency, because use of Cefditoren Pivoxil causes renal excretion of carnitine.
- Cefditoren Pivoxil tablets contain sodium caseinate, a milk protein. Patients with milk protein hypersensitivity (not lactose intolerance) should not be administered Cefditoren Pivoxil.
# Warnings
- Before therapy with cefditoren pivoxil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefditoren pivoxil, other cephalosporins, penicillins, or other drugs. If cefditoren pivoxil is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among ß-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefditoren pivoxil occurs, the drug should be discontinued. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
- Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefditoren pivoxil, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
- Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile (C. difficile) is a primary cause of antibiotic-associated colitis.
- After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
### Precautions
- Prescribing Cefditoren Pivoxil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Cefditoren Pivoxil is not recommended when prolonged antibiotic treatment is necessary, since other pivalate-containing compounds have caused clinical manifestations of carnitine deficiency when used over a period of months. No clinical effects of carnitine decrease have been associated with short-term treatment. The effects on carnitine concentrations of repeat short-term courses of Cefditoren Pivoxil are not known.
- In community-acquired pneumonia patients (N=192, mean age 50.3 ± 17.2 years) given a 200 mg BID regimen for 14 days, the mean decrease in serum concentrations of total carnitine while on therapy was 13.8 ± 10.8 nmole/mL, representing a 30% decrease in serum carnitine concentrations. In community-acquired pneumonia patients (N=192, mean age 51.3 ± 17.8 years) given a 400 mg BID regimen for 14 days, the mean decrease in serum concentrations of total carnitine while on therapy was 21.5 ± 13.1 mole/mL, representing a 46% decrease in serum carnitine concentrations. Plasma concentrations of carnitine returned to the normal control range within 7 days after discontinuation of cefditoren pivoxil. Comparable decreases in carnitine were observed in healthy volunteers (mean age 33.6 ± 7.4 years) following a 200 mg or 400 mg BID regimen. Community-acquired pneumonia clinical trials demonstrated no adverse events attributable to decreases in serum carnitine concentrations.
- However, some sub-populations (e.g., patients with renal impairment, patients with decreased muscle mass) may be at increased risk for reductions in serum carnitine concentrations during cefditoren pivoxil therapy. Furthermore, the appropriate dose in patients with end-stage renal disease has not been determined.
- As with other antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy should be administered.
- Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. In clinical trials, there was no difference between cefditoren and comparator cephalosporins in the incidence of increased prothrombin time.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, 4834 adult and adolescent patients have been treated with the recommended doses of cefditoren pivoxil tablets (200 mg or 400 mg BID). Most adverse events were mild and self-limiting. No deaths or permanent disabilities have been attributed to cefditoren.
- The following adverse events were thought by the investigators to be possibly, probably, or definitely related to cefditoren tablets in multiple-dose clinical trials:
- The overall incidence of adverse events, and in particular diarrhea, increased with the higher recommended dose of Cefditoren Pivoxil.
- Treatment related adverse events experienced by 0.1% of patients who received 200 mg or 400 mg BID of cefditoren pivoxil were abnormal dreams, allergic reaction, anorexia, asthenia, asthma, coagulation time increased, constipation, dizziness, dry mouth, eructation, face edema, fever, flatulence, fungal infection, gastrointestinal disorder, hyperglycemia, increased appetite, insomnia, leukopenia, leukorrhea, liver function test abnormal, myalgia, nervousness, oral moniliasis, pain, peripheral edema, pharyngitis, pseudomembranous colitis, pruritus, rash, rhinitis, sinusitis, somnolence, stomatitis, sweating, taste perversion, thirst, thrombocythemia, urticaria, and vaginitis. Pseudomembranous colitis symptoms may begin during or after antibiotic treatment.
- Sixty-one of 2675 (2%) patients who received 200 mg BID and 69 of 2159 (3%) patients who received 400 mg BID of cefditoren pivoxil discontinued medication due to adverse events thought by the investigators to be possibly, probably, or definitely associated with cefditoren therapy. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or nausea. Diarrhea was the reason for discontinuation in 19 of 2675 (0.7%) patients who received 200 mg BID and in 31 of 2159 (1.4%) patients who received 400 mg BID of cefditoren pivoxil.
- Changes in laboratory parameters of possible clinical significance, without regard to drug relationship and which occurred in ≥1% of patients who received cefditoren pivoxil 200 mg or 400 mg BID, were hematuria (3.0% and 3.1%), increased urine white blood cells (2.3% and 2.3%), decreased hematocrit (2.1% and 2.2%), and increased glucose (1.8% and 1.1%). Those events which occurred in 0.1% of patients included the following: increased/decreased white blood cells, increased eosinophils, decreased neutrophils, increased lymphocytes, increased platelet count, decreased hemoglobin, decreased sodium, increased potassium, decreased chloride, decreased inorganic phosphorus, decreased calcium, increased SGPT/ALT, increased SGOT/AST, increased cholesterol, decreased albumin, proteinuria, and increased BUN. It is not known if these abnormalities were caused by the drug or the underlying condition being treated.
- Cephalosporin Class Adverse Reactions
- In addition to the adverse reactions listed above which have been observed in patients treated with cefditoren pivoxil, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics:
- Adverse Reactions: Allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, serum sickness-like reaction, erythema multiforme, toxic epidermal necrolysis, colitis, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and superinfection.
- Altered Laboratory Tests: Prolonged prothrombin time, positive direct Coombs’ test, false-positive test for urinary glucose, elevated alkaline phosphatase, elevated bilirubin, elevated LDH, increased creatinine, pancytopenia, neutropenia, and agranulocytosis.
- Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
## Postmarketing Experience
- The following adverse experiences, regardless of their relationship to cefditoren pivoxil, have been reported during extensive postmarketing experience, beginning with approval in Japan in 1994: pneumonia interstitial, eosinophilic pneumonia acute, acute renal failure, arthralgia, thrombocytopenia, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis and anaphylactoid reactions which may be accompanied by hypotension.
# Drug Interactions
- Oral Contraceptives
- Multiple doses of cefditoren pivoxil had no effect on the pharmacokinetics of ethinyl estradiol, the estrogenic component in most oral contraceptives.
- Antacids
- Co-administration of a single dose of an antacid which contained both magnesium (800 mg) and aluminum (900 mg) hydroxides reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 14% decrease in mean Cmax and an 11% decrease in mean AUC. Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with antacids.
- H2-Receptor Antagonists
- Co-administration of a single dose of intravenously administered famotidine (20 mg) reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 27% decrease in mean Cmax and a 22% decrease in mean AUC. Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with H2 receptor antagonists.
- Probenecid
- As with other ß-lactam antibiotics, co-administration of probenecid with cefditoren pivoxil resulted in an increase in the plasma exposure of cefditoren, with a 49% increase in mean Cmax, a 122% increase in mean AUC, and a 53% increase in t1/2.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Cefditoren pivoxil was not teratogenic up to the highest doses tested in rats and rabbits. In rats, this dose was 1000 mg/kg/day, which is approximately 24 times a human dose of 200 mg BID based on mg/m2/day. In rabbits, the highest dose tested was 90 mg/kg/day, which is approximately four times a human dose of 200 mg BID based on mg/m2/day. This dose produced severe maternal toxicity and resulted in fetal toxicity and abortions.
- In a postnatal development study in rats, cefditoren pivoxil produced no adverse effects on postnatal survival, physical and behavioral development, learning abilities, and reproductive capability at sexual maturity when tested at doses of up to 750 mg/kg/day, the highest dose tested. This is approximately 18 times a human dose of 200 mg BID based on mg/m2/day.
- There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefditoren in women who are pregnant.
### Labor and Delivery
- Cefditoren pivoxil has not been studied for use during labor and delivery.
### Nursing Mothers
- Cefditoren was detected in the breast milk of lactating rats. Because many drugs are excreted in human breast milk, caution should be exercised when cefditoren pivoxil is administered to nursing women.
### Pediatric Use
- Use of cefditoren pivoxil is not recommended for pediatric patients less than 12 years of age. The safety and efficacy of cefditoren pivoxil tablets in this population, including any effects of altered carnitine concentration, have not been established.
### Geriatic Use
- Of the 2675 patients in clinical studies who received cefditoren pivoxil 200 mg BID, 308 (12%) were >65 years of age. Of the 2159 patients in clinical studies who received cefditoren pivoxil 400 mg BID, 307 (14%) were >65 years of age. No clinically significant differences in effectiveness or safety were observed between older and younger patients. No dose adjustments are necessary in geriatric patients with normal (for their age) renal function. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Cefditoren with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefditoren with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cefditoren in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cefditoren in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefditoren in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefditoren in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cefditoren in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cefditoren in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cefditoren in the drug label.
# Pharmacology
## Mechanism of Action
- Cefditoren is a cephalosporin with antibacterial activity against gram-positive and gram-negative pathogens. The bactericidal activity of cefditoren results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs).
## Structure
- Cefditoren Pivoxil tablets contain cefditoren pivoxil, a semi-synthetic cephalosporin antibiotic for oral administration. It is a prodrug which is hydrolyzed by esterases during absorption, and the drug is distributed in the circulating blood as active cefditoren.
- Chemically, cefditoren pivoxil is (-)-(6R,7R)-2,2-dimethylpropionyloxymethyl 7--3--8-oxo-5-thia-1-azabicyclooct-2-ene-2-carboxylate. The empirical formula is C25H28N6O7S3 and the molecular weight is 620.73. The structural formula of cefditoren pivoxil is shown below:
- The amorphous form of cefditoren pivoxil developed for clinical use is a light yellow powder. It is freely soluble in dilute hydrochloric acid and soluble at levels equal to 6.06 mg/mL in ethanol and <0.1 mg/mL in water.
- Cefditoren Pivoxil tablets contain 200 mg or 400 mg of cefditoren as cefditoren pivoxil and the following inactive ingredients: croscarmellose sodium, mannitol, magnesium stearate, sodium caseinate (a milk protein), and sodium tripolyphosphate. The tablet coating contains carnauba wax, hypromellose, polyethylene glycol, and titanium dioxide. Tablets are printed with ink containing opacode blue S-1-10533.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cefditoren in the drug label.
## Pharmacokinetics
- Absorption
- Oral Bioavailability
- Following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations (Cmax) of cefditoren under fasting conditions average 1.8 ± 0.6 µg/mL following a single 200 mg dose and occur 1.5 to 3 hours following dosing.
- Less than dose-proportional increases in Cmax and area under the concentration-time curve (AUC) were observed at doses of 400 mg and above. Cefditoren does not accumulate in plasma following twice daily administration to subjects with normal renal function. Under fasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%. The absolute bioavailability of cefditoren pivoxil administered with a low fat meal (693 cal, 14 g fat, 122 g carb, 23 g protein) is 16.1 ± 3.0%.
- Food Effect
- Administration of cefditoren pivoxil following a high fat meal (858 cal, 64 g fat, 43 g carb, 31 g protein) resulted in a 70% increase in mean AUC and a 50% increase in mean Cmax compared to administration of cefditoren pivoxil in the fasted state. After a high fat meal, the Cmax averaged 3.1 ± 1.0 µg/mL following a single 200 mg dose of cefditoren pivoxil and 4.4 ± 0.9 µg/mL following a 400 mg dose. Cefditoren AUC and Cmax values from studies conducted with a moderate fat meal (648 cal, 27 g fat, 73 g carb, 29 g protein) are similar to those obtained following a high fat meal.
- Distribution
- The mean volume of distribution at steady state (Vss) of cefditoren is 9.3 ± 1.6 L. Binding of cefditoren to plasma proteins averages 88% from in vitro determinations, and is concentration-independent at cefditoren concentrations ranging from 0.05 to10 µg/mL. Cefditoren is primarily bound to human serum albumin and its binding is decreased when serum albumin concentrations are reduced. Binding to α-1-acid glycoprotein ranges from 3.3 to 8.1%. Penetration into red blood cells is negligible.
- Skin blister fluid
- Maximal concentrations of cefditoren in suction-induced blister fluid were observed 4 to 6 hours following administration of a 400 mg dose of cefditoren pivoxil with a mean of 1.1 ± 0.42 µg/mL. Mean blister fluid AUC values were 56 ± 15% of corresponding plasma concentrations.
- Tonsil tissue
- In fasted patients undergoing elective tonsillectomy, the mean concentration of cefditoren in tonsil tissue 2 to 4 hours following administration of a 200 mg dose of cefditoren pivoxil was 0.18 ± 0.07 µg/g. Mean tonsil tissue concentrations of cefditoren were 12 ± 3% of the corresponding serum concentrations.
- Cerebrospinal Fluid (CSF)
- Data on the penetration of cefditoren into human cerebrospinal fluid are not available.
- Metabolism and Excretion
- Cefditoren is eliminated from the plasma, with a mean terminal elimination half-life (t1/2) of 1.6 ± 0.4 hours in young healthy adults. Cefditoren is not appreciably metabolized. After absorption, cefditoren is mainly eliminated by excretion into the urine, with a renal clearance of approximately 4-5 L/h. Studies with the renal tubular transport blocking agent probenecid indicate that tubular secretion, along with glomerular filtration is involved in the renal elimination of cefditoren. Cefditoren renal clearance is reduced in patients with renal insufficiency.
- Hydrolysis of cefditoren pivoxil to its active component, cefditoren, results in the formation of pivalate. Following multiple doses of cefditoren pivoxil, greater than 70% of the pivalate is absorbed. Pivalate is mainly eliminated (>99%) through renal excretion, nearly exclusively as pivaloylcarnitine. Following a 200 mg BID regimen for 10 days, the mean decrease in plasma concentrations of total carnitine was 18.1 ± 7.2 nmole/mL, representing a 39% decrease in plasma carnitine concentrations. Following a 400 mg BID regimen for 14 days, the mean decrease in plasma concentrations of carnitine was 33.3 ± 9.7 nmole/mL, representing a 63% decrease in plasma carnitine concentrations. Plasma concentrations of carnitine returned to the normal control range within 7 to 10 days after discontinuation of cefditoren pivoxil.
- Special Populations
- Geriatric
- The effect of age on the pharmacokinetics of cefditoren was evaluated in 48 male and female subjects aged 25 to 75 years given 400 mg cefditoren pivoxil BID for 7 days. Physiological changes related to increasing age increased the extent of cefditoren exposure in plasma, as evidenced by a 26% higher Cmax and a 33% higher AUC for subjects aged ≥ 65 years compared with younger subjects. The rate of elimination of cefditoren from plasma was lower in subjects aged ≥ 65 years, with t1/2 values 16-26% longer than for younger subjects. Renal clearance of cefditoren in subjects aged ≥ 65 years was 20-24% lower than in younger subjects. These changes could be attributed to age-related changes in creatinine clearance. No dose adjustments are necessary for elderly patients with normal (for their age) renal function.
- Gender
- The effect of gender on the pharmacokinetics of cefditoren was evaluated in 24 male and 24 female subjects given 400 mg cefditoren pivoxil BID for 7 days. The extent of exposure in plasma was greater in females than in males, as evidenced by a 14% higher Cmax and a 16% higher AUC for females compared to males. Renal clearance of cefditoren in females was 13% lower than in males. These differences could be attributed to gender-related differences in lean body mass. No dose adjustments are necessary for gender.
- Renal Insufficiency
- Cefditoren pharmacokinetics were investigated in 24 adult subjects with varying degrees of renal function following administration of cefditoren pivoxil 400 mg BID for 7 days. Decreased creatinine clearance (CLcr) was associated with an increase in the fraction of unbound cefditoren in plasma and a decrease in the cefditoren elimination rate, resulting in greater systemic exposure in subjects with renal impairment. The unbound Cmax and AUC were similar in subjects with mild renal impairment (CLcr: 50-80 mL/min/1.73 m2) compared to subjects with normal renal function (CLcr: >80 mL/min/1.73 m2). Moderate (CLcr: 30-49 mL/min/1.73 m2) or severe (CLcr: <30 mL/min/1.73 m2) renal impairment increased the extent of exposure in plasma, as evidenced by mean unbound Cmax values 90% and 114% higher and AUC values 232% and 324% higher than that for subjects with normal renal function. The rate of elimination from plasma was lower in subjects with moderate or severe renal impairment, with respective mean t1/2 values of 2.7 and 4.7 hours. No dose adjustment is necessary for patients with mild renal impairment (CLcr: 50-80 mL/min/1.73 m2). It is recommended that not more than 200 mg BID be administered to patients with moderate renal impairment (CLcr: 30-49 mL/min/1.73 m2) and 200 mg QD be administered to patients with severe renal impairment (CLcr: <30 mL/min/1.73 m2).
- Hemodialysis
- Cefditoren pharmacokinetics investigated in six adult subjects with end-stage renal disease (ESRD) undergoing hemodialysis given a single 400 mg dose of cefditoren pivoxil were highly variable. The mean t1/2 was 4.7 hours and ranged from 1.5 to 15 hours. Hemodialysis (4 hours duration) removed approximately 30% of cefditoren from systemic circulation but did not change the apparent terminal elimination half-life. The appropriate dose for ESRD patients has not been determined.
- Hepatic Disease
- Cefditoren pharmacokinetics were evaluated in six adult subjects with mild hepatic impairment (Child-Pugh Class A) and six with moderate hepatic impairment (Child-Pugh Class B). Following administration of cefditoren pivoxil 400 mg BID for 7 days in these subjects, mean Cmax and AUC values were slightly (<15%) greater than those observed in normal subjects. No dose adjustments are necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). The pharmacokinetics of cefditoren in subjects with severe hepatic impairment (Child-Pugh Class C) have not been studied.
## Nonclinical Toxicology
- No long-term animal carcinogenicity studies have been conducted with cefditoren pivoxil. Cefditoren pivoxil was not mutagenic in the Ames bacterial reverse mutation assay, or in the mouse lymphoma mutation assay at the hypoxanthineguanine phosphoribosyltransferase locus. In Chinese hamster lung cells, chromosomal aberrations were produced by cefditoren pivoxil, but not by cefditoren. Subsequent studies showed that the chromosome aberrations were due to the release of formaldehyde from the pivoxil ester moiety in the in vitro assay system. Neither cefditoren nor cefditoren pivoxil produced chromosomal aberrations when tested in an in vitro human peripheral blood lymphocyte assay, or in the in vivo mouse micronucleus assay. Cefditoren pivoxil did not induce unscheduled DNA syntheses when tested. In rats, fertility and reproduction were not affected by cefditoren pivoxil at oral doses up to 1000 mg/kg/day, approximately 24 times a human dose of 200 mg BID based on mg/m2/day.
# Clinical Studies
There is limited information regarding Clinical Studies of Cefditoren in the drug label.
# How Supplied
- Cefditoren Pivoxil tablets containing cefditoren pivoxil equivalent to 200 mg or 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 200” or “CBP 400” in blue. These tablets are available in blister packages, as follows:
- NDC 44009-802-20: 400 mg 20 count blister pack. Cefditoren Pivoxil tablets containing cefditoren pivoxil equivalent to 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 400” in blue.
- NDC 44009-802-28: 400 mg 28 count blister pack. Cefditoren Pivoxil tablets containing cefditoren pivoxil equivalent to 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 400” in blue.
- NDC 44009-801-20: 20 count blister pack. Cefditoren Pivoxil tablets containing cefditoren pivoxil equivalent to 200 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 200” in blue.
## Storage
There is limited information regarding Cefditoren Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including Cefditoren Pivoxil should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefditoren Pivoxil is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefditoren Pivoxil or other antibacterial drugs in the future.
- Cefditoren Pivoxil should be taken with meals to enhance absorption.
- Cefditoren Pivoxil may be taken concomitantly with oral contraceptives.
- It is not recommended that Cefditoren Pivoxil be taken concomitantly with antacids or other drugs taken to reduce stomach acids.
- Cefditoren Pivoxil tablets contain sodium caseinate, a milk protein. Patients with milk protein hypersensitivity (not lactose intolerance) should not be administered Cefditoren Pivoxil.
# Precautions with Alcohol
- Alcohol-Cefditoren interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CEFDITOREN PIVOXIL®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Cefditoren
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
Cefditoren is a 3rd generation cephalosporin that is FDA approved for the treatment of acute bacterial exacerbation of chronic bronchitis, community acquired pneumonia, infection of skin and/or subcutaneous tissue, and pharyngitis/tonsillitis. Common adverse reactions include diarrhea, nausea and candida vaginitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Caused by Haemophilus influenzae (including ß-lactamase-producing strains), Haemophilus parainfluenzae (including ß-lactamase producing strains), Streptococcus pneumoniae (penicillin susceptible strains only), or Moraxella catarrhalis (including ß-lactamase-producing strains).
- Caused by Haemophilus influenzae (including ß-lactamase-producing strains), Haemophilus parainfluenzae (including ß-lactamase-producing strains), Streptococcus pneumoniae (penicillin-susceptible strains only), or Moraxella catarrhalis (including ß-lactamase producing strains).
- Caused by Streptococcus pyogenes. NOTE: Cefditoren Pivoxil is effective in the eradication of Streptococcus pyogenes from the oropharynx. Cefditoren Pivoxil Tablets has not been studied for the prevention of rheumatic fever following Streptococcus pyogenes pharyngitis/tonsillitis. Only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever.
- Caused by Staphylococcus aureus (including ß-lactamase-producing strains) or Streptococcus pyogenes.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefditoren in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cefditoren in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Use of cefditoren pivoxil is not recommended for pediatric patients less than 12 years of age. The safety and efficacy of cefditoren pivoxil tablets in this population, including any effects of altered carnitine concentration, have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cefditoren in pediatric patients.
### Non–Guideline-Supported Use
- Cefditoren pivoxil 9 milligrams/kilogram (mg/kg) daily.
# Contraindications
- Cefditoren Pivoxil is contraindicated in patients with known allergy to the cephalosporin class of antibiotics or any of its components.
- Cefditoren Pivoxil is contraindicated in patients with carnitine deficiency or inborn errors of metabolism that may result in clinically significant carnitine deficiency, because use of Cefditoren Pivoxil causes renal excretion of carnitine.
- Cefditoren Pivoxil tablets contain sodium caseinate, a milk protein. Patients with milk protein hypersensitivity (not lactose intolerance) should not be administered Cefditoren Pivoxil.
# Warnings
- Before therapy with cefditoren pivoxil is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefditoren pivoxil, other cephalosporins, penicillins, or other drugs. If cefditoren pivoxil is to be given to penicillin-sensitive patients, caution should be exercised because cross-hypersensitivity among ß-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy. If an allergic reaction to cefditoren pivoxil occurs, the drug should be discontinued. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
- Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefditoren pivoxil, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
- Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile (C. difficile) is a primary cause of antibiotic-associated colitis.
- After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
### Precautions
- Prescribing Cefditoren Pivoxil in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Cefditoren Pivoxil is not recommended when prolonged antibiotic treatment is necessary, since other pivalate-containing compounds have caused clinical manifestations of carnitine deficiency when used over a period of months. No clinical effects of carnitine decrease have been associated with short-term treatment. The effects on carnitine concentrations of repeat short-term courses of Cefditoren Pivoxil are not known.
- In community-acquired pneumonia patients (N=192, mean age 50.3 ± 17.2 years) given a 200 mg BID regimen for 14 days, the mean decrease in serum concentrations of total carnitine while on therapy was 13.8 ± 10.8 nmole/mL, representing a 30% decrease in serum carnitine concentrations. In community-acquired pneumonia patients (N=192, mean age 51.3 ± 17.8 years) given a 400 mg BID regimen for 14 days, the mean decrease in serum concentrations of total carnitine while on therapy was 21.5 ± 13.1 mole/mL, representing a 46% decrease in serum carnitine concentrations. Plasma concentrations of carnitine returned to the normal control range within 7 days after discontinuation of cefditoren pivoxil. Comparable decreases in carnitine were observed in healthy volunteers (mean age 33.6 ± 7.4 years) following a 200 mg or 400 mg BID regimen. Community-acquired pneumonia clinical trials demonstrated no adverse events attributable to decreases in serum carnitine concentrations.
- However, some sub-populations (e.g., patients with renal impairment, patients with decreased muscle mass) may be at increased risk for reductions in serum carnitine concentrations during cefditoren pivoxil therapy. Furthermore, the appropriate dose in patients with end-stage renal disease has not been determined.
- As with other antibiotics, prolonged treatment may result in the possible emergence and overgrowth of resistant organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate alternative therapy should be administered.
- Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. In clinical trials, there was no difference between cefditoren and comparator cephalosporins in the incidence of increased prothrombin time.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, 4834 adult and adolescent patients have been treated with the recommended doses of cefditoren pivoxil tablets (200 mg or 400 mg BID). Most adverse events were mild and self-limiting. No deaths or permanent disabilities have been attributed to cefditoren.
- The following adverse events were thought by the investigators to be possibly, probably, or definitely related to cefditoren tablets in multiple-dose clinical trials:
- The overall incidence of adverse events, and in particular diarrhea, increased with the higher recommended dose of Cefditoren Pivoxil.
- Treatment related adverse events experienced by <1% but >0.1% of patients who received 200 mg or 400 mg BID of cefditoren pivoxil were abnormal dreams, allergic reaction, anorexia, asthenia, asthma, coagulation time increased, constipation, dizziness, dry mouth, eructation, face edema, fever, flatulence, fungal infection, gastrointestinal disorder, hyperglycemia, increased appetite, insomnia, leukopenia, leukorrhea, liver function test abnormal, myalgia, nervousness, oral moniliasis, pain, peripheral edema, pharyngitis, pseudomembranous colitis, pruritus, rash, rhinitis, sinusitis, somnolence, stomatitis, sweating, taste perversion, thirst, thrombocythemia, urticaria, and vaginitis. Pseudomembranous colitis symptoms may begin during or after antibiotic treatment.
- Sixty-one of 2675 (2%) patients who received 200 mg BID and 69 of 2159 (3%) patients who received 400 mg BID of cefditoren pivoxil discontinued medication due to adverse events thought by the investigators to be possibly, probably, or definitely associated with cefditoren therapy. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea or nausea. Diarrhea was the reason for discontinuation in 19 of 2675 (0.7%) patients who received 200 mg BID and in 31 of 2159 (1.4%) patients who received 400 mg BID of cefditoren pivoxil.
- Changes in laboratory parameters of possible clinical significance, without regard to drug relationship and which occurred in ≥1% of patients who received cefditoren pivoxil 200 mg or 400 mg BID, were hematuria (3.0% and 3.1%), increased urine white blood cells (2.3% and 2.3%), decreased hematocrit (2.1% and 2.2%), and increased glucose (1.8% and 1.1%). Those events which occurred in <1% but >0.1% of patients included the following: increased/decreased white blood cells, increased eosinophils, decreased neutrophils, increased lymphocytes, increased platelet count, decreased hemoglobin, decreased sodium, increased potassium, decreased chloride, decreased inorganic phosphorus, decreased calcium, increased SGPT/ALT, increased SGOT/AST, increased cholesterol, decreased albumin, proteinuria, and increased BUN. It is not known if these abnormalities were caused by the drug or the underlying condition being treated.
- Cephalosporin Class Adverse Reactions
- In addition to the adverse reactions listed above which have been observed in patients treated with cefditoren pivoxil, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics:
- Adverse Reactions: Allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, serum sickness-like reaction, erythema multiforme, toxic epidermal necrolysis, colitis, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, and superinfection.
- Altered Laboratory Tests: Prolonged prothrombin time, positive direct Coombs’ test, false-positive test for urinary glucose, elevated alkaline phosphatase, elevated bilirubin, elevated LDH, increased creatinine, pancytopenia, neutropenia, and agranulocytosis.
- Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
## Postmarketing Experience
- The following adverse experiences, regardless of their relationship to cefditoren pivoxil, have been reported during extensive postmarketing experience, beginning with approval in Japan in 1994: pneumonia interstitial, eosinophilic pneumonia acute, acute renal failure, arthralgia, thrombocytopenia, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis and anaphylactoid reactions which may be accompanied by hypotension.
# Drug Interactions
- Oral Contraceptives
- Multiple doses of cefditoren pivoxil had no effect on the pharmacokinetics of ethinyl estradiol, the estrogenic component in most oral contraceptives.
- Antacids
- Co-administration of a single dose of an antacid which contained both magnesium (800 mg) and aluminum (900 mg) hydroxides reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 14% decrease in mean Cmax and an 11% decrease in mean AUC. Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with antacids.
- H2-Receptor Antagonists
- Co-administration of a single dose of intravenously administered famotidine (20 mg) reduced the oral absorption of a single 400 mg dose of cefditoren pivoxil administered following a meal, as evidenced by a 27% decrease in mean Cmax and a 22% decrease in mean AUC. Although the clinical significance is not known, it is not recommended that cefditoren pivoxil be taken concomitantly with H2 receptor antagonists.
- Probenecid
- As with other ß-lactam antibiotics, co-administration of probenecid with cefditoren pivoxil resulted in an increase in the plasma exposure of cefditoren, with a 49% increase in mean Cmax, a 122% increase in mean AUC, and a 53% increase in t1/2.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Cefditoren pivoxil was not teratogenic up to the highest doses tested in rats and rabbits. In rats, this dose was 1000 mg/kg/day, which is approximately 24 times a human dose of 200 mg BID based on mg/m2/day. In rabbits, the highest dose tested was 90 mg/kg/day, which is approximately four times a human dose of 200 mg BID based on mg/m2/day. This dose produced severe maternal toxicity and resulted in fetal toxicity and abortions.
- In a postnatal development study in rats, cefditoren pivoxil produced no adverse effects on postnatal survival, physical and behavioral development, learning abilities, and reproductive capability at sexual maturity when tested at doses of up to 750 mg/kg/day, the highest dose tested. This is approximately 18 times a human dose of 200 mg BID based on mg/m2/day.
- There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cefditoren in women who are pregnant.
### Labor and Delivery
- Cefditoren pivoxil has not been studied for use during labor and delivery.
### Nursing Mothers
- Cefditoren was detected in the breast milk of lactating rats. Because many drugs are excreted in human breast milk, caution should be exercised when cefditoren pivoxil is administered to nursing women.
### Pediatric Use
- Use of cefditoren pivoxil is not recommended for pediatric patients less than 12 years of age. The safety and efficacy of cefditoren pivoxil tablets in this population, including any effects of altered carnitine concentration, have not been established.
### Geriatic Use
- Of the 2675 patients in clinical studies who received cefditoren pivoxil 200 mg BID, 308 (12%) were >65 years of age. Of the 2159 patients in clinical studies who received cefditoren pivoxil 400 mg BID, 307 (14%) were >65 years of age. No clinically significant differences in effectiveness or safety were observed between older and younger patients. No dose adjustments are necessary in geriatric patients with normal (for their age) renal function. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Cefditoren with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cefditoren with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cefditoren in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cefditoren in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cefditoren in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cefditoren in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cefditoren in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cefditoren in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cefditoren in the drug label.
# Pharmacology
## Mechanism of Action
- Cefditoren is a cephalosporin with antibacterial activity against gram-positive and gram-negative pathogens. The bactericidal activity of cefditoren results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs).
## Structure
- Cefditoren Pivoxil tablets contain cefditoren pivoxil, a semi-synthetic cephalosporin antibiotic for oral administration. It is a prodrug which is hydrolyzed by esterases during absorption, and the drug is distributed in the circulating blood as active cefditoren.
- Chemically, cefditoren pivoxil is (-)-(6R,7R)-2,2-dimethylpropionyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxy-iminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate. The empirical formula is C25H28N6O7S3 and the molecular weight is 620.73. The structural formula of cefditoren pivoxil is shown below:
- The amorphous form of cefditoren pivoxil developed for clinical use is a light yellow powder. It is freely soluble in dilute hydrochloric acid and soluble at levels equal to 6.06 mg/mL in ethanol and <0.1 mg/mL in water.
- Cefditoren Pivoxil tablets contain 200 mg or 400 mg of cefditoren as cefditoren pivoxil and the following inactive ingredients: croscarmellose sodium, mannitol, magnesium stearate, sodium caseinate (a milk protein), and sodium tripolyphosphate. The tablet coating contains carnauba wax, hypromellose, polyethylene glycol, and titanium dioxide. Tablets are printed with ink containing opacode blue S-1-10533.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cefditoren in the drug label.
## Pharmacokinetics
- Absorption
- Oral Bioavailability
- Following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations (Cmax) of cefditoren under fasting conditions average 1.8 ± 0.6 µg/mL following a single 200 mg dose and occur 1.5 to 3 hours following dosing.
- Less than dose-proportional increases in Cmax and area under the concentration-time curve (AUC) were observed at doses of 400 mg and above. Cefditoren does not accumulate in plasma following twice daily administration to subjects with normal renal function. Under fasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%. The absolute bioavailability of cefditoren pivoxil administered with a low fat meal (693 cal, 14 g fat, 122 g carb, 23 g protein) is 16.1 ± 3.0%.
- Food Effect
- Administration of cefditoren pivoxil following a high fat meal (858 cal, 64 g fat, 43 g carb, 31 g protein) resulted in a 70% increase in mean AUC and a 50% increase in mean Cmax compared to administration of cefditoren pivoxil in the fasted state. After a high fat meal, the Cmax averaged 3.1 ± 1.0 µg/mL following a single 200 mg dose of cefditoren pivoxil and 4.4 ± 0.9 µg/mL following a 400 mg dose. Cefditoren AUC and Cmax values from studies conducted with a moderate fat meal (648 cal, 27 g fat, 73 g carb, 29 g protein) are similar to those obtained following a high fat meal.
- Distribution
- The mean volume of distribution at steady state (Vss) of cefditoren is 9.3 ± 1.6 L. Binding of cefditoren to plasma proteins averages 88% from in vitro determinations, and is concentration-independent at cefditoren concentrations ranging from 0.05 to10 µg/mL. Cefditoren is primarily bound to human serum albumin and its binding is decreased when serum albumin concentrations are reduced. Binding to α-1-acid glycoprotein ranges from 3.3 to 8.1%. Penetration into red blood cells is negligible.
- Skin blister fluid
- Maximal concentrations of cefditoren in suction-induced blister fluid were observed 4 to 6 hours following administration of a 400 mg dose of cefditoren pivoxil with a mean of 1.1 ± 0.42 µg/mL. Mean blister fluid AUC values were 56 ± 15% of corresponding plasma concentrations.
- Tonsil tissue
- In fasted patients undergoing elective tonsillectomy, the mean concentration of cefditoren in tonsil tissue 2 to 4 hours following administration of a 200 mg dose of cefditoren pivoxil was 0.18 ± 0.07 µg/g. Mean tonsil tissue concentrations of cefditoren were 12 ± 3% of the corresponding serum concentrations.
- Cerebrospinal Fluid (CSF)
- Data on the penetration of cefditoren into human cerebrospinal fluid are not available.
- Metabolism and Excretion
- Cefditoren is eliminated from the plasma, with a mean terminal elimination half-life (t1/2) of 1.6 ± 0.4 hours in young healthy adults. Cefditoren is not appreciably metabolized. After absorption, cefditoren is mainly eliminated by excretion into the urine, with a renal clearance of approximately 4-5 L/h. Studies with the renal tubular transport blocking agent probenecid indicate that tubular secretion, along with glomerular filtration is involved in the renal elimination of cefditoren. Cefditoren renal clearance is reduced in patients with renal insufficiency.
- Hydrolysis of cefditoren pivoxil to its active component, cefditoren, results in the formation of pivalate. Following multiple doses of cefditoren pivoxil, greater than 70% of the pivalate is absorbed. Pivalate is mainly eliminated (>99%) through renal excretion, nearly exclusively as pivaloylcarnitine. Following a 200 mg BID regimen for 10 days, the mean decrease in plasma concentrations of total carnitine was 18.1 ± 7.2 nmole/mL, representing a 39% decrease in plasma carnitine concentrations. Following a 400 mg BID regimen for 14 days, the mean decrease in plasma concentrations of carnitine was 33.3 ± 9.7 nmole/mL, representing a 63% decrease in plasma carnitine concentrations. Plasma concentrations of carnitine returned to the normal control range within 7 to 10 days after discontinuation of cefditoren pivoxil.
- Special Populations
- Geriatric
- The effect of age on the pharmacokinetics of cefditoren was evaluated in 48 male and female subjects aged 25 to 75 years given 400 mg cefditoren pivoxil BID for 7 days. Physiological changes related to increasing age increased the extent of cefditoren exposure in plasma, as evidenced by a 26% higher Cmax and a 33% higher AUC for subjects aged ≥ 65 years compared with younger subjects. The rate of elimination of cefditoren from plasma was lower in subjects aged ≥ 65 years, with t1/2 values 16-26% longer than for younger subjects. Renal clearance of cefditoren in subjects aged ≥ 65 years was 20-24% lower than in younger subjects. These changes could be attributed to age-related changes in creatinine clearance. No dose adjustments are necessary for elderly patients with normal (for their age) renal function.
- Gender
- The effect of gender on the pharmacokinetics of cefditoren was evaluated in 24 male and 24 female subjects given 400 mg cefditoren pivoxil BID for 7 days. The extent of exposure in plasma was greater in females than in males, as evidenced by a 14% higher Cmax and a 16% higher AUC for females compared to males. Renal clearance of cefditoren in females was 13% lower than in males. These differences could be attributed to gender-related differences in lean body mass. No dose adjustments are necessary for gender.
- Renal Insufficiency
- Cefditoren pharmacokinetics were investigated in 24 adult subjects with varying degrees of renal function following administration of cefditoren pivoxil 400 mg BID for 7 days. Decreased creatinine clearance (CLcr) was associated with an increase in the fraction of unbound cefditoren in plasma and a decrease in the cefditoren elimination rate, resulting in greater systemic exposure in subjects with renal impairment. The unbound Cmax and AUC were similar in subjects with mild renal impairment (CLcr: 50-80 mL/min/1.73 m2) compared to subjects with normal renal function (CLcr: >80 mL/min/1.73 m2). Moderate (CLcr: 30-49 mL/min/1.73 m2) or severe (CLcr: <30 mL/min/1.73 m2) renal impairment increased the extent of exposure in plasma, as evidenced by mean unbound Cmax values 90% and 114% higher and AUC values 232% and 324% higher than that for subjects with normal renal function. The rate of elimination from plasma was lower in subjects with moderate or severe renal impairment, with respective mean t1/2 values of 2.7 and 4.7 hours. No dose adjustment is necessary for patients with mild renal impairment (CLcr: 50-80 mL/min/1.73 m2). It is recommended that not more than 200 mg BID be administered to patients with moderate renal impairment (CLcr: 30-49 mL/min/1.73 m2) and 200 mg QD be administered to patients with severe renal impairment (CLcr: <30 mL/min/1.73 m2).
- Hemodialysis
- Cefditoren pharmacokinetics investigated in six adult subjects with end-stage renal disease (ESRD) undergoing hemodialysis given a single 400 mg dose of cefditoren pivoxil were highly variable. The mean t1/2 was 4.7 hours and ranged from 1.5 to 15 hours. Hemodialysis (4 hours duration) removed approximately 30% of cefditoren from systemic circulation but did not change the apparent terminal elimination half-life. The appropriate dose for ESRD patients has not been determined.
- Hepatic Disease
- Cefditoren pharmacokinetics were evaluated in six adult subjects with mild hepatic impairment (Child-Pugh Class A) and six with moderate hepatic impairment (Child-Pugh Class B). Following administration of cefditoren pivoxil 400 mg BID for 7 days in these subjects, mean Cmax and AUC values were slightly (<15%) greater than those observed in normal subjects. No dose adjustments are necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). The pharmacokinetics of cefditoren in subjects with severe hepatic impairment (Child-Pugh Class C) have not been studied.
## Nonclinical Toxicology
- No long-term animal carcinogenicity studies have been conducted with cefditoren pivoxil. Cefditoren pivoxil was not mutagenic in the Ames bacterial reverse mutation assay, or in the mouse lymphoma mutation assay at the hypoxanthineguanine phosphoribosyltransferase locus. In Chinese hamster lung cells, chromosomal aberrations were produced by cefditoren pivoxil, but not by cefditoren. Subsequent studies showed that the chromosome aberrations were due to the release of formaldehyde from the pivoxil ester moiety in the in vitro assay system. Neither cefditoren nor cefditoren pivoxil produced chromosomal aberrations when tested in an in vitro human peripheral blood lymphocyte assay, or in the in vivo mouse micronucleus assay. Cefditoren pivoxil did not induce unscheduled DNA syntheses when tested. In rats, fertility and reproduction were not affected by cefditoren pivoxil at oral doses up to 1000 mg/kg/day, approximately 24 times a human dose of 200 mg BID based on mg/m2/day.
# Clinical Studies
There is limited information regarding Clinical Studies of Cefditoren in the drug label.
# How Supplied
- Cefditoren Pivoxil tablets containing cefditoren pivoxil equivalent to 200 mg or 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 200” or “CBP 400” in blue. These tablets are available in blister packages, as follows:
- NDC 44009-802-20: 400 mg 20 count blister pack. Cefditoren Pivoxil tablets containing cefditoren pivoxil equivalent to 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 400” in blue.
- NDC 44009-802-28: 400 mg 28 count blister pack. Cefditoren Pivoxil tablets containing cefditoren pivoxil equivalent to 400 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 400” in blue.
- NDC 44009-801-20: 20 count blister pack. Cefditoren Pivoxil tablets containing cefditoren pivoxil equivalent to 200 mg of cefditoren are available as white, elliptical, film-coated tablets imprinted with “CBP 200” in blue.
## Storage
There is limited information regarding Cefditoren Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including Cefditoren Pivoxil should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefditoren Pivoxil is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Cefditoren Pivoxil or other antibacterial drugs in the future.
- Cefditoren Pivoxil should be taken with meals to enhance absorption.
- Cefditoren Pivoxil may be taken concomitantly with oral contraceptives.
- It is not recommended that Cefditoren Pivoxil be taken concomitantly with antacids or other drugs taken to reduce stomach acids.
- Cefditoren Pivoxil tablets contain sodium caseinate, a milk protein. Patients with milk protein hypersensitivity (not lactose intolerance) should not be administered Cefditoren Pivoxil.
# Precautions with Alcohol
- Alcohol-Cefditoren interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CEFDITOREN PIVOXIL®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cefditoren | |
0e9c97819f29da3649fe69f6124bc026efd843f3 | wikidoc | Cefquinome | Cefquinome
# Overview
Cefquinome is a fourth-generation cephalosporin with pharmacological and antibacterial properties valuable in the treatment of coliform mastitis and other infections. It is only used in veterinary applications.
# Properties
Cefquinome is resistant to beta-lactamase. Chemically, its zwitterionic structure can facilitate rapid penetration across biological membranes, including porins of bacterial cell walls. Plus, it has a higher affinity to target penicillin-binding proteins. The reactive site is a beta-lactam nucleus, while the main peripheral functional groups are a quaternary quinolinium, an aminothiazolyl moiety and an unusual O-alkylated oxime.
Cefquinome acts by inhibition of the cell wall synthesis, but it has a relatively short half-life of about 2.5 hours. It is less than 5% protein bound and is excreted unchanged in the urine.
# Studies
Many studies have been conducted, mostly for animal use. One such study was conducted by the Pharma Research in Germany.
## Test groups
Groups of albino mice, weighing 191 g, were dosed with 10 and 40 mg of cefquinome per kg. Blood samples were obtained from a cut at the tip of the tail and kept at 4°C. Urine was collected in metabolism cages.
Three male beagle dogs, weighing about 22 kg each, were dosed with 5, 10, and 20 mg/kg at the cephalic vein. Blood samples were drawn from the same vein in the opposite leg. Meanwhile, urine was collected by catheterization.
Pigs, five or six male and female in each group weighing about 18 kg each, were injected with 10 mg of cefquinome at the venajuglaris in the base of the left ear. Blood samples were withdrawn from the contralateral jugular vein.
Male and female calves weighing between 110 and 140 kg were dosed with 10 mg of cefquinome per kg through the vera jucular.
Standard solutions were prepared from pooled murine blood and urine taken from untreated dogs, pigs, and calves.
## Calculations
Cefquinome concentrations were calculated by regression analysis, using the standard curves in which logarithms of the concentration were proportional to the areas of the inhibition zones. Curve fitting was carried out by nonlinear regression with the computer program PHAKOK. Pharmokinetic analysis of the concentration-time data after administration indicated that the best curve fits were usually achieved by using an open two-compartment model.
## Conclusion
Data indicate that cefquinome has high antibacterial activity in vitro against nearly all strains tested. In general, cefquinome is within the same range as cefpirome and cefotaxime. Against Gram-negative species, cefquinome has very limited in vitro activity. The in vitro activity of cefquinome does not depend on the composition or pH of the test medium. The broad antibacterial spectrum and the high in vitro activity are reflected by high in vivo efficacy in experimental infections. In mouse models of septicemia, cefquinome possessed high therapetic efficacy. All infections were cured.
## Treatment
In cattle, the injection should help against respiratory disease caused by Mannheimia haemolytica and Pasteurella multocida. It also helps with acute E. coli mastitis, dermatitis, infectious ulbar necrosis, and interdigital necrobacillosis. In calves, it is effective against E. coli septicaemia.
For pigs, it is used to treat bacterial infections of the lungs and respiratory tract caused by P. multocida, Haemophilus parasuis, Actinobacillus pleuropneumoniae, and Streptococcus suis. Mastitis-metritis-agalactia syndrome involved with E. coli, Staphylococcus, Streptococcus, and other cefquinome-sensitive organisms are also treated. In piglets, the mortality rate in cases of meningitis caused by Streptococcus sues is reduced. It is used in the treatment of mild or moderate lesions caused by Staphylococcus hyicus and arthritis caused by Streptococcus spp. and E. coli.
## Caution/warnings
These are some factors to be aware of before treating:
- This product should not be used in animals known to be hypersensitive to β-lactam antibiotics.
- It should not be administered to animals with a body weight less than 1.25 kg.
- Use of the product may result in localised tissue reaction. Tissue lesions are repaired by 15 days after the last administration of the product.
- Hypersensitivity reactions to cephalosporins occur rarely.
- The product does not contain an antimicrobial preservative.
- To prevent the claimed infections in piglets, attention should be paid to hygiene and ventilation, and overcrowding should be avoided. When the first piglets are affected, careful examination of all animals in the same pen is recommended to enable an early treatment of any other infected piglets.
# Clinical usage
## Human use
Cefquinome is not approved for human use.
## Veterinary medicine
Conditions of use are limited to therapeutic, parenteral, and individual animal use. Individual parenteral therapy of bovine respiratory disease data on cefquinome-related residues demonstrate only very small amounts are present in the intestinal tract of treated cattle with gastrointestinal activation. However, treatment should be short, meaning a single injection daily for about a week. Treatment should only be given by prescription. Cefquinome should not be used in feed or water.
Since 1994, in Europe, it was allowed to treat cattle by prescription only. In 1999, swine were included. By 2005, horses were allowed as well. In the United States, approval is pending for treatment of bovine respiratory disease. Even so, this is only available by prescription.
Cefquinome is also used for other illnesses, such as “shipping fever”, a pneumonia-like illness commonly found in cattle.
# Concerns
## Resistance and food-borne transmission
Of concern, the use of the drug in animals may lead to increases in antibiotic resistance. Humans can be exposed to bacteria through food-borne transmission, raising chances of becoming exposed to resistant bacterial species, such as Salmonella or E. coli. The potential for the development of antibiotic resistance increases as usage increases, by selecting bacteria which have acquired beta-lactamases.
## Salmonella
The use may cause resistance in Salmonella present in the intestinal tract of the target animal. Resistant Salmonella may also contaminate the carcass at slaughter and transfer to humans when used as food. When humans are infected and treated with a fourth-generation cephalosporin, effectiveness may be compromised.
Although fourth-generation cephalosporin resistance is very rare, they are active against bacteria carrying the AmpC-type β-lactamase resistance mechanism. Since the late 1990s, the US and EU have surveyed and gathered data for fourth-generation cephalosporins for both human and veterinary use. Data indicate no changes occur in resistance patterns of relevant food-borne pathogens.
# FDA guidelines
- Administered products will be used in individual animals for short duration and by prescription only.
- The extent of use is ranked low.
- Avoid human drug resistance to fourth-generation cephalosporins by authorizing extra-label prohibition. | Cefquinome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cefquinome is a fourth-generation cephalosporin with pharmacological and antibacterial properties valuable in the treatment of coliform mastitis and other infections. It is only used in veterinary applications.
# Properties
Cefquinome is resistant to beta-lactamase. Chemically, its zwitterionic structure can facilitate rapid penetration across biological membranes, including porins of bacterial cell walls. Plus, it has a higher affinity to target penicillin-binding proteins. The reactive site is a beta-lactam nucleus, while the main peripheral functional groups are a quaternary quinolinium, an aminothiazolyl moiety and an unusual O-alkylated oxime.
Cefquinome acts by inhibition of the cell wall synthesis, but it has a relatively short half-life of about 2.5 hours. It is less than 5% protein bound and is excreted unchanged in the urine.[1]
# Studies
Many studies have been conducted, mostly for animal use. One such study was conducted by the Pharma Research in Germany.
## Test groups
Groups of albino mice, weighing 191 g, were dosed with 10 and 40 mg of cefquinome per kg. Blood samples were obtained from a cut at the tip of the tail and kept at 4°C. Urine was collected in metabolism cages.
Three male beagle dogs, weighing about 22 kg each, were dosed with 5, 10, and 20 mg/kg at the cephalic vein. Blood samples were drawn from the same vein in the opposite leg. Meanwhile, urine was collected by catheterization.
Pigs, five or six male and female in each group weighing about 18 kg each, were injected with 10 mg of cefquinome at the venajuglaris in the base of the left ear. Blood samples were withdrawn from the contralateral jugular vein.
Male and female calves weighing between 110 and 140 kg were dosed with 10 mg of cefquinome per kg through the vera jucular.
Standard solutions were prepared from pooled murine blood and urine taken from untreated dogs, pigs, and calves.
## Calculations
Cefquinome concentrations were calculated by regression analysis, using the standard curves in which logarithms of the concentration were proportional to the areas of the inhibition zones. Curve fitting was carried out by nonlinear regression with the computer program PHAKOK. Pharmokinetic analysis of the concentration-time data after administration indicated that the best curve fits were usually achieved by using an open two-compartment model.
## Conclusion
Data indicate that cefquinome has high antibacterial activity in vitro against nearly all strains tested. In general, cefquinome is within the same range as cefpirome and cefotaxime. Against Gram-negative species, cefquinome has very limited in vitro activity. The in vitro activity of cefquinome does not depend on the composition or pH of the test medium. The broad antibacterial spectrum and the high in vitro activity are reflected by high in vivo efficacy in experimental infections. In mouse models of septicemia, cefquinome possessed high therapetic efficacy. All infections were cured.
## Treatment
In cattle, the injection should help against respiratory disease caused by Mannheimia haemolytica and Pasteurella multocida. It also helps with acute E. coli mastitis, dermatitis, infectious ulbar necrosis, and interdigital necrobacillosis. In calves, it is effective against E. coli septicaemia.
For pigs, it is used to treat bacterial infections of the lungs and respiratory tract caused by P. multocida, Haemophilus parasuis, Actinobacillus pleuropneumoniae, and Streptococcus suis. Mastitis-metritis-agalactia syndrome involved with E. coli, Staphylococcus, Streptococcus, and other cefquinome-sensitive organisms are also treated. In piglets, the mortality rate in cases of meningitis caused by Streptococcus sues is reduced. It is used in the treatment of mild or moderate lesions caused by Staphylococcus hyicus and arthritis caused by Streptococcus spp. and E. coli.
## Caution/warnings
These are some factors to be aware of before treating:
- This product should not be used in animals known to be hypersensitive to β-lactam antibiotics.
- It should not be administered to animals with a body weight less than 1.25 kg.
- Use of the product may result in localised tissue reaction. Tissue lesions are repaired by 15 days after the last administration of the product.
- Hypersensitivity reactions to cephalosporins occur rarely.
- The product does not contain an antimicrobial preservative.
- To prevent the claimed infections in piglets, attention should be paid to hygiene and ventilation, and overcrowding should be avoided. When the first piglets are affected, careful examination of all animals in the same pen is recommended to enable an early treatment of any other infected piglets.
# Clinical usage
## Human use
Cefquinome is not approved for human use.
## Veterinary medicine
Conditions of use are limited to therapeutic, parenteral, and individual animal use. Individual parenteral therapy of bovine respiratory disease data on cefquinome-related residues demonstrate only very small amounts are present in the intestinal tract of treated cattle with gastrointestinal activation. However, treatment should be short, meaning a single injection daily for about a week. Treatment should only be given by prescription. Cefquinome should not be used in feed or water.
Since 1994, in Europe, it was allowed to treat cattle by prescription only. In 1999, swine were included. By 2005, horses were allowed as well. In the United States, approval is pending for treatment of bovine respiratory disease. Even so, this is only available by prescription.
Cefquinome is also used for other illnesses, such as “shipping fever”, a pneumonia-like illness commonly found in cattle.[2]
# Concerns
## Resistance and food-borne transmission
Of concern, the use of the drug in animals may lead to increases in antibiotic resistance. Humans can be exposed to bacteria through food-borne transmission, raising chances of becoming exposed to resistant bacterial species, such as Salmonella or E. coli. The potential for the development of antibiotic resistance increases as usage increases, by selecting bacteria which have acquired beta-lactamases.
## Salmonella
The use may cause resistance in Salmonella present in the intestinal tract of the target animal. Resistant Salmonella may also contaminate the carcass at slaughter and transfer to humans when used as food. When humans are infected and treated with a fourth-generation cephalosporin, effectiveness may be compromised.
Although fourth-generation cephalosporin resistance is very rare, they are active against bacteria carrying the AmpC-type β-lactamase resistance mechanism. Since the late 1990s, the US and EU have surveyed and gathered data for fourth-generation cephalosporins for both human and veterinary use. Data indicate no changes occur in resistance patterns of relevant food-borne pathogens.
# FDA guidelines
- Administered products will be used in individual animals for short duration and by prescription only.
- The extent of use is ranked low.
- Avoid human drug resistance to fourth-generation cephalosporins by authorizing extra-label prohibition. | https://www.wikidoc.org/index.php/Cefquinome | |
8b77d7a4583c5aeba6ff6ce3608ffbc8c4d71e05 | wikidoc | Cefsulodin | Cefsulodin
# Overview
Cefsulodin is a third-generation cephalosporin antibiotic with specific activity against Pseudomonas aeruginosa. It has no significant activity against other Gram-negative bacteria and very limited activity against Gram-positive bacteria and anaerobic bacteria. Cefsulodin was first synthesized and patented by the Takeda Pharmaceutical Company in 1977. In 2002, Takeda stopped production of cefsulodin. Many years of low-stability cefsulodin production has led to a widespread reduction of laboratory and research uses. Current attempts (i.e. IDEXX Laboratories) of increasing purity and stability of cefsulodin center around recrystallization. Typically, the process entails: Cefsulodin is dissolved in an organic solvent, sodium ions, water, or any mixture thereof, then subsequently recrystallized through separation of the unwanted fraction. Recently, TOKU-E has found the main cause of cefsulodin instability stems from one key impurity in 7-aminocephalosporanic acid, a raw material used in the synthesis of cefsulodin. To produce high-purity, high-stability cefsulodin, TOKU-E uses industrial HPLC to remove significant quantities of this impurity in 7-ACA and thus produces ultrapure, ultrastable, and ultrapotent cefsulodin.
# General use
Cefuslodin is most commonly used in cefsulodin-irgasan-novobiocin agar to select for Yersinia microorganisms. This agar is most often used in water and beverage testing.
# Susceptibility data
The following represents MIC susceptibility data for various P. aeruginosa strains.
- Pseudomonas aeruginosa PA13 (resistant strain): 32 μg/ml
- Pseudomonas aeruginosa (wild-type, susceptible): 4 - 8 μg/ml | Cefsulodin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Cefsulodin is a third-generation cephalosporin antibiotic with specific activity against Pseudomonas aeruginosa. It has no significant activity against other Gram-negative bacteria and very limited activity against Gram-positive bacteria and anaerobic bacteria. Cefsulodin was first synthesized and patented by the Takeda Pharmaceutical Company in 1977. In 2002, Takeda stopped production of cefsulodin. Many years of low-stability cefsulodin production has led to a widespread reduction of laboratory and research uses. Current attempts (i.e. IDEXX Laboratories) of increasing purity and stability of cefsulodin center around recrystallization. Typically, the process entails: Cefsulodin is dissolved in an organic solvent, sodium ions, water, or any mixture thereof, then subsequently recrystallized through separation of the unwanted fraction. Recently, TOKU-E has found the main cause of cefsulodin instability stems from one key impurity in 7-aminocephalosporanic acid, a raw material used in the synthesis of cefsulodin. To produce high-purity, high-stability cefsulodin, TOKU-E uses industrial HPLC to remove significant quantities of this impurity in 7-ACA and thus produces ultrapure, ultrastable, and ultrapotent cefsulodin.[1]
# General use
Cefuslodin is most commonly used in cefsulodin-irgasan-novobiocin agar to select for Yersinia microorganisms.[2] This agar is most often used in water and beverage testing.
# Susceptibility data
The following represents MIC susceptibility data for various P. aeruginosa strains.
- Pseudomonas aeruginosa PA13 (resistant strain): 32 μg/ml
- Pseudomonas aeruginosa (wild-type, susceptible): 4 - 8 μg/ml
[3] | https://www.wikidoc.org/index.php/Cefsulodin | |
4d70ef16f7ebd17abd4cf2b05cf88cd57e0296fa | wikidoc | Ceftibuten | Ceftibuten
# 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
Ceftibuten is a 3rd generation cephalosporin that is FDA approved for the treatment of acute bacterial exacerbations of chronic bronchitis, acute bacterial otitis media, pharyngitis and tonsillitis. Common adverse reactions include diarrhea, nausea, vomiting and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Ceftibuten is indicated for the treatment of individuals with mild-to-moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below.
- Due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin-susceptible strains only).
- Dosage: 400 mg ORALLY once daily for 10 days
- Due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pyogenes.
- Dosage: 400 mg ORALLY once daily for 10 days
- Due to Streptococcus pyogenes.
- Dosage: 400 mg ORALLY once daily for 10 days
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftibuten in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftibuten in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of ceftibuten in infants less than 6 months of age has not been established.
Ceftibuten is indicated for the treatment of individuals with mild-to-moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below.
- Due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin-susceptible strains only).
- Dosage: 400 mg ORALLY once daily for 10 days
- Due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pyogenes.
- Dosage for 6 months to 12 years old: 9 mg/kg ORALLY once daily for 10 days; MAX, 400 mg/day
- Dosage for 12 years and older: 400 mg ORALLY once daily for 10 days
- Due to Streptococcus pyogenes.
- Dosage for 6 months to 12 years old: 9 mg/kg ORALLY once daily for 10 days; MAX, 400 mg/day
- Dosage for 12 years and older: 400 mg ORALLY once daily for 10 days
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftibuten in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftibuten in pediatric patients.
# Contraindications
Ceftibuten is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
# Warnings
BEFORE THERAPY WITH CEFTIBUTEN IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFTIBUTEN, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO THE CEFTIBUTEN OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftibuten, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile.
# Adverse Reactions
## Clinical Trials Experience
In clinical trials, 1728 adult patients (1092 US and 636 international) were treated with the recommended dose of ceftibuten capsules (400 mg per day). There were no deaths or permanent disabilities thought due to drug toxicity in any of the patients in these studies. Thirty-six of 1728 (2%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea, vomiting, or nausea. Six of 1728 (0.3%) patients were discontinued due to rash or pruritus thought related to ceftibuten administration.
In the US trials, the following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to ceftibuten capsules in multipledose clinical trials (n = 1092 ceftibuten-treated patients).
In clinical trials, 1152 pediatric patients (772 US and 380 international), 97% of whom were younger than 12 years of age, were treated with the recommended dose of ceftibuten (9 mg/kg once daily up to a maximum dose of 400 mg per day) for 10 days. There were no deaths, life-threatening adverse events, or permanent disabilities in any of the patients in these studies. Eight of 1152 (<1%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. The discontinuations were primarily (7 out of 8) for gastrointestinal disturbances, usually diarrhea or vomiting. One patient was discontinued due to a cutaneous rash thought possibly related to ceftibuten administration.
In the US trials, the following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to ceftibuten oral suspension in multipledose clinical trials (n = 772 ceftibuten-treated patients).
## Postmarketing Experience
The following adverse experiences have been reported during worldwide post-marketing surveillance: aphasia, jaundice, melena, psychosis, serum sickness-like reactions, stridor, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
In addition to the adverse reactions listed above that have been observed in patients treated with ceftibuten capsules, the following adverse events and altered laboratory tests have been reported for cephalosporin-class antibiotics:
- allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, renal dysfunction, toxic nephropathy, hepatic cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, false-positive test for urinary glucose, neutropenia, pancytopenia, and agranulocytosis. Pseudomembranous colitis; onset of symptoms may occur during or after antibiotic treatment.
Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
# Drug Interactions
Twelve healthy male volunteers were administered one 200-mg ceftibuten capsule twice daily for 6 days. With the morning dose of ceftibuten on day 6, each volunteer received a single intravenous infusion of theophylline (4 mg/kg). The pharmacokinetics of theophylline were not altered. The effect of ceftibuten on the pharmacokinetics of theophylline administered orally has not been investigated.
The effect of increased gastric pH on the bioavailability of ceftibuten was evaluated in 18 healthy adult volunteers. Each volunteer was administered one 400-mg ceftibuten capsule. A single dose of liquid antacid did not affect the Cmax or AUC of ceftibuten; however, 150 mg of ranitidine q12h for 3 days increased the ceftibuten Cmax by 23% and ceftibuten AUC by 16%. The clinical relevance of these increases is not known.
There have been no chemical or laboratory test interactions with ceftibuten noted to date. False-positive direct Coombs' tests have been reported during treatment with other cephalosporins. Therefore, it should be recognized that a positive Coombs' test could be due to the drug. The results of assays using red cells from healthy subjects to determine whether ceftibuten would cause direct Coombs' reactions in vitro showed no positive reaction at ceftibuten concentrations as high as 40 µg/mL.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Ceftibuten was not teratogenic in the pregnant rat at oral doses up to 400 mg/kg/day (approximately 8.6 times the human dose based on mg/m2/day). Ceftibuten was not teratogenic in the pregnant rabbit at oral doses up to 40 mg/kg/day (approximately 1.5 times the human dose based on mg/m2/day) and has revealed no evidence of harm to the fetus. There are no adequate and well-controlled studies in pregnant 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 Ceftibuten in women who are pregnant.
### Labor and Delivery
Ceftibuten has not been studied for use during labor and delivery. Its use during such clinical situations should be weighed in terms of potential risk and benefit to both mother and fetus.
### Nursing Mothers
It is not known whether ceftibuten (at recommended dosages) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ceftibuten is administered to a nursing woman.
### Pediatric Use
The safety and efficacy of ceftibuten in infants less than 6 months of age has not been established.
### Geriatic Use
The usual adult dosage recommendation may be followed for patients in this age group. However, these patients should be monitored closely, particularly their renal function, as dosage adjustment may be required.
### Gender
There is no FDA guidance on the use of Ceftibuten with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ceftibuten with respect to specific racial populations.
### Renal Impairment
Ceftibuten pharmacokinetics have been investigated in adult patients with renal dysfunction. The ceftibuten plasma half-life increased and apparent total clearance (CI/F) decreased proportionately with increasing degree of renal dysfunction. In 6 patients with moderate renal dysfunction (creatinine clearance 30 to 49 mL/min), the plasma half-life of ceftibuten increased to 7.1 hours and CI/F decreased to 30 mL/min. In 6 patients with severe renal dysfunction (creatinine clearance 5 to 29 mL/min), the half-life increased to 13.4 hours and CI/F decreased to 16 mL/min. In 6 functionally anephric patients (creatinine clearance <5 mL/min), the half-life increased to 22.3 hours and CI/F decreased to 11 mL/min (a 7- to 8-fold change compared to healthy volunteers). Hemodialysis removed 65% of the drug from the blood in 2 to 4 hours. These changes serve as the basis for dosage adjustment recommendations in adult patients with mild to severe renal dysfunction.
### Hepatic Impairment
There is no FDA guidance on the use of Ceftibuten in patients with hepatic impairment.
### Females of Reproductive Potential and Males
No impairment of fertility occurred when rats were administered ceftibuten orally up to 2000 mg/kg/day (approximately 43 times the human dose based on mg/m2/day).
### Immunocompromised Patients
There is no FDA guidance one the use of Ceftibuten in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Ceftibuten Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ceftibuten and IV administrations.
# Overdosage
Overdosage of cephalosporins can cause cerebral irritation leading to convulsions. Ceftibuten is readily dialyzable and significant quantities (65% of plasma concentrations) can be removed from the circulation by a single hemodialysis session. Information does not exist with regard to removal of ceftibuten by peritoneal dialysis.
# Pharmacology
## Mechanism of Action
Ceftibuten exerts its bactericidal action by binding to essential target proteins of the bacterial cell wall. This binding leads to inhibition of cell-wall synthesis.
Ceftibuten is stable in the presence of most plasmid-mediated beta-lactamases, but it is not stable in the presence of chromosomally-mediated cephalosporinases produced in organisms such as Bacteroides, Citrobacter, Enterobacter, Morganella, and Serratia. Like other beta-lactam agents, ceftibuten should not be used against strains resistant to beta-lactams due to general mechanisms such as permeability or penicillin-binding protein changes like penicillin-resistant S. pneumoniae.
Ceftibuten has been shown to be active against most strains of the following organisms both in vitro and in clinical infections:
- Gram-positive aerobes:
- Streptococcus pneumoniae (penicillin-susceptible strains only) Streptococcus pyogenes
- Gram-negative aerobes:
- Haemophilus influenzae (including β-lactamase-producing strains) Moraxella catarrhalis (including β-lactamase-producing strains)
## Structure
Ceftibuten dihydrate has the following structural formula:
## Pharmacodynamics
There is limited information regarding Ceftibuten Pharmacodynamics in the drug label.
## Pharmacokinetics
Ceftibuten is rapidly absorbed after oral administration of Ceftibuten Capsules. The plasma concentrations and pharmacokinetic parameters of ceftibuten after a single 400-mg dose of Ceftibuten Capsules to 12 healthy adult male volunteers (20 to 39 years of age) are displayed in the table below. When Ceftibuten Capsules were administered once daily for 7 days, the average Cmax was 17.9 µg/mL on day 7. Therefore, ceftibuten accumulation in plasma is about 20% at steady state.
Ceftibuten is rapidly absorbed after oral administration of Ceftibuten Oral Suspension. The plasma concentrations and pharmacokinetic parameters of ceftibuten after a single 9-mg/kg dose of Ceftibuten Oral Suspension to 32 fasting pediatric patients (6 months to 12 years of age) are displayed in the following table:
The absolute bioavailability of Ceftibuten Oral Suspension has not been determined. The plasma concentrations of ceftibuten in pediatric patients are dose proportional following single doses of Ceftibuten Capsules of 200 mg and 400 mg and of Ceftibuten Oral Suspension between 4.5 mg/kg and 9 mg/kg.
The average apparent volume of distribution (V/F) of ceftibuten in 6 adult subjects is 0.21 L/kg (± 1 SD = 0.03 L/kg).
The average apparent volume of distribution (V/F) of ceftibuten in 32 fasting pediatric patients is 0.5 L/kg (± 1 SD = 0.2 L/kg).
Ceftibuten is 65% bound to plasma proteins. The protein binding is independent of plasma ceftibuten concentration.
In a study of 15 adults administered a single 400-mg dose of ceftibuten and scheduled to undergo bronchoscopy, the mean concentrations in epithelial lining fluid and bronchial mucosa were 15% and 37%, respectively, of the plasma concentrations.
Ceftibuten sputum levels average approximately 7% of the concomitant plasma ceftibuten level. In a study of 24 adults administered ceftibuten 200 mg bid or 400 mg qd, the average Cmax in sputum (1.5 µg/mL) occurred at 2 hours postdose and the average Cmax in plasma (17 µg/mL) occurred at 2 hours postdose.
In a study of 12 pediatric patients administered 9 mg/kg, ceftibuten MEF area under the curve (AUC) averaged approximately 70% of the plasma AUC. In the same study, Cmax values were 14.3 ± 2.7 µg/mL in MEF at 4 hours postdose and 14.5 ± 3.7 µg/mL in plasma at 2 hours postdose.
Data on ceftibuten penetration into tonsillar tissue are not available.
Data on ceftibuten penetration into cerebrospinal fluid are not available.
A study with radiolabeled ceftibuten administered to 6 healthy adult male volunteers demonstrated that cis-ceftibuten is the predominant component in both plasma and urine. About 10% of ceftibuten is converted to the trans-isomer. The trans-isomer is approximately ⅛ as antimicrobially potent as the cis-isomer.
Ceftibuten is excreted in the urine; 95% of the administered radioactivity was recovered either in urine or feces. In 6 healthy adult male volunteers, approximately 56% of the administered dose of ceftibuten was recovered from urine and 39% from the feces within 24 hours. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment.
Food affects the bioavailability of ceftibuten from Cefitbuten Capsules and Ceftibuten Oral Suspension.
The effect of food on the bioavailability of Ceftibuten Capsules was evaluated in 26 healthy adult male volunteers who ingested 400 mg of Ceftibuten Capsules after an overnight fast or immediately after a standardized breakfast. Results showed that food delays the time of Cmax by 1.75 hours, decreases the Cmax by 18%, and decreases the extent of absorption (AUC) by 8%.
The effect of food on the bioavailability of Ceftibuten Oral Suspension was evaluated in 18 healthy adult male volunteers who ingested 400 mg of Ceftibuten Oral Suspension after an overnight fast or immediately after a standardized breakfast. Results obtained demonstrated a decrease in Cmax of 26% and an AUC of 17% when Ceftibuten Oral Suspension was administered with a high-fat breakfast, and a decrease in Cmax of 17% and an AUC of 12% when Ceftibuten Oral Suspension was administered with a low-calorie nonfat breakfast.
## Nonclinical Toxicology
Long-term animal studies have not been performed to evaluate the carcinogenic potential of ceftibuten. No mutagenic effects were seen in the following studies: in vitro chromosome assay in human lymphocytes, in vivo chromosome assay in mouse bone marrow cells, Chinese Hamster Ovary (CHO) cell point mutation assay at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus, and in a bacterial reversion point mutation test (Ames).
# Clinical Studies
Three clinical trials (two domestic, the third abroad) have been conducted testing ceftibuten in the treatment of acute exacerbations of chronic bronchitis (AECB). Overall, the clinical outcome among patients who had signs and symptoms of AECB, who had a gram stain showing a predominance of PMNs and few epithelial cells, and who were evaluated at approximately 1 to 2 weeks after completing therapy were equivalent to comparators. The bacterial eradication rates of specific pathogens are presented below.
Four clinical trials (three domestic, the fourth abroad) have been conducted testing ceftibuten in the treatment of acute bacterial otitis media. Overall, the clinical outcome among patients who had signs and symptoms of acute bacterial otitis media and who were evaluated at approximately 1 to 2 weeks after completing therapy were equivalent to comparators. Tympanocentesis was performed on patients in three of the above-mentioned studies; the bacterial eradication rates of specific pathogens are presented below.
# How Supplied
- Ceftibuten Capsules, 400 mg
- 20 Capsules/Bottle (NDC 44183-400-22)
- Ceftibuten oral suspension, 180 mg/5 mL
- 36 mg/mL 30-mL Bottle (NDC 44183-180-30)
- 36 mg/mL 60-mL Bottle (NDC 44183-180-02)
## Storage
- Store the capsules between 2° and 25°C (36° and 77°F).
- Store de oral suspension between 2° and 25°C (36° and 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that:
- If the patient is diabetic, he/she should be informed that Ceftibuten Oral Suspension contains 1 gram sucrose per teaspoon of suspension.
- Ceftibuten Oral Suspension should be taken at least 2 hours before a meal or at least 1 hour after a meal
# Precautions with Alcohol
Alcohol-Ceftibuten interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cedax
# Look-Alike Drug Names
There is limited information regarding Ceftibuten Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ceftibuten
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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
Ceftibuten is a 3rd generation cephalosporin that is FDA approved for the treatment of acute bacterial exacerbations of chronic bronchitis, acute bacterial otitis media, pharyngitis and tonsillitis. Common adverse reactions include diarrhea, nausea, vomiting and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Ceftibuten is indicated for the treatment of individuals with mild-to-moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below.
- Due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin-susceptible strains only).
- Dosage: 400 mg ORALLY once daily for 10 days
- Due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pyogenes.
- Dosage: 400 mg ORALLY once daily for 10 days
- Due to Streptococcus pyogenes.
- Dosage: 400 mg ORALLY once daily for 10 days
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftibuten in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftibuten in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of ceftibuten in infants less than 6 months of age has not been established.
Ceftibuten is indicated for the treatment of individuals with mild-to-moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below.
- Due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pneumoniae (penicillin-susceptible strains only).
- Dosage: 400 mg ORALLY once daily for 10 days
- Due to Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), or Streptococcus pyogenes.
- Dosage for 6 months to 12 years old: 9 mg/kg ORALLY once daily for 10 days; MAX, 400 mg/day
- Dosage for 12 years and older: 400 mg ORALLY once daily for 10 days
- Due to Streptococcus pyogenes.
- Dosage for 6 months to 12 years old: 9 mg/kg ORALLY once daily for 10 days; MAX, 400 mg/day
- Dosage for 12 years and older: 400 mg ORALLY once daily for 10 days
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ceftibuten in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ceftibuten in pediatric patients.
# Contraindications
Ceftibuten is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
# Warnings
BEFORE THERAPY WITH CEFTIBUTEN IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFTIBUTEN, OTHER CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO THE CEFTIBUTEN OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ceftibuten, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile.
# Adverse Reactions
## Clinical Trials Experience
In clinical trials, 1728 adult patients (1092 US and 636 international) were treated with the recommended dose of ceftibuten capsules (400 mg per day). There were no deaths or permanent disabilities thought due to drug toxicity in any of the patients in these studies. Thirty-six of 1728 (2%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. The discontinuations were primarily for gastrointestinal disturbances, usually diarrhea, vomiting, or nausea. Six of 1728 (0.3%) patients were discontinued due to rash or pruritus thought related to ceftibuten administration.
In the US trials, the following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to ceftibuten capsules in multipledose clinical trials (n = 1092 ceftibuten-treated patients).
In clinical trials, 1152 pediatric patients (772 US and 380 international), 97% of whom were younger than 12 years of age, were treated with the recommended dose of ceftibuten (9 mg/kg once daily up to a maximum dose of 400 mg per day) for 10 days. There were no deaths, life-threatening adverse events, or permanent disabilities in any of the patients in these studies. Eight of 1152 (<1%) patients discontinued medication due to adverse events thought by the investigators to be possibly, probably, or almost certainly related to drug toxicity. The discontinuations were primarily (7 out of 8) for gastrointestinal disturbances, usually diarrhea or vomiting. One patient was discontinued due to a cutaneous rash thought possibly related to ceftibuten administration.
In the US trials, the following adverse events were thought by the investigators to be possibly, probably, or almost certainly related to ceftibuten oral suspension in multipledose clinical trials (n = 772 ceftibuten-treated patients).
## Postmarketing Experience
The following adverse experiences have been reported during worldwide post-marketing surveillance: aphasia, jaundice, melena, psychosis, serum sickness-like reactions, stridor, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
In addition to the adverse reactions listed above that have been observed in patients treated with ceftibuten capsules, the following adverse events and altered laboratory tests have been reported for cephalosporin-class antibiotics:
- allergic reactions, anaphylaxis, drug fever, Stevens-Johnson syndrome, renal dysfunction, toxic nephropathy, hepatic cholestasis, aplastic anemia, hemolytic anemia, hemorrhage, false-positive test for urinary glucose, neutropenia, pancytopenia, and agranulocytosis. Pseudomembranous colitis; onset of symptoms may occur during or after antibiotic treatment.
Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.
# Drug Interactions
Twelve healthy male volunteers were administered one 200-mg ceftibuten capsule twice daily for 6 days. With the morning dose of ceftibuten on day 6, each volunteer received a single intravenous infusion of theophylline (4 mg/kg). The pharmacokinetics of theophylline were not altered. The effect of ceftibuten on the pharmacokinetics of theophylline administered orally has not been investigated.
The effect of increased gastric pH on the bioavailability of ceftibuten was evaluated in 18 healthy adult volunteers. Each volunteer was administered one 400-mg ceftibuten capsule. A single dose of liquid antacid did not affect the Cmax or AUC of ceftibuten; however, 150 mg of ranitidine q12h for 3 days increased the ceftibuten Cmax by 23% and ceftibuten AUC by 16%. The clinical relevance of these increases is not known.
There have been no chemical or laboratory test interactions with ceftibuten noted to date. False-positive direct Coombs' tests have been reported during treatment with other cephalosporins. Therefore, it should be recognized that a positive Coombs' test could be due to the drug. The results of assays using red cells from healthy subjects to determine whether ceftibuten would cause direct Coombs' reactions in vitro showed no positive reaction at ceftibuten concentrations as high as 40 µg/mL.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Ceftibuten was not teratogenic in the pregnant rat at oral doses up to 400 mg/kg/day (approximately 8.6 times the human dose based on mg/m2/day). Ceftibuten was not teratogenic in the pregnant rabbit at oral doses up to 40 mg/kg/day (approximately 1.5 times the human dose based on mg/m2/day) and has revealed no evidence of harm to the fetus. There are no adequate and well-controlled studies in pregnant 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 Ceftibuten in women who are pregnant.
### Labor and Delivery
Ceftibuten has not been studied for use during labor and delivery. Its use during such clinical situations should be weighed in terms of potential risk and benefit to both mother and fetus.
### Nursing Mothers
It is not known whether ceftibuten (at recommended dosages) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ceftibuten is administered to a nursing woman.
### Pediatric Use
The safety and efficacy of ceftibuten in infants less than 6 months of age has not been established.
### Geriatic Use
The usual adult dosage recommendation may be followed for patients in this age group. However, these patients should be monitored closely, particularly their renal function, as dosage adjustment may be required.
### Gender
There is no FDA guidance on the use of Ceftibuten with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ceftibuten with respect to specific racial populations.
### Renal Impairment
Ceftibuten pharmacokinetics have been investigated in adult patients with renal dysfunction. The ceftibuten plasma half-life increased and apparent total clearance (CI/F) decreased proportionately with increasing degree of renal dysfunction. In 6 patients with moderate renal dysfunction (creatinine clearance 30 to 49 mL/min), the plasma half-life of ceftibuten increased to 7.1 hours and CI/F decreased to 30 mL/min. In 6 patients with severe renal dysfunction (creatinine clearance 5 to 29 mL/min), the half-life increased to 13.4 hours and CI/F decreased to 16 mL/min. In 6 functionally anephric patients (creatinine clearance <5 mL/min), the half-life increased to 22.3 hours and CI/F decreased to 11 mL/min (a 7- to 8-fold change compared to healthy volunteers). Hemodialysis removed 65% of the drug from the blood in 2 to 4 hours. These changes serve as the basis for dosage adjustment recommendations in adult patients with mild to severe renal dysfunction.
### Hepatic Impairment
There is no FDA guidance on the use of Ceftibuten in patients with hepatic impairment.
### Females of Reproductive Potential and Males
No impairment of fertility occurred when rats were administered ceftibuten orally up to 2000 mg/kg/day (approximately 43 times the human dose based on mg/m2/day).
### Immunocompromised Patients
There is no FDA guidance one the use of Ceftibuten in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Ceftibuten Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ceftibuten and IV administrations.
# Overdosage
Overdosage of cephalosporins can cause cerebral irritation leading to convulsions. Ceftibuten is readily dialyzable and significant quantities (65% of plasma concentrations) can be removed from the circulation by a single hemodialysis session. Information does not exist with regard to removal of ceftibuten by peritoneal dialysis.
# Pharmacology
## Mechanism of Action
Ceftibuten exerts its bactericidal action by binding to essential target proteins of the bacterial cell wall. This binding leads to inhibition of cell-wall synthesis.
Ceftibuten is stable in the presence of most plasmid-mediated beta-lactamases, but it is not stable in the presence of chromosomally-mediated cephalosporinases produced in organisms such as Bacteroides, Citrobacter, Enterobacter, Morganella, and Serratia. Like other beta-lactam agents, ceftibuten should not be used against strains resistant to beta-lactams due to general mechanisms such as permeability or penicillin-binding protein changes like penicillin-resistant S. pneumoniae.
Ceftibuten has been shown to be active against most strains of the following organisms both in vitro and in clinical infections:
- Gram-positive aerobes:
- Streptococcus pneumoniae (penicillin-susceptible strains only) Streptococcus pyogenes
- Gram-negative aerobes:
- Haemophilus influenzae (including β-lactamase-producing strains) Moraxella catarrhalis (including β-lactamase-producing strains)
## Structure
Ceftibuten dihydrate has the following structural formula:
[[|File:Ceftibuten chemical structure.pngthumb|none|500px]]
## Pharmacodynamics
There is limited information regarding Ceftibuten Pharmacodynamics in the drug label.
## Pharmacokinetics
Ceftibuten is rapidly absorbed after oral administration of Ceftibuten Capsules. The plasma concentrations and pharmacokinetic parameters of ceftibuten after a single 400-mg dose of Ceftibuten Capsules to 12 healthy adult male volunteers (20 to 39 years of age) are displayed in the table below. When Ceftibuten Capsules were administered once daily for 7 days, the average Cmax was 17.9 µg/mL on day 7. Therefore, ceftibuten accumulation in plasma is about 20% at steady state.
Ceftibuten is rapidly absorbed after oral administration of Ceftibuten Oral Suspension. The plasma concentrations and pharmacokinetic parameters of ceftibuten after a single 9-mg/kg dose of Ceftibuten Oral Suspension to 32 fasting pediatric patients (6 months to 12 years of age) are displayed in the following table:
The absolute bioavailability of Ceftibuten Oral Suspension has not been determined. The plasma concentrations of ceftibuten in pediatric patients are dose proportional following single doses of Ceftibuten Capsules of 200 mg and 400 mg and of Ceftibuten Oral Suspension between 4.5 mg/kg and 9 mg/kg.
The average apparent volume of distribution (V/F) of ceftibuten in 6 adult subjects is 0.21 L/kg (± 1 SD = 0.03 L/kg).
The average apparent volume of distribution (V/F) of ceftibuten in 32 fasting pediatric patients is 0.5 L/kg (± 1 SD = 0.2 L/kg).
Ceftibuten is 65% bound to plasma proteins. The protein binding is independent of plasma ceftibuten concentration.
In a study of 15 adults administered a single 400-mg dose of ceftibuten and scheduled to undergo bronchoscopy, the mean concentrations in epithelial lining fluid and bronchial mucosa were 15% and 37%, respectively, of the plasma concentrations.
Ceftibuten sputum levels average approximately 7% of the concomitant plasma ceftibuten level. In a study of 24 adults administered ceftibuten 200 mg bid or 400 mg qd, the average Cmax in sputum (1.5 µg/mL) occurred at 2 hours postdose and the average Cmax in plasma (17 µg/mL) occurred at 2 hours postdose.
In a study of 12 pediatric patients administered 9 mg/kg, ceftibuten MEF area under the curve (AUC) averaged approximately 70% of the plasma AUC. In the same study, Cmax values were 14.3 ± 2.7 µg/mL in MEF at 4 hours postdose and 14.5 ± 3.7 µg/mL in plasma at 2 hours postdose.
Data on ceftibuten penetration into tonsillar tissue are not available.
Data on ceftibuten penetration into cerebrospinal fluid are not available.
A study with radiolabeled ceftibuten administered to 6 healthy adult male volunteers demonstrated that cis-ceftibuten is the predominant component in both plasma and urine. About 10% of ceftibuten is converted to the trans-isomer. The trans-isomer is approximately ⅛ as antimicrobially potent as the cis-isomer.
Ceftibuten is excreted in the urine; 95% of the administered radioactivity was recovered either in urine or feces. In 6 healthy adult male volunteers, approximately 56% of the administered dose of ceftibuten was recovered from urine and 39% from the feces within 24 hours. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment.
Food affects the bioavailability of ceftibuten from Cefitbuten Capsules and Ceftibuten Oral Suspension.
The effect of food on the bioavailability of Ceftibuten Capsules was evaluated in 26 healthy adult male volunteers who ingested 400 mg of Ceftibuten Capsules after an overnight fast or immediately after a standardized breakfast. Results showed that food delays the time of Cmax by 1.75 hours, decreases the Cmax by 18%, and decreases the extent of absorption (AUC) by 8%.
The effect of food on the bioavailability of Ceftibuten Oral Suspension was evaluated in 18 healthy adult male volunteers who ingested 400 mg of Ceftibuten Oral Suspension after an overnight fast or immediately after a standardized breakfast. Results obtained demonstrated a decrease in Cmax of 26% and an AUC of 17% when Ceftibuten Oral Suspension was administered with a high-fat breakfast, and a decrease in Cmax of 17% and an AUC of 12% when Ceftibuten Oral Suspension was administered with a low-calorie nonfat breakfast.
## Nonclinical Toxicology
Long-term animal studies have not been performed to evaluate the carcinogenic potential of ceftibuten. No mutagenic effects were seen in the following studies: in vitro chromosome assay in human lymphocytes, in vivo chromosome assay in mouse bone marrow cells, Chinese Hamster Ovary (CHO) cell point mutation assay at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus, and in a bacterial reversion point mutation test (Ames).
# Clinical Studies
Three clinical trials (two domestic, the third abroad) have been conducted testing ceftibuten in the treatment of acute exacerbations of chronic bronchitis (AECB). Overall, the clinical outcome among patients who had signs and symptoms of AECB, who had a gram stain showing a predominance of PMNs and few epithelial cells, and who were evaluated at approximately 1 to 2 weeks after completing therapy were equivalent to comparators. The bacterial eradication rates of specific pathogens are presented below.
Four clinical trials (three domestic, the fourth abroad) have been conducted testing ceftibuten in the treatment of acute bacterial otitis media. Overall, the clinical outcome among patients who had signs and symptoms of acute bacterial otitis media and who were evaluated at approximately 1 to 2 weeks after completing therapy were equivalent to comparators. Tympanocentesis was performed on patients in three of the above-mentioned studies; the bacterial eradication rates of specific pathogens are presented below.
# How Supplied
- Ceftibuten Capsules, 400 mg
- 20 Capsules/Bottle (NDC 44183-400-22)
- Ceftibuten oral suspension, 180 mg/5 mL
- 36 mg/mL 30-mL Bottle (NDC 44183-180-30)
- 36 mg/mL 60-mL Bottle (NDC 44183-180-02)
## Storage
- Store the capsules between 2° and 25°C (36° and 77°F).
- Store de oral suspension between 2° and 25°C (36° and 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that:
- If the patient is diabetic, he/she should be informed that Ceftibuten Oral Suspension contains 1 gram sucrose per teaspoon of suspension.
- Ceftibuten Oral Suspension should be taken at least 2 hours before a meal or at least 1 hour after a meal
# Precautions with Alcohol
Alcohol-Ceftibuten interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cedax [1]
# Look-Alike Drug Names
There is limited information regarding Ceftibuten Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ceftibuten | |
aaa12c93e55c657af5d788b4e1b57b4a78230a34 | wikidoc | Citalopram | Citalopram
# 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
Citalopram is an antidepressive agent that is FDA approved for the treatment of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diaphoresis, constipation, diarrhea, nausea, vomiting, xerostomia, dizziness, headache, insomnia, sedation, somnolence, tremor, agitation, disorder of ejaculation, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### DEPRESSION
- Citalopram tablets, USP are indicated for the treatment of depression.
- The efficacy of citalopram tablets, USP in the treatment of depression was established in 4 to 6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the DSM-III and DSM-III-R category of major depressive disorder.
- A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The antidepressant action of citalopram tablets, USP in hospitalized depressed patients has not been adequately studied.
- The efficacy of citalopram tablets, USP in maintaining an antidepressant response for up to 24 weeks following 6 to 8 weeks of acute treatment was demonstrated in two placebo-controlled trials. Nevertheless, the physician who elects to use citalopram tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing information:
- Discontinue with gradual dose reduction and monitoring for withdrawal symptoms
- Doses above 40 mg/day are not recommended due to the risk for QT prolongation
- Depression: initial, 20 mg/day ORALLY as a single dose in the morning or evening; dose increases should usually occur in increments of 20 mg at intervals of no less than one week; MAX, 40 mg/day
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Citalopram Hydrobromide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Citalopram Hydrobromide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Citalopram 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 Citalopram Hydrobromide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Citalopram Hydrobromide in pediatric patients.
# Contraindications
- The use of MAOIs intended to treat psychiatric disorders with citalopram tablets or within 14 days of stopping treatment with citalopram tablets are contraindicated because of an increased risk of serotonin syndrome. The use of citalopram tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders are also contraindicated.
- Starting citalopram tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
- Concomitant use in patients taking pimozide is contraindicated.
- Citalopram tablets are contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in citalopram tablets.
# Warnings
WARNINGS-Clinical Worsening and Suicide Risk
Clinical Worsening and Suicide Risk
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
- Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
- There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment with Citalopram Tablets, for a description of the risks of discontinuation of citalopram).
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for citalopram should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
QT-Prolongation and Torsade de Pointes
- Citalopram causes dose-dependent QTc prolongation, an ECG abnormality that has been associated with Torsade de Pointes (TdP), ventricular tachycardia, and sudden death, all of which have been observed in postmarketing reports for citalopram.
- Individually corrected QTc (QTcNi) interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 119 healthy subjects. The maximum mean (upper bound of the 95% one-sided confidence interval) difference from placebo were 8.5 (10.8) and 18.5 (21) msec for 20 mg and 60 mg citalopram, respectively. Based on the established exposure-response relationship, the predicted QTcNi change from placebo (upper bound of the 95% one-sided confidence interval) under the Cmax for the dose of 40 mg is 12.6 (14.3) msec.
- Because of the risk of QTc prolongation at higher citalopram doses, it is recommended that citalopram should not be given at doses above 40 mg/day.
- It is recommended that citalopram should not be used in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. Citalopram should also not be used in patients who are taking other drugs that prolong the QTc interval. Such drugs include Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).
- The citalopram dose should be limited in certain populations. The maximum dose should be limited to 20 mg/day in patients who are CYP2C19 poor metabolizers or those patients who may be taking concomitant cimetidine or another CYP2C19 inhibitor, since higher citalopram exposures would be expected. The maximum dose should also be limited to 20 mg/day in patients with hepatic impairment and in patients who are greater than 60 years of age because of expected higher exposures.
- Electrolyte and/or ECG monitoring is recommended in certain circumstances. Patients being considered for citalopram treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QTc prolongation and arrhythmia, and should be corrected prior to initiation of treatment and periodically monitored. ECG monitoring is recommended in patients for whom citalopram use is not recommended (see above), but, nevertheless, considered essential. These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval.
- Citalopram should be discontinued in patients who are found to have persistent QTc measurements >500 ms. If patients taking citalopram experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.
Screening Patients for Bipolar Disorder
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that citalopram is not approved for use in treating bipolar depression.
Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including citalopram, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, trytophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of citalopram with MAOIs intended to treat psychiatric disorders is contraindicated. Citalopram should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking citalopram. Citalopram should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and ADMINISTRATION).
- If concomitant use of citalopram with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, trytophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome particularly during treatment initiation and dose increases.
- Treatment with citalopram and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
- The pupillary dilation that occurs following use of many antidepressant drugs including citalopram may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
### PRECAUTIONS
General
Discontinuation of Treatment with Citalopram
- During marketing of citalopram and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Patients should be monitored for these symptoms when discontinuing treatment with citalopram. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).
Abnormal Bleeding
- SSRIs and SNRIs, including citalopram, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of citalopram and NSAIDs, aspirin, or other drugs that affect coagulation.
Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including citalopram. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when citalopram was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
- Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Activation of Mania/Hypomania
- In placebo-controlled trials of citalopram, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with citalopram and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. As with all antidepressants, citalopram should be used cautiously in patients with a history of mania.
Seizures
- Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product’s premarketing testing. In clinical trials of citalopram, seizures occurred in 0.3% of patients treated with citalopram (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Like other antidepressants, citalopram should be introduced with care in patients with a history of seizure disorder.
Interference with Cognitive and Motor Performance
- In studies in normal volunteers, citalopram in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities.
Use in Patients with Concomitant Illness
- Clinical experience with citalopram in patients with certain concomitant systemic illnesses is limited. Due to the risk of QT prolongation, citalopram use should be avoided in patients with certain cardiac conditions, and ECG monitoring is advised if citalopram must be used in such patients. Electrolytes should be monitored in treating patients with diseases or conditions that cause hypokalemia or hypomagnesemia (see WARNINGS).
- In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION).
- Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with citalopram, however, they should be used with caution in such patients (see ADMINISTRATION).
# Adverse Reactions
## Clinical Trials Experience
- The premarketing development program for citalopram included citalopram exposures in patients and/or normal subjects from 3 different groups of studies: 429 normal subjects in clinical pharmacology/pharmacokinetic studies; 4422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1370 patient-exposure years. There were, in addition, over 19,000 exposures from mostly open-label, European postmarketing studies. The conditions and duration of treatment with citalopram varied greatly and included (in overlapping categories) open-label and double-blind studies, inpatient and outpatient studies, fixed-dose and dose-titration studies, and short-term and long-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.
- Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.
- The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials
Adverse Events Associated with Discontinuation of Treatment:
- Among 1063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse event, as compared to 8% of 446 patients receiving placebo. The adverse events associated with discontinuation and considered drug-related (i.e., associated with discontinuation in at least 1% of citalopram-treated patients at a rate at least twice that of placebo) are shown in TABLE 2. It should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table.
- Adverse Events Occurring at an Incidence of 2% or More Among Citalopram-Treated Patients
- Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 1063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration. Events included are those occurring in 2% or more of patients treated with citalopram and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients.
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.
- The only commonly observed adverse event that occurred in citalopram patients with an incidence of 5% or greater and at least twice the incidence in placebo patients was ejaculation disorder (primarily ejaculatory delay) in male patients (see TABLE 3).
Dose Dependency of Adverse Events
- The potential relationship between the dose of citalopram administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or citalopram 10 mg, 20 mg, 40 mg, and 60 mg. Jonckheere’s trend test revealed a positive dose response (p<0.05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning.
Male and Female Sexual Dysfunction with SSRIs
- Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.
- Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.
- The table below displays the incidence of sexual side effects reported by at least 2% of patients taking citalopram tablets in a pool of placebo-controlled clinical trials in patients with depression.
- In female depressed patients receiving citalopram, the reported incidence of decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively.
- There are no adequately designed studies examining sexual dysfunction with citalopram treatment.
- Priapism has been reported with all SSRIs.
- While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Vital Sign Changes
- Citalopram and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with citalopram treatment. In addition, a comparison of supine and standing vital sign measures for citalopram and placebo treatments indicated that citalopram treatment is not associated with orthostatic changes.
Weight Changes
- Patients treated with citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.
Laboratory Changes
- Citalopram and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with citalopram treatment.
ECG Changes
- In a thorough QT study, citalopram was found to be associated with a dose-dependent increase in the QTc interval (see WARNINGS - QT-Prolongation and Torsade de Pointes).
- Electrocardiograms from citalopram (N=802) and placebo (N=241) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). In the citalopram group 1.9% of the patients had a change from baseline in QTcF >60 msec compared to 1.2% of the patients in the placebo group. None of the patients in the placebo group had a post-dose QTcF >500 msec compared to 0.5% of the patients in the citalopram group. The incidence of tachycardic outliers was 0.5% in the citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the citalopram group and 0.4% in the placebo group.
Other Events Observed During the Premarketing Evaluation of Citalopram Hydrobromide
- Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by patients treated with citalopram at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4422 patients. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those occurring in only one patient. It is important to emphasize that, although the events reported occurred during treatment with citalopram, they were not necessarily caused by it.
- Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
- Cardiovascular - Frequent: tachycardia, postural hypotension, hypotension. Infrequent: hypertension, bradycardia, edema (extremities), angina pectoris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident, myocardial ischemia. Rare: transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block.
- Central and Peripheral Nervous System Disorders - Frequent: paresthesia, migraine. Infrequent: hyperkinesia, vertigo, hypertonia, extrapyramidal disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia. Rare: abnormal coordination, hyperesthesia, ptosis, stupor.
- Endocrine Disorders - Rare: hypothyroidism, goiter, gynecomastia.
- Gastrointestinal Disorders - Frequent: saliva increased, flatulence. Infrequent: gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis. Rare: colitis, gastric ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups.
- General - Infrequent: hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms. Rare: hayfever.
- Hemic and Lymphatic Disorders - Infrequent: purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy. Rare: pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding.
- Metabolic and Nutritional Disorders - Frequent: decreased weight, increased weight. Infrequent: increased hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance. Rare: bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration.
- Musculoskeletal System Disorders - Infrequent: arthritis, muscle weakness, skeletal pain. Rare: bursitis, osteoporosis.
- Psychiatric Disorders - Frequent: impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion. Infrequent: increased libido, aggressive reaction, paroniria, drug dependence, depersonalization, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis. Rare: catatonic reaction, melancholia.
- Reproductive Disorders/Female- - Frequent: amenorrhea. Infrequent: galactorrhea, breast pain, breast enlargement, vaginal hemorrhage.
- % based on female subjects only: 2955
- Respiratory System Disorders - Frequent: coughing. Infrequent: bronchitis, dyspnea, pneumonia. Rare: asthma, laryngitis, bronchospasm, pneumonitis, sputum increased.
- Skin and Appendages Disorders - Frequent: rash, pruritus. Infrequent: photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. Rare: hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani.
- Special Senses - Frequent: accommodation abnormal, taste perversion. Infrequent: tinnitus, conjunctivitis, eye pain. Rare: mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss.
- Urinary System Disorders - Frequent: polyuria. Infrequent: micturition frequency, urinary incontinence, urinary retention, dysuria. Rare: facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
- Citalopram hydrobromide is not a controlled substance.
Physical and Psychological Dependence
- Animal studies suggest that the abuse liability of citalopram is low. Citalopram has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with citalopram did not reveal any drug-seeking behavior. However, these observations were not systematic and it is not possible to predict, on the basis of this limited experience, the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate citalopram patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
## Postmarketing Experience
- Other Events Observed During the Postmarketing Evaluation of Citalopram Hydrobromide
- It is estimated that over 30 million patients have been treated with citalopram since market introduction. Although no causal relationship to citalopram treatment has been found, the following adverse events have been reported to be temporally associated with citalopram treatment, and have not been described elsewhere in labeling: acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, angle-closure glaucoma, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsade de pointes, and withdrawal syndrome.
# Drug Interactions
- Serotonergic Drugs: See CONTRAINDICATIONS, WARNINGS, and ADMINISTRATION.
- Triptans:
- There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of citalopram with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS - Serotonin Syndrome).
- CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.
- Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended.
- Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.
- Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when citalopram is initiated or discontinued.
- Cimetidine - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively.
- Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation (see WARNINGS and ADMINISTRATION).
- Digoxin – In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram tablets and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.
- Lithium - Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram tablets and lithium are coadministered.
- Pimozide – In a controlled study, a single dose of pimozide 2 mg coadministered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.
- Theophylline - Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.
- Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised.
- Warfarin - Administration of 40 mg/day citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.
- Carbamazepine - Combined administration of citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.
- Triazolam - Combined administration of citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.
- Ketoconazole - Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
- CYP2C19 Inhibitors - Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation (see WARNINGS, ADMINISTRATION, and PHARMACOLOGY).
- Metoprolol - Administration of 40 mg/day citalopram for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram and metoprolol had no clinically significant effects on blood pressure or heart rate.
- Imipramine and Other Tricyclic Antidepressants (TCAs) - In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with citalopram.
- Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.
- In two rat embryo/fetal development studies, oral administration of citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a body surface area (mg/m2) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/m2 basis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m2 basis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit.
- When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/m2 basis. The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m2 basis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m2 basis. A no-effect dose was not determined in that study.
- There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy-Nonteratogenic Effects
- Neonates exposed to citalopram and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome).
- Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including citalopram) in pregnancy and PPHN. Other studies do not show a significant statistical association.
- Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
- When treating a pregnant woman with citalopram, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see ADMINISTRATION).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Citalopram in women who are pregnant.
### Labor and Delivery
The effect of citalopram on labor and delivery in humans is unknown.
### Nursing Mothers
- As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram treatment for the mother.
### Pediatric Use
- Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS–-Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with citalopram, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of citalopram in a child or adolescent must balance the potential risks with the clinical need.
- Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with citalopram.
### Geriatic Use
- Of 4422 patients in clinical studies of citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Most elderly patients treated with citalopram in clinical trials received daily doses between 20 mg and 40 mg (see DOSAGE AND ADMINISTRATION).
- SSRIs and SNRIs, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
- In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in subjects ≥ 60 years of age as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively (see PHARMACOLOGY).
- 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see WARNINGS and DOSAGE AND ADMINISTRATION).
### Gender
There is no FDA guidance on the use of Citalopram with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Citalopram with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Citalopram in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Citalopram in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Citalopram in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Citalopram in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Citalopram tablets
- should be administered once daily, in the morning or evening, with or without food.
Initial Treatment
Citalopram tablets
- should be administered at an initial dose of 20 mg once daily, with an increase to a maximum dose of 40 mg/day at an interval of no less than one week. Doses above 40 mg/day are not recommended due to the risk of QT prolongation. Additionally, the only study pertinent to dose response for effectiveness did not demonstrate an advantage for the 60 mg/day dose over the 40 mg/day dose.
Special Populations
- 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers or those patients taking cimetidine or another CYP2C19 inhibitor (see WARNINGS).
- No dosage adjustment is necessary for patients with mild or moderate renal impairment. Citalopram tablets should be used with caution in patients with severe renal impairment.
Treatment of Pregnant Women During the Third Trimester
- Neonates exposed to citalopram tablets and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with citalopram tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Maintenance Treatment
- It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of citalopram tablets in two studies have shown that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment (32 weeks total). In one study, patients were assigned randomly to placebo or to the same dose of citalopram tablets (20 to 60 mg/day) during maintenance treatment as they had received during the acute stabilization phase, while in the other study, patients were assigned randomly to continuation of citalopram tablets 20 or 40 mg/day, or placebo, for maintenance treatment. In the latter study, the rates of relapse to depression were similar for the two dose groups (see Clinical Trials). Based on these limited data, it is not known whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. If adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered.
Discontinuation of Treatment with Citalopram Tablets
- Symptoms associated with discontinuation of citalopram tablets and other SSRIs and SNRIs have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
- At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with citalopram tablets. Conversely, at least 14 days should be allowed after stopping citalopram tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).
- Use of Citalopram Tablets with Other MAOIs, Such as Linezolid or Methylene Blue
- Do not start citalopram tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).
- In some cases, a patient already receiving citalopram tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, citalopram tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with citalopram tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).
- The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with citalopram tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
### Monitoring
- Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.
- Electrolyte and/or ECG monitoring is recommended in certain circumstances. Patients being considered for citalopram treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QTc prolongation and arrhythmia, and should be corrected prior to initiation of treatment and periodically monitored. ECG monitoring is recommended in patients for whom citalopram use is not recommended (see above), but, nevertheless, considered essential. These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval.
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- Patients should be monitored for the following symptoms when discontinuing treatment with citalopram: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when citalopram is initiated or discontinued.
- Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram tablets and lithium are coadministered.
- Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with citalopram.
# IV Compatibility
There is limited information regarding the compatibility of Citalopram and IV administrations.
# Overdosage
Human Experience
- In clinical trials of citalopram, there were reports of citalopram overdose, including overdoses of up to 2000 mg, with no associated fatalities. During the postmarketing evaluation of citalopram, citalopram overdoses, including overdoses of up to 6000 mg, have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of citalopram has been rarely reported.
- Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.
Management of Overdose
- Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for citalopram.
- In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.
# Pharmacology
## Mechanism of Action
- The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.
## Structure
- Citalopram hydrobromide is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram hydrobromide is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, hydrobromide with the following structural formula:
- The molecular formula is C20H22BrFN2O and its molecular weight is 405.35.
- Citalopram hydrobromide USP occurs as a fine, white to off-white powder. Citalopram hydrobromide is sparingly soluble in water and soluble in ethanol.
- Citalopram hydrobromide is available only in tablet dosage form.
- Citalopram 10 mg tablets are biconvex, round shaped film coated tablets in strengths equivalent to 10 mg citalopram base. Citalopram 20 mg and 40 mg tablets are scored biconvex capsule shaped film coated tablets containing citalopram hydrobromide in strengths equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the following inactive ingredients: copovidone, corn starch, croscarmellose sodium, lactose monohydrate, magnesium stearate, hypromellose, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Iron oxides are used as coloring agents in the peach (10 mg) and light pink (20 mg) tablets.
## Pharmacodynamics
- The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.
- Citalopram has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and β-adrenergic, histamine H1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.
## Pharmacokinetics
- The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose.
Absorption and Distribution
- Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%.
Metabolism and Elimination
- Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance.
- Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of citalopram’s metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram.
- In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram.
Population Subgroups
- Age - Citalopram pharmacokinetics in subjects ≥ 60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the subjects ≥ 60 years old by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see WARNINGS and DOSAGE AND ADMINISTRATION), due to the risk of QT prolongation.
- Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum citalopram levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender is recommended.
- Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg/day is the maximum recommended dose for hepatically impaired patients (see WARNINGS and DOSAGE AND ADMINISTRATION), due to the risk of QT prolongation.
- CYP2C19 poor metabolizers – In CYP2C19 poor metabolizers, citalopram steady state Cmax and AUC was increased by 68% and 107%, respectively. Citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation (see WARNINGS AND ADMINISTRATION).
- CYP2D6 poor metabolizers - Citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of CYP2D6.
- Reduced renal function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of citalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min).
Drug-Drug Interactions
- In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these enzymes. However, in vivo data to address this question are limited.
- CYP3A4 and CYP2C19 Inhibitors: Since CYP3A4 and CYP2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent CYP3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Citalopram 20 mg/day is the maximum recommended dose in patients taking concomitant cimetidine or another CYP2C19 inhibitor, because of the risk of QT prolongation (see WARNINGS AND ADMINISTRATION).
- CYP2D6 Inhibitors: Coadministration of a drug that inhibits CYP2D6 with citalopram is unlikely to have clinically significant effects on citalopram metabolism, based on the study results in CYP2D6 poor metabolizers.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m2) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/m2 basis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.
Mutagenesis
- Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.
Impairment of Fertility
- When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥ 32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m2) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD.
# Clinical Studies
- The efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity Scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose.
- In two long-term studies, depressed patients who had responded to citalopram during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20 to 60 mg/day in the second study) were randomized to continuation of citalopram or to placebo. In both studies, patients receiving continued citalopram treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of citalopram.
- Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
Comparison of Clinical Trial Results
- Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.
# How Supplied
Citalopram tablets, USP are supplied as:
10 mg Tablets – Peach colored, biconvex, round shaped film coated tablets debossed with ‘A’ on one side and ‘05’ on the other side.
Bottles of 30- NDC 65862-005-30
Bottles of 60- NDC 65862-005-60
Bottles of 90- NDC 65862-005-90
Bottles of 100- NDC 65862-005-01
Bottles of 500- NDC 65862-005-05
10 x 10 Unit Dose- NDC 65862-005-10
30 Unit-of-use packaging- NDC 65862-005-32
20 mg Tablets – Light pink colored, biconvex, capsule shaped film coated tablets debossed with ‘A’ on one side and with a score line in between ‘0’ and ‘6’ on other side.
Bottles of 30- NDC 65862-006-30
Bottles of 60- NDC 65862-006-60
Bottles of 90- NDC 65862-006-90
Bottles of 100- NDC 65862-006-01
Bottles of 500- NDC 65862-006-05
10 x 10 Unit Dose- NDC 65862-006-10
30 Unit-of-use packaging- NDC 65862-006-32
40 mg Tablets – White colored, biconvex, capsule shaped film coated tablets debossed with ‘A’ on one side and with a score line in between ‘0’ and ‘7’ on other side.
Bottles of 30- NDC 65862-007-30
Bottles of 60- NDC 65862-007-60
Bottles of 90- NDC 65862-007-90
Bottles of 100- NDC 65862-007-01
Bottles of 500- NDC 65862-007-05
10 x 10 Unit Dose- NDC 65862-007-10
30 Unit-of-use packaging- NDC 65862-007-32
## Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Physicians are advised to discuss the following issues with patients for whom they prescribe citalopram.
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of citalopram and triptans, tramadol or other serotonergic agents.
- Patients should be advised that taking citalopram can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Although in controlled studies citalopram has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking, or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities.
- Patients should be told that, although citalopram has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of citalopram and alcohol in depressed patients is not advised.
- Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.
- Patients should be cautioned about the concomitant use of citalopram and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
- Patients should be advised to notify their physician if they are breastfeeding an infant.
- While patients may notice improvement with citalopram therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with citalopram and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for citalopram. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking citalopram.
Clinical Worsening and Suicide Risk
- Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
# Precautions with Alcohol
- Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended.
# Brand Names
CeleXA
# Look-Alike Drug Names
There is limited information regarding Citalopram Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Citalopram
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Black Box Warning
# Overview
Citalopram is an antidepressive agent that is FDA approved for the treatment of depression. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diaphoresis, constipation, diarrhea, nausea, vomiting, xerostomia, dizziness, headache, insomnia, sedation, somnolence, tremor, agitation, disorder of ejaculation, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### DEPRESSION
- Citalopram tablets, USP are indicated for the treatment of depression.
- The efficacy of citalopram tablets, USP in the treatment of depression was established in 4 to 6 week, controlled trials of outpatients whose diagnosis corresponded most closely to the DSM-III and DSM-III-R category of major depressive disorder.
- A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The antidepressant action of citalopram tablets, USP in hospitalized depressed patients has not been adequately studied.
- The efficacy of citalopram tablets, USP in maintaining an antidepressant response for up to 24 weeks following 6 to 8 weeks of acute treatment was demonstrated in two placebo-controlled trials. Nevertheless, the physician who elects to use citalopram tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
- Dosing information:
- Discontinue with gradual dose reduction and monitoring for withdrawal symptoms
- Doses above 40 mg/day are not recommended due to the risk for QT prolongation
- Depression: initial, 20 mg/day ORALLY as a single dose in the morning or evening; dose increases should usually occur in increments of 20 mg at intervals of no less than one week; MAX, 40 mg/day
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Citalopram Hydrobromide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Citalopram Hydrobromide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Citalopram 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 Citalopram Hydrobromide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Citalopram Hydrobromide in pediatric patients.
# Contraindications
- The use of MAOIs intended to treat psychiatric disorders with citalopram tablets or within 14 days of stopping treatment with citalopram tablets are contraindicated because of an increased risk of serotonin syndrome. The use of citalopram tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders are also contraindicated.
- Starting citalopram tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
- Concomitant use in patients taking pimozide is contraindicated.
- Citalopram tablets are contraindicated in patients with a hypersensitivity to citalopram or any of the inactive ingredients in citalopram tablets.
# Warnings
WARNINGS-Clinical Worsening and Suicide Risk
Clinical Worsening and Suicide Risk
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
- Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
- There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment with Citalopram Tablets, for a description of the risks of discontinuation of citalopram).
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for citalopram should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
QT-Prolongation and Torsade de Pointes
- Citalopram causes dose-dependent QTc prolongation, an ECG abnormality that has been associated with Torsade de Pointes (TdP), ventricular tachycardia, and sudden death, all of which have been observed in postmarketing reports for citalopram.
- Individually corrected QTc (QTcNi) interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 119 healthy subjects. The maximum mean (upper bound of the 95% one-sided confidence interval) difference from placebo were 8.5 (10.8) and 18.5 (21) msec for 20 mg and 60 mg citalopram, respectively. Based on the established exposure-response relationship, the predicted QTcNi change from placebo (upper bound of the 95% one-sided confidence interval) under the Cmax for the dose of 40 mg is 12.6 (14.3) msec.
- Because of the risk of QTc prolongation at higher citalopram doses, it is recommended that citalopram should not be given at doses above 40 mg/day.
- It is recommended that citalopram should not be used in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. Citalopram should also not be used in patients who are taking other drugs that prolong the QTc interval. Such drugs include Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine, levomethadyl acetate, methadone).
- The citalopram dose should be limited in certain populations. The maximum dose should be limited to 20 mg/day in patients who are CYP2C19 poor metabolizers or those patients who may be taking concomitant cimetidine or another CYP2C19 inhibitor, since higher citalopram exposures would be expected. The maximum dose should also be limited to 20 mg/day in patients with hepatic impairment and in patients who are greater than 60 years of age because of expected higher exposures.
- Electrolyte and/or ECG monitoring is recommended in certain circumstances. Patients being considered for citalopram treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QTc prolongation and arrhythmia, and should be corrected prior to initiation of treatment and periodically monitored. ECG monitoring is recommended in patients for whom citalopram use is not recommended (see above), but, nevertheless, considered essential. These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval.
- Citalopram should be discontinued in patients who are found to have persistent QTc measurements >500 ms. If patients taking citalopram experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring.
Screening Patients for Bipolar Disorder
- A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that citalopram is not approved for use in treating bipolar depression.
Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including citalopram, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, trytophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of citalopram with MAOIs intended to treat psychiatric disorders is contraindicated. Citalopram should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking citalopram. Citalopram should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and ADMINISTRATION).
- If concomitant use of citalopram with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, trytophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome particularly during treatment initiation and dose increases.
- Treatment with citalopram and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
- The pupillary dilation that occurs following use of many antidepressant drugs including citalopram may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
### PRECAUTIONS
General
Discontinuation of Treatment with Citalopram
- During marketing of citalopram and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Patients should be monitored for these symptoms when discontinuing treatment with citalopram. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).
Abnormal Bleeding
- SSRIs and SNRIs, including citalopram, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of citalopram and NSAIDs, aspirin, or other drugs that affect coagulation.
Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including citalopram. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when citalopram was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
- Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Activation of Mania/Hypomania
- In placebo-controlled trials of citalopram, some of which included patients with bipolar disorder, activation of mania/hypomania was reported in 0.2% of 1063 patients treated with citalopram and in none of the 446 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. As with all antidepressants, citalopram should be used cautiously in patients with a history of mania.
Seizures
- Although anticonvulsant effects of citalopram have been observed in animal studies, citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product’s premarketing testing. In clinical trials of citalopram, seizures occurred in 0.3% of patients treated with citalopram (a rate of one patient per 98 years of exposure) and 0.5% of patients treated with placebo (a rate of one patient per 50 years of exposure). Like other antidepressants, citalopram should be introduced with care in patients with a history of seizure disorder.
Interference with Cognitive and Motor Performance
- In studies in normal volunteers, citalopram in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities.
Use in Patients with Concomitant Illness
- Clinical experience with citalopram in patients with certain concomitant systemic illnesses is limited. Due to the risk of QT prolongation, citalopram use should be avoided in patients with certain cardiac conditions, and ECG monitoring is advised if citalopram must be used in such patients. Electrolytes should be monitored in treating patients with diseases or conditions that cause hypokalemia or hypomagnesemia (see WARNINGS).
- In subjects with hepatic impairment, citalopram clearance was decreased and plasma concentrations were increased. The use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION).
- Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with citalopram, however, they should be used with caution in such patients (see ADMINISTRATION).
# Adverse Reactions
## Clinical Trials Experience
- The premarketing development program for citalopram included citalopram exposures in patients and/or normal subjects from 3 different groups of studies: 429 normal subjects in clinical pharmacology/pharmacokinetic studies; 4422 exposures from patients in controlled and uncontrolled clinical trials, corresponding to approximately 1370 patient-exposure years. There were, in addition, over 19,000 exposures from mostly open-label, European postmarketing studies. The conditions and duration of treatment with citalopram varied greatly and included (in overlapping categories) open-label and double-blind studies, inpatient and outpatient studies, fixed-dose and dose-titration studies, and short-term and long-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.
- Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.
- The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
Adverse Findings Observed in Short-Term, Placebo-Controlled Trials
Adverse Events Associated with Discontinuation of Treatment:
- Among 1063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse event, as compared to 8% of 446 patients receiving placebo. The adverse events associated with discontinuation and considered drug-related (i.e., associated with discontinuation in at least 1% of citalopram-treated patients at a rate at least twice that of placebo) are shown in TABLE 2. It should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table.
- Adverse Events Occurring at an Incidence of 2% or More Among Citalopram-Treated Patients
- Table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 1063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration. Events included are those occurring in 2% or more of patients treated with citalopram and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients.
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.
- The only commonly observed adverse event that occurred in citalopram patients with an incidence of 5% or greater and at least twice the incidence in placebo patients was ejaculation disorder (primarily ejaculatory delay) in male patients (see TABLE 3).
Dose Dependency of Adverse Events
- The potential relationship between the dose of citalopram administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or citalopram 10 mg, 20 mg, 40 mg, and 60 mg. Jonckheere’s trend test revealed a positive dose response (p<0.05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning.
Male and Female Sexual Dysfunction with SSRIs
- Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.
- Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.
- The table below displays the incidence of sexual side effects reported by at least 2% of patients taking citalopram tablets in a pool of placebo-controlled clinical trials in patients with depression.
- In female depressed patients receiving citalopram, the reported incidence of decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively.
- There are no adequately designed studies examining sexual dysfunction with citalopram treatment.
- Priapism has been reported with all SSRIs.
- While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
Vital Sign Changes
- Citalopram and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with citalopram treatment. In addition, a comparison of supine and standing vital sign measures for citalopram and placebo treatments indicated that citalopram treatment is not associated with orthostatic changes.
Weight Changes
- Patients treated with citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.
Laboratory Changes
- Citalopram and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with citalopram treatment.
ECG Changes
- In a thorough QT study, citalopram was found to be associated with a dose-dependent increase in the QTc interval (see WARNINGS - QT-Prolongation and Torsade de Pointes).
- Electrocardiograms from citalopram (N=802) and placebo (N=241) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). In the citalopram group 1.9% of the patients had a change from baseline in QTcF >60 msec compared to 1.2% of the patients in the placebo group. None of the patients in the placebo group had a post-dose QTcF >500 msec compared to 0.5% of the patients in the citalopram group. The incidence of tachycardic outliers was 0.5% in the citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the citalopram group and 0.4% in the placebo group.
Other Events Observed During the Premarketing Evaluation of Citalopram Hydrobromide
- Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by patients treated with citalopram at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4422 patients. All reported events are included except those already listed in Table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those occurring in only one patient. It is important to emphasize that, although the events reported occurred during treatment with citalopram, they were not necessarily caused by it.
- Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
- Cardiovascular - Frequent: tachycardia, postural hypotension, hypotension. Infrequent: hypertension, bradycardia, edema (extremities), angina pectoris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident, myocardial ischemia. Rare: transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block.
- Central and Peripheral Nervous System Disorders - Frequent: paresthesia, migraine. Infrequent: hyperkinesia, vertigo, hypertonia, extrapyramidal disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia. Rare: abnormal coordination, hyperesthesia, ptosis, stupor.
- Endocrine Disorders - Rare: hypothyroidism, goiter, gynecomastia.
- Gastrointestinal Disorders - Frequent: saliva increased, flatulence. Infrequent: gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis. Rare: colitis, gastric ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups.
- General - Infrequent: hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms. Rare: hayfever.
- Hemic and Lymphatic Disorders - Infrequent: purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy. Rare: pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding.
- Metabolic and Nutritional Disorders - Frequent: decreased weight, increased weight. Infrequent: increased hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance. Rare: bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration.
- Musculoskeletal System Disorders - Infrequent: arthritis, muscle weakness, skeletal pain. Rare: bursitis, osteoporosis.
- Psychiatric Disorders - Frequent: impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion. Infrequent: increased libido, aggressive reaction, paroniria, drug dependence, depersonalization, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis. Rare: catatonic reaction, melancholia.
- Reproductive Disorders/Female* - Frequent: amenorrhea. Infrequent: galactorrhea, breast pain, breast enlargement, vaginal hemorrhage.
- % based on female subjects only: 2955
- Respiratory System Disorders - Frequent: coughing. Infrequent: bronchitis, dyspnea, pneumonia. Rare: asthma, laryngitis, bronchospasm, pneumonitis, sputum increased.
- Skin and Appendages Disorders - Frequent: rash, pruritus. Infrequent: photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. Rare: hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani.
- Special Senses - Frequent: accommodation abnormal, taste perversion. Infrequent: tinnitus, conjunctivitis, eye pain. Rare: mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss.
- Urinary System Disorders - Frequent: polyuria. Infrequent: micturition frequency, urinary incontinence, urinary retention, dysuria. Rare: facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
- Citalopram hydrobromide is not a controlled substance.
Physical and Psychological Dependence
- Animal studies suggest that the abuse liability of citalopram is low. Citalopram has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with citalopram did not reveal any drug-seeking behavior. However, these observations were not systematic and it is not possible to predict, on the basis of this limited experience, the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate citalopram patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
## Postmarketing Experience
- Other Events Observed During the Postmarketing Evaluation of Citalopram Hydrobromide
- It is estimated that over 30 million patients have been treated with citalopram since market introduction. Although no causal relationship to citalopram treatment has been found, the following adverse events have been reported to be temporally associated with citalopram treatment, and have not been described elsewhere in labeling: acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, angle-closure glaucoma, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsade de pointes, and withdrawal syndrome.
# Drug Interactions
- Serotonergic Drugs: See CONTRAINDICATIONS, WARNINGS, and ADMINISTRATION.
- Triptans:
- There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of citalopram with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS - Serotonin Syndrome).
- CNS Drugs - Given the primary CNS effects of citalopram, caution should be used when it is taken in combination with other centrally acting drugs.
- Alcohol - Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended.
- Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS, WARNINGS and DOSAGE AND ADMINISTRATION.
- Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) - Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when citalopram is initiated or discontinued.
- Cimetidine - In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively.
- Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation (see WARNINGS and ADMINISTRATION).
- Digoxin – In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram tablets and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.
- Lithium - Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram tablets and lithium are coadministered.
- Pimozide – In a controlled study, a single dose of pimozide 2 mg coadministered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.
- Theophylline - Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.
- Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) is clinically warranted, appropriate observation of the patient is advised.
- Warfarin - Administration of 40 mg/day citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.
- Carbamazepine - Combined administration of citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.
- Triazolam - Combined administration of citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.
- Ketoconazole - Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
- CYP2C19 Inhibitors - Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation (see WARNINGS, ADMINISTRATION, and PHARMACOLOGY).
- Metoprolol - Administration of 40 mg/day citalopram for 22 days resulted in a two-fold increase in the plasma levels of the beta-adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram and metoprolol had no clinically significant effects on blood pressure or heart rate.
- Imipramine and Other Tricyclic Antidepressants (TCAs) - In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of TCAs with citalopram.
- Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of electroconvulsive therapy (ECT) and citalopram.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.
- In two rat embryo/fetal development studies, oral administration of citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose, which is approximately 18 times the MRHD of 60 mg/day on a body surface area (mg/m2) basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental, no-effect dose of 56 mg/kg/day is approximately 9 times the MRHD on a mg/m2 basis. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of up to 16 mg/kg/day, or approximately 5 times the MRHD on a mg/m2 basis. Thus, teratogenic effects were observed at a maternally toxic dose in the rat and were not observed in the rabbit.
- When female rats were treated with citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose, which is approximately 5 times the MRHD on a mg/m2 basis. The no-effect dose of 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m2 basis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m2 basis. A no-effect dose was not determined in that study.
- There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy-Nonteratogenic Effects
- Neonates exposed to citalopram and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS: Serotonin Syndrome).
- Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including citalopram) in pregnancy and PPHN. Other studies do not show a significant statistical association.
- Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
- When treating a pregnant woman with citalopram, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see ADMINISTRATION).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Citalopram in women who are pregnant.
### Labor and Delivery
The effect of citalopram on labor and delivery in humans is unknown.
### Nursing Mothers
- As has been found to occur with many other drugs, citalopram is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or citalopram therapy should take into account the risks of citalopram exposure for the infant and the benefits of citalopram treatment for the mother.
### Pediatric Use
- Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS–-Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 407 pediatric patients with MDD have been conducted with citalopram, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of citalopram in a child or adolescent must balance the potential risks with the clinical need.
- Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with citalopram.
### Geriatic Use
- Of 4422 patients in clinical studies of citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Most elderly patients treated with citalopram in clinical trials received daily doses between 20 mg and 40 mg (see DOSAGE AND ADMINISTRATION).
- SSRIs and SNRIs, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).
- In two pharmacokinetic studies, citalopram AUC was increased by 23% and 30%, respectively, in subjects ≥ 60 years of age as compared to younger subjects, and its half-life was increased by 30% and 50%, respectively (see PHARMACOLOGY).
- 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see WARNINGS and DOSAGE AND ADMINISTRATION).
### Gender
There is no FDA guidance on the use of Citalopram with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Citalopram with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Citalopram in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Citalopram in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Citalopram in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Citalopram in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Citalopram tablets
- should be administered once daily, in the morning or evening, with or without food.
Initial Treatment
Citalopram tablets
- should be administered at an initial dose of 20 mg once daily, with an increase to a maximum dose of 40 mg/day at an interval of no less than one week. Doses above 40 mg/day are not recommended due to the risk of QT prolongation. Additionally, the only study pertinent to dose response for effectiveness did not demonstrate an advantage for the 60 mg/day dose over the 40 mg/day dose.
Special Populations
- 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age, patients with hepatic impairment, and for CYP2C19 poor metabolizers or those patients taking cimetidine or another CYP2C19 inhibitor (see WARNINGS).
- No dosage adjustment is necessary for patients with mild or moderate renal impairment. Citalopram tablets should be used with caution in patients with severe renal impairment.
Treatment of Pregnant Women During the Third Trimester
- Neonates exposed to citalopram tablets and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with citalopram tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Maintenance Treatment
- It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. Systematic evaluation of citalopram tablets in two studies have shown that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment (32 weeks total). In one study, patients were assigned randomly to placebo or to the same dose of citalopram tablets (20 to 60 mg/day) during maintenance treatment as they had received during the acute stabilization phase, while in the other study, patients were assigned randomly to continuation of citalopram tablets 20 or 40 mg/day, or placebo, for maintenance treatment. In the latter study, the rates of relapse to depression were similar for the two dose groups (see Clinical Trials). Based on these limited data, it is not known whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. If adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered.
Discontinuation of Treatment with Citalopram Tablets
- Symptoms associated with discontinuation of citalopram tablets and other SSRIs and SNRIs have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
- At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with citalopram tablets. Conversely, at least 14 days should be allowed after stopping citalopram tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).
- Use of Citalopram Tablets with Other MAOIs, Such as Linezolid or Methylene Blue
- Do not start citalopram tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).
- In some cases, a patient already receiving citalopram tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, citalopram tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with citalopram tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).
- The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with citalopram tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
### Monitoring
- Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.
- Electrolyte and/or ECG monitoring is recommended in certain circumstances. Patients being considered for citalopram treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QTc prolongation and arrhythmia, and should be corrected prior to initiation of treatment and periodically monitored. ECG monitoring is recommended in patients for whom citalopram use is not recommended (see above), but, nevertheless, considered essential. These include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the QTc interval.
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- Patients should be monitored for the following symptoms when discontinuing treatment with citalopram: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when citalopram is initiated or discontinued.
- Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of citalopram, caution should be exercised when citalopram tablets and lithium are coadministered.
- Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with citalopram.
# IV Compatibility
There is limited information regarding the compatibility of Citalopram and IV administrations.
# Overdosage
Human Experience
- In clinical trials of citalopram, there were reports of citalopram overdose, including overdoses of up to 2000 mg, with no associated fatalities. During the postmarketing evaluation of citalopram, citalopram overdoses, including overdoses of up to 6000 mg, have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of citalopram has been rarely reported.
- Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.
Management of Overdose
- Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for citalopram.
- In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.
# Pharmacology
## Mechanism of Action
- The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.
## Structure
- Citalopram hydrobromide is an orally administered selective serotonin reuptake inhibitor (SSRI) with a chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other available antidepressant agents. Citalopram hydrobromide is a racemic bicyclic phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, hydrobromide with the following structural formula:
- The molecular formula is C20H22BrFN2O and its molecular weight is 405.35.
- Citalopram hydrobromide USP occurs as a fine, white to off-white powder. Citalopram hydrobromide is sparingly soluble in water and soluble in ethanol.
- Citalopram hydrobromide is available only in tablet dosage form.
- Citalopram 10 mg tablets are biconvex, round shaped film coated tablets in strengths equivalent to 10 mg citalopram base. Citalopram 20 mg and 40 mg tablets are scored biconvex capsule shaped film coated tablets containing citalopram hydrobromide in strengths equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the following inactive ingredients: copovidone, corn starch, croscarmellose sodium, lactose monohydrate, magnesium stearate, hypromellose, microcrystalline cellulose, polyethylene glycol, and titanium dioxide. Iron oxides are used as coloring agents in the peach (10 mg) and light pink (20 mg) tablets.
## Pharmacodynamics
- The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.
- Citalopram has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1-, α2-, and β-adrenergic, histamine H1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.
## Pharmacokinetics
- The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose.
Absorption and Distribution
- Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%.
Metabolism and Elimination
- Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance.
- Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of citalopram’s metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram.
- In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram.
Population Subgroups
- Age - Citalopram pharmacokinetics in subjects ≥ 60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the subjects ≥ 60 years old by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see WARNINGS and DOSAGE AND ADMINISTRATION), due to the risk of QT prolongation.
- Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum citalopram levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender is recommended.
- Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg/day is the maximum recommended dose for hepatically impaired patients (see WARNINGS and DOSAGE AND ADMINISTRATION), due to the risk of QT prolongation.
- CYP2C19 poor metabolizers – In CYP2C19 poor metabolizers, citalopram steady state Cmax and AUC was increased by 68% and 107%, respectively. Citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation (see WARNINGS AND ADMINISTRATION).
- CYP2D6 poor metabolizers - Citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of CYP2D6.
- Reduced renal function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of citalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min).
Drug-Drug Interactions
- In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these enzymes. However, in vivo data to address this question are limited.
- CYP3A4 and CYP2C19 Inhibitors: Since CYP3A4 and CYP2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent CYP3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Citalopram 20 mg/day is the maximum recommended dose in patients taking concomitant cimetidine or another CYP2C19 inhibitor, because of the risk of QT prolongation (see WARNINGS AND ADMINISTRATION).
- CYP2D6 Inhibitors: Coadministration of a drug that inhibits CYP2D6 with citalopram is unlikely to have clinically significant effects on citalopram metabolism, based on the study results in CYP2D6 poor metabolizers.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m2) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/m2 basis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.
Mutagenesis
- Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.
Impairment of Fertility
- When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥ 32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m2) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD.
# Clinical Studies
- The efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity Scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose.
- In two long-term studies, depressed patients who had responded to citalopram during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20 to 60 mg/day in the second study) were randomized to continuation of citalopram or to placebo. In both studies, patients receiving continued citalopram treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of citalopram.
- Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.
Comparison of Clinical Trial Results
- Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.
# How Supplied
Citalopram tablets, USP are supplied as:
10 mg Tablets – Peach colored, biconvex, round shaped film coated tablets debossed with ‘A’ on one side and ‘05’ on the other side.
Bottles of 30- NDC 65862-005-30
Bottles of 60- NDC 65862-005-60
Bottles of 90- NDC 65862-005-90
Bottles of 100- NDC 65862-005-01
Bottles of 500- NDC 65862-005-05
10 x 10 Unit Dose- NDC 65862-005-10
30 Unit-of-use packaging- NDC 65862-005-32
20 mg Tablets – Light pink colored, biconvex, capsule shaped film coated tablets debossed with ‘A’ on one side and with a score line in between ‘0’ and ‘6’ on other side.
Bottles of 30- NDC 65862-006-30
Bottles of 60- NDC 65862-006-60
Bottles of 90- NDC 65862-006-90
Bottles of 100- NDC 65862-006-01
Bottles of 500- NDC 65862-006-05
10 x 10 Unit Dose- NDC 65862-006-10
30 Unit-of-use packaging- NDC 65862-006-32
40 mg Tablets – White colored, biconvex, capsule shaped film coated tablets debossed with ‘A’ on one side and with a score line in between ‘0’ and ‘7’ on other side.
Bottles of 30- NDC 65862-007-30
Bottles of 60- NDC 65862-007-60
Bottles of 90- NDC 65862-007-90
Bottles of 100- NDC 65862-007-01
Bottles of 500- NDC 65862-007-05
10 x 10 Unit Dose- NDC 65862-007-10
30 Unit-of-use packaging- NDC 65862-007-32
## Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Information for Patients
- Physicians are advised to discuss the following issues with patients for whom they prescribe citalopram.
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of citalopram and triptans, tramadol or other serotonergic agents.
- Patients should be advised that taking citalopram can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Although in controlled studies citalopram has not been shown to impair psychomotor performance, any psychoactive drug may impair judgment, thinking, or motor skills, so patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that citalopram therapy does not affect their ability to engage in such activities.
- Patients should be told that, although citalopram has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of citalopram and alcohol in depressed patients is not advised.
- Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.
- Patients should be cautioned about the concomitant use of citalopram and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
- Patients should be advised to notify their physician if they are breastfeeding an infant.
- While patients may notice improvement with citalopram therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with citalopram and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for citalopram. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking citalopram.
Clinical Worsening and Suicide Risk
- Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
# Precautions with Alcohol
- Although citalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by depressed patients taking citalopram is not recommended.
# Brand Names
CeleXA
# Look-Alike Drug Names
There is limited information regarding Citalopram Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Celexa | |
8d8be69f448cfaad54f2dabd6caaa733e06065e0 | wikidoc | Cell cycle | Cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a eukaryotic cell leading to its replication. These events can be divided in two broad periods: interphase—during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA—and the mitotic (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells". The cell-division cycle is an essential process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and some internal organs are renewed.
# Phases of the cell cycle
The cell cycle consists of four distinct phases: G1 phase, S phase, G2 phase (collectively known as interphase) and M phase. M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm divides forming distinct cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.
## M phase
The relatively brief M phase consists of nuclear division (mitosis) and cytoplasmic division (cytokinesis). In plants and algae, cytokinesis is accompanied by the formation of a new cell wall.
## Interphase
After M phase, the daughter cells each begin interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.
### G1 phase
The first phase within interphase, from the end of the previous M phase till the beginning of DNA synthesis is called G1 (G indicating gap or growth). During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of the same species.
### S phase
The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy of the cell remains the same. Rates of RNA transcription and protein synthesis are very low during this phase. An exception to this is histone production, most of which occurs during the S phase. The duration of S phase is relatively constant among cells of the same species.
### G2 phase
The cell then enters the G2 phase, which lasts until the cell enters mitosis. Again, significant protein synthesis occurs during this phase, mainly involving the production of microtubules, which are required during the process of mitosis. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis.
## G0 phase
The term "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis. Some cell types in mature organisms, such as parenchymal cells of the liver and kidney, enter the G0 phase semi-permanently and can only be induced to begin dividing again under very specific circumstances; other types, such as epithelial cells, continue to divide throughout an organism's life.
# Regulation of cell cycle
Regulation of the cell cycle involves steps crucial to the cell, including detecting and repairing genetic damage, and provision of various checks to prevent uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.
## Role of Cyclins and CDKs
Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle. Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules. Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae; genetic nomenclature in yeast dubs many of these genes cdc (for "cell division cycle") followed by an identifying number, e.g., cdc25.
Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.
### General mechanism of cyclin-CDK interaction
Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome.
Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes would also prove deleterious to the daughter cells.
Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.
### Specific action of cyclin-CDK complexes
Cyclin D is the first cyclin produced in the cell cycle, in response to extracellular signals (eg. growth factors). Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (RB). The hyperphosphorylated RB dissociates from the E2F/DP1/RB complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S transition). Cyclin A along with CDK2 forms the cyclin A-CDK2 complex, which initiates the G2/M transition. Cyclin B-CDK1 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, it's deactivation causes the cell to exit mitosis.
## Cell cycle inhibitors
Two families of genes, the cip/kip family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.
The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage eg. due to radiation). p27 is activated by Transforming Growth Factor β (TGF β), a growth inhibitor.
The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14arf which prevents p53 degradation.
# Checkpoints
Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle. Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met.
Several checkpoints are designed to ensure that damaged or incomplete DNA is not passed on to daughter cells. Two main checkpoints exist: the G1/S checkpoint and the G2/M checkpoint. G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point. An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint.
p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints.
# Role of cell cycle in tumor formation
A disregulation of the cell cycle components may lead to tumor formation. As mentioned above, some genes like the cell cycle inhibitors, RB, p53 etc., when they mutate, may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumor cells are much more compared to that in normal cells. Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.
The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs or radiation. This fact is made use of in cancer treatment; by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle.
# Synchronization of cell cultures
Several methods can be used to synchronise cell cultures by halting the cell cycle at a particular phase. For example, Serum starvation and treatment with Thymidine or Aphidicolin halt the cell in the G1 phase, Mitotic shake-off, treatment with colchicine and treatment with Nocodazole halt the cell in M phase and treatment with 5-fluorodeoxyuridine halts the cell in S phase.
# Observation
There are numerous ways to observe the cell cycle occurring. Onion bulbs or garlic root tips are often used.
A sample of root tip is fixed in a mixture of 99% of 70% aqueous industrial methylated spirit and 1% glacial ethanoic acid for two hours. Treat the root tips in 1 molar hydrochloric acid at 60C for 6 -7 minutes. Rinse thoroughly with water. Add Schiff's reagent and leave for one hour. Rinse again in distilled water. Observe under a microscope. | Cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a eukaryotic cell leading to its replication. These events can be divided in two broad periods: interphase—during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA—and the mitotic (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells". The cell-division cycle is an essential process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and some internal organs are renewed.
# Phases of the cell cycle
The cell cycle consists of four distinct phases: G1 phase, S phase, G2 phase (collectively known as interphase) and M phase. M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm divides forming distinct cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.
## M phase
The relatively brief M phase consists of nuclear division (mitosis) and cytoplasmic division (cytokinesis). In plants and algae, cytokinesis is accompanied by the formation of a new cell wall.
## Interphase
After M phase, the daughter cells each begin interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.
### G1 phase
The first phase within interphase, from the end of the previous M phase till the beginning of DNA synthesis is called G1 (G indicating gap or growth). During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of the same species. [1]
### S phase
The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy of the cell remains the same. Rates of RNA transcription and protein synthesis are very low during this phase. An exception to this is histone production, most of which occurs during the S phase. [2] [3] The duration of S phase is relatively constant among cells of the same species. [4]
### G2 phase
The cell then enters the G2 phase, which lasts until the cell enters mitosis. Again, significant protein synthesis occurs during this phase, mainly involving the production of microtubules, which are required during the process of mitosis. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis.
## G0 phase
The term "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis. Some cell types in mature organisms, such as parenchymal cells of the liver and kidney, enter the G0 phase semi-permanently and can only be induced to begin dividing again under very specific circumstances; other types, such as epithelial cells, continue to divide throughout an organism's life.
# Regulation of cell cycle
Regulation of the cell cycle involves steps crucial to the cell, including detecting and repairing genetic damage, and provision of various checks to prevent uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.
## Role of Cyclins and CDKs
Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle.[5] Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules. [6] Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae; [7] genetic nomenclature in yeast dubs many of these genes cdc (for "cell division cycle") followed by an identifying number, e.g., cdc25.
Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals. [8]
### General mechanism of cyclin-CDK interaction
Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome.
Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes would also prove deleterious to the daughter cells.
Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.
### Specific action of cyclin-CDK complexes
Cyclin D is the first cyclin produced in the cell cycle, in response to extracellular signals (eg. growth factors). Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (RB). The hyperphosphorylated RB dissociates from the E2F/DP1/RB complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S transition). Cyclin A along with CDK2 forms the cyclin A-CDK2 complex, which initiates the G2/M transition. Cyclin B-CDK1 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, it's deactivation causes the cell to exit mitosis.[8]
## Cell cycle inhibitors
Two families of genes, the cip/kip family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.
The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage eg. due to radiation). p27 is activated by Transforming Growth Factor β (TGF β), a growth inhibitor.
The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14arf which prevents p53 degradation.
# Checkpoints
Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle.[9] Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met.
Several checkpoints are designed to ensure that damaged or incomplete DNA is not passed on to daughter cells. Two main checkpoints exist: the G1/S checkpoint and the G2/M checkpoint. G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point.[8] An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint.
p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints.
# Role of cell cycle in tumor formation
A disregulation of the cell cycle components may lead to tumor formation. As mentioned above, some genes like the cell cycle inhibitors, RB, p53 etc., when they mutate, may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumor cells are much more compared to that in normal cells. Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.
The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs or radiation. This fact is made use of in cancer treatment; by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle. [8]
# Synchronization of cell cultures
Several methods can be used to synchronise cell cultures by halting the cell cycle at a particular phase. For example, Serum starvation [10] and treatment with Thymidine or Aphidicolin [11] halt the cell in the G1 phase, Mitotic shake-off, treatment with colchicine [12] and treatment with Nocodazole [13] halt the cell in M phase and treatment with 5-fluorodeoxyuridine halts the cell in S phase.
# Observation
There are numerous ways to observe the cell cycle occurring. Onion bulbs or garlic root tips are often used.
A sample of root tip is fixed in a mixture of 99% of 70% aqueous industrial methylated spirit and 1% glacial ethanoic acid for two hours. Treat the root tips in 1 molar hydrochloric acid at 60C for 6 -7 minutes. Rinse thoroughly with water. Add Schiff's reagent and leave for one hour. Rinse again in distilled water. Observe under a microscope. | https://www.wikidoc.org/index.php/Cell_cycle | |
0baa104b0762cd4b7e3b443d67df7a4022ee3f8a | wikidoc | Metabolism | Metabolism
Metabolism is the complete set of chemical reactions that occur in living cells. These processes are the basis of life, allowing cells to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism, which yields energy, an example being is the breakdown of food in cellular respiration. Anabolism, on the other hand, uses this energy to construct components of cells such as proteins and nucleic acids.
The chemical reactions of metabolism are organised into metabolic pathways, in which one chemical is transformed into another by a sequence of enzymes. Enzymes are crucial to metabolism because they allow cells to drive desirable but thermodynamically unfavorable reactions by coupling them to favorable ones. Enzymes also allow the regulation of metabolic pathways in response to changes in the cell's environment or signals from other cells.
The metabolism of an organism determines which substances it will find nutritious and which it will find poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals. The speed of metabolism, the metabolic rate, also influences how much food an organism will require.
A striking feature of metabolism is the similarity of the basic metabolic pathways between even vastly different species. For example, the set of chemical intermediates in the citric acid cycle are found universally, among living cells as diverse as the unicellular bacteria Escherichia coli and huge multicellular organisms like elephants. This shared metabolic structure is most likely the result of the high efficiency of these pathways, and of their early appearance in evolutionary history.
# Key biochemicals
Most of the structures that make up animals, plants and microbes are made from three basic classes of molecule: amino acids, carbohydrates and lipids (often called fats). As these molecules are vital for life, metabolism focuses on making these molecules, in the construction of cells and tissues, or breaking them down and using them as a source of energy, in the digestion and use of food. Many important biochemicals can be joined together to make polymers such as DNA and proteins. These macromolecules are essential parts of all living organisms. Some of the most common biological polymers are listed in the table below.
## Amino acids and proteins
Proteins are made of amino acids arranged in a linear chain and joined together by peptide bonds. Many proteins are the enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as the proteins in the cytoskeleton that form a system of scaffolding to maintain cell shape. Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes and the cell cycle.
## Lipids
Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes such as the cell membrane, or as a source of energy. Lipids are usually defined as hydrophobic or amphipathic biological molecules that will dissolve in organic solvents such as benzene or chloroform. The fats are a large group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is a triacylglyceride. Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, and hydrophilic groups such as phosphate in phospholipids. Steroids such as cholesterol are another major class of lipids that are made in cells.
## Carbohydrates
Carbohydrates are straight-chain aldehydes or ketones with many hydroxyl groups that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals). The basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose. Monosaccharides can be linked together to form polysaccharides in almost limitless ways.
## Nucleotides
The polymers DNA and RNA are long chains of nucleotides. These molecules are critical for the storage and use of genetic information, through the processes of transcription and protein biosynthesis. This information is protected by DNA repair mechanisms and propagated through DNA replication. A few viruses have an RNA genome, for example HIV, which uses reverse transcription to create a DNA template from its viral RNA genome. RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as coenzymes in metabolic group transfer reactions.
## Coenzymes
Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups. This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions. These group-transfer intermediates are called coenzymes. Each class of group-transfer reaction is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously being made, consumed and then recycled.
The most central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day. ATP acts as a bridge between catabolism and anabolism, with catabolic reactions generating ATP and anabolic reactions consuming it. It also serves as a carrier of phosphate groups in phosphorylation reactions.
A vitamin is an organic compound needed in small quantities that cannot be made in the cells. In human nutrition, most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells. Nicotinamide adenine dinucleotide (NADH), a derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD+ into NADH. This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates. Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD+/NADH form is more important in catabolic reactions, while NADP+/NADPH is used in anabolic reactions.
## Minerals and cofactors
Inorganic elements play critical roles in metabolism; some are abundant (e.g. sodium and potassium) while others function at minute concentrations. About 99% of mammals' mass are the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, oxygen and sulfur. The organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen and most of the oxygen and hydrogen is present as water.
The abundant inorganic elements act as ionic electrolytes. The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate, and the organic ion bicarbonate. The maintenance of precise gradients across cell membranes maintains osmotic pressure and pH. Ions are also critical for nerves and muscles, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cytosol. Electrolytes enter and leave cells through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules.
The transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant. These metals are used in some proteins as cofactors and are essential for the activity of enzymes such as catalase and oxygen-carrier proteins such as hemoglobin. These cofactors are bound tightly to a specific protein; although enzyme cofactors can be modified during catalysis, cofactors always return to their original state after catalysis has taken place. The metal micronutrients are taken up into organisms by specific transporters and bound to storage proteins such as ferritin or metallothionein when not being used.
# Catabolism
Catabolism is the set of metabolic processes that release energy. These include breaking down and oxidising food molecules as well as reactions that trap the energy in sunlight. The purpose of these catabolic reactions is to provide the energy and components needed by anabolic reactions. The exact nature of these catabolic reactions differ from organism to organism, with organic molecules being used as a source of energy in organotrophs, while lithotrophs use inorganic substrates and phototrophs capture sunlight as chemical energy. However, all these different forms of metabolism depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulphate. In animals these reactions involve complex organic molecules being broken down to simpler molecules, such as carbon dioxide and water. In photosynthetic organisms such as plants and cyanobacteria, these electron-transfer reactions do not release energy, but are used as a way of storing energy absorbed from sunlight.
The most common set of catabolic reactions in animals can be separated into three main stages. In the first, large organic molecules such as proteins, polysaccharides or lipids are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to yet smaller molecules, usually acetyl coenzyme A (CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by reducing the coenzyme nicotinamide adenine dinucleotide (NAD+) into NADH.
## Digestion
Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and need to be broken into their smaller units before they can be used in cell metabolism. Several common classes of enzymes digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into monosaccharides.
Microbes simply secrete digestive enzymes into their surroundings, while animals only secrete these enzymes from specialized cells in their guts. The amino acids or sugars released by these extracellular enzymes are then pumped into cells by specific active transport proteins.
## Energy from organic compounds
Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into monosaccharides. Once inside, the major route of breakdown is glycolysis, where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated. Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA and fed into the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD+ as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for re-use in glycolysis. An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.
Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their structures.
Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy. The oxidation pathway starts with the removal of the amino group by a transaminase. The amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms α-ketoglutarate. The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below).
## Oxidative phosphorylation
In oxidative phosphorylation, the electrons removed from food molecules in pathways such as the citric acid cycle are transferred to oxygen and the energy released used to make ATP. This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are found in the cell's inner membrane. These proteins use the energy released from passing electrons from reduced molecules like NADH onto oxygen to pump protons across a membrane.
Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates a electrochemical gradient. This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase. The flow of protons makes the stalk subunit rotate, causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate - turning it into ATP.
## Energy from inorganic compounds
Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds. These organisms can use hydrogen, reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate), ferrous iron (FeII) or ammonia as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as oxygen or nitrite. These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for soil fertility.
## Energy from light
The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists. This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can however operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching between carbon fixation and the fermentation of organic compounds.
The capture of solar energy is a process that is similar in principle to oxidative phosphorylation, as it involves energy being stored as a proton concentration gradient and this proton motive force then driving ATP synthesis. The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic reaction centres. These structures are classed into two types depending on the type of photosynthetic pigment present, with most photosynthetic bacteria only having one type of reaction center, while plants and cyanobacteria have two.
In plants, photosystem II uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump protons across the thylakoid membrane in the chloroplast. These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through photosystem I and can then either be used to reduce the coenzyme NADP+, for use in the Calvin cycle which is discussed below, or recycled for further ATP generation.
# Anabolism
Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed step-by-step from small and simple precursors. Anabolism involves three basic stages. Firstly, the production of precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic acids.
Organisms differ in how many of the molecules in their cells they can construct for themselves. Autotrophs such as plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions.
## Carbon fixation
Photosynthesis is the synthesis of glucose from sunlight, carbon dioxide (CO2) and water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the photosynthetic reaction centres, as described above, to convert CO2 into glycerate 3-phosphate, which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin – Benson cycle. Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon fixation and CAM photosynthesis. These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and CAM photosynthesis incorporate the CO2 into other compounds first, as adaptations to deal with intense sunlight and dry conditions.
In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a reversed citric acid cycle, or the carboxylation of acetyl-CoA. Prokaryotic chemoautotrophs also fix CO2 through the Calvin – Benson cycle, but use energy from inorganic compounds to drive the reaction.
## Carbohydrates and glycans
In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis. However, this pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately and prevents both pathways from running simultaneously in a futile cycle.
Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate. As a result, after long-term starvation, vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids. In other organisms such as plants and bacteria, this metabolic problem is solved using the glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate, where it can be used for the production of glucose.
Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-glucose) to an acceptor hydroxyl group on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures. The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases.
## Fatty acids, isoprenoids and steroids
Fatty acids are made by fatty acid synthases that polymerize and reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the actyl group, reduce it to the alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional type I protein, while in plant plastids and bacteria separate type II enzymes perform each step in the pathway.
Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products. These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate. These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA, while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates. One important reaction that uses these activated isoprene donors is steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol. Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.
## Proteins
Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can synthesize only the ten nonessential amino acids. Thus, the essential amino acids must be obtained from food. All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid.
Amino acids are made into proteins by being joined together in a chain by peptide bonds. Each different protein has a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase. This aminoacyl-tRNA is then a substrate for the ribosome, which joins the amino acid onto the elongating protein chain, using the sequence information in a messenger RNA.
## Nucleotide synthesis and salvage
Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy. Consequently, most organisms have efficient systems to salvage preformed nucleotides. Purines are synthesized as nucleosides (bases attached to ribose). Both adenine and guanine are made from the precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.
# Xenobiotics and redox metabolism
All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called xenobiotics. Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases, UDP-glucuronosyltransferasess, and glutathione S-transferases. This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial biodegradation of pollutants and the bioremediation of contaminated land and oil spills. Many of these microbial reactions are shared with multicellular organisms, but due to their incredible diversity, microbes are able to deal with a far wider range of xenobiotics than multicellular organisms and can degrade even persistent organic pollutants such as organochloride compounds.
A related problem for aerobic organisms is oxidative stress. Here, processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide. These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases.
# Thermodynamics of living organisms
Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second law of thermodynamics states that in any closed system, the amount of entropy (disorder) will tend to increase. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are open systems that exchange matter and energy with their surroundings. Thus living systems are not in equilibrium, but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments. The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder.
# Regulation and control
As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells, a condition called homeostasis. Metabolic regulation also allows organisms to respond to signals and interact actively with their environments. Two closely-linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux through the pathway). For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway.
There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the flux through the pathway to compensate. This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway. Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface. These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins.
A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin. Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen. The metabolism of glycogen is controlled by activity of phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes.
# Evolution
The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all three domains of living things and were present in the last universal ancestor. This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism. The retention of these ancient pathways during later evolution may be the result of these reactions being an optimal solution to their particular metabolic problems, with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps.
The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, with previous metabolic pathways being part of the ancient RNA world.
Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway. The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions being created from pre-existing steps in the pathway. Another possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and perform similar functions on different molecules.
The evolution of organisms can also produce the loss of metabolic pathways. For example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the host. Similar reduced metabolic capabilities are seen in endosymbiotic organisms.
# Investigation and manipulation
Classically, metabolism is studied by a reductionist approach that focuses on a single metabolic pathway. Particularly valuable is the use of radioactive tracers at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively-labelled intermediates and products. The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitors investigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called the metabolome. Overall, these studies give a good view of the structure and function of simple metabolic pathways, but are inadequate when applied to more complex systems such as the metabolism of a complete cell.
An idea of the complexity of the metabolic networks in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide lists containing anything up to 45,000 genes. However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more holistic mathematical models that may explain and predict their behavior. These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on gene expression from proteomic and DNA microarray studies.
A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants or bacteria are genetically-modified to make them more useful in biotechnology and aid the production of drugs such as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid. These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.
# History
The term metabolism is derived from the Greek Μεταβολισμός – "Metabolismos" for "change", or "overthrow". The history of the scientific study of metabolism spans 400 years and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medecina. He described how he weighed himself before and after eating, sleeping, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called "insensible perspiration".
In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue. In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called "ferments". He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells." This discovery, along with the publication by Friedrich Wöhler in 1828 of the chemical synthesis of urea, proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.
It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry. The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism. He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle. Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells. | Metabolism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Metabolism is the complete set of chemical reactions that occur in living cells. These processes are the basis of life, allowing cells to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism, which yields energy, an example being is the breakdown of food in cellular respiration. Anabolism, on the other hand, uses this energy to construct components of cells such as proteins and nucleic acids.
The chemical reactions of metabolism are organised into metabolic pathways, in which one chemical is transformed into another by a sequence of enzymes. Enzymes are crucial to metabolism because they allow cells to drive desirable but thermodynamically unfavorable reactions by coupling them to favorable ones. Enzymes also allow the regulation of metabolic pathways in response to changes in the cell's environment or signals from other cells.
The metabolism of an organism determines which substances it will find nutritious and which it will find poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals.[1] The speed of metabolism, the metabolic rate, also influences how much food an organism will require.
A striking feature of metabolism is the similarity of the basic metabolic pathways between even vastly different species. For example, the set of chemical intermediates in the citric acid cycle are found universally, among living cells as diverse as the unicellular bacteria Escherichia coli and huge multicellular organisms like elephants.[2] This shared metabolic structure is most likely the result of the high efficiency of these pathways, and of their early appearance in evolutionary history.[3][4]
# Key biochemicals
Most of the structures that make up animals, plants and microbes are made from three basic classes of molecule: amino acids, carbohydrates and lipids (often called fats). As these molecules are vital for life, metabolism focuses on making these molecules, in the construction of cells and tissues, or breaking them down and using them as a source of energy, in the digestion and use of food. Many important biochemicals can be joined together to make polymers such as DNA and proteins. These macromolecules are essential parts of all living organisms. Some of the most common biological polymers are listed in the table below.
## Amino acids and proteins
Proteins are made of amino acids arranged in a linear chain and joined together by peptide bonds. Many proteins are the enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as the proteins in the cytoskeleton that form a system of scaffolding to maintain cell shape.[5] Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes and the cell cycle.[6]
## Lipids
Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes such as the cell membrane, or as a source of energy.[6] Lipids are usually defined as hydrophobic or amphipathic biological molecules that will dissolve in organic solvents such as benzene or chloroform.[7] The fats are a large group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is a triacylglyceride.[8] Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, and hydrophilic groups such as phosphate in phospholipids. Steroids such as cholesterol are another major class of lipids that are made in cells.[9]
## Carbohydrates
Carbohydrates are straight-chain aldehydes or ketones with many hydroxyl groups that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals).[6] The basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose. Monosaccharides can be linked together to form polysaccharides in almost limitless ways.[10]
## Nucleotides
The polymers DNA and RNA are long chains of nucleotides. These molecules are critical for the storage and use of genetic information, through the processes of transcription and protein biosynthesis.[6] This information is protected by DNA repair mechanisms and propagated through DNA replication. A few viruses have an RNA genome, for example HIV, which uses reverse transcription to create a DNA template from its viral RNA genome.[11] RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as coenzymes in metabolic group transfer reactions.[12]
## Coenzymes
Metabolism involves a vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups.[13] This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions.[12] These group-transfer intermediates are called coenzymes. Each class of group-transfer reaction is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously being made, consumed and then recycled.[14]
The most central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day.[14] ATP acts as a bridge between catabolism and anabolism, with catabolic reactions generating ATP and anabolic reactions consuming it. It also serves as a carrier of phosphate groups in phosphorylation reactions.
A vitamin is an organic compound needed in small quantities that cannot be made in the cells. In human nutrition, most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells.[15] Nicotinamide adenine dinucleotide (NADH), a derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD+ into NADH. This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.[16] Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD+/NADH form is more important in catabolic reactions, while NADP+/NADPH is used in anabolic reactions.
## Minerals and cofactors
Inorganic elements play critical roles in metabolism; some are abundant (e.g. sodium and potassium) while others function at minute concentrations. About 99% of mammals' mass are the elements carbon, nitrogen, calcium, sodium, chlorine, potassium, hydrogen, oxygen and sulfur.[17] The organic compounds (proteins, lipids and carbohydrates) contain the majority of the carbon and nitrogen and most of the oxygen and hydrogen is present as water.[17]
The abundant inorganic elements act as ionic electrolytes. The most important ions are sodium, potassium, calcium, magnesium, chloride, phosphate, and the organic ion bicarbonate. The maintenance of precise gradients across cell membranes maintains osmotic pressure and pH.[18] Ions are also critical for nerves and muscles, as action potentials in these tissues are produced by the exchange of electrolytes between the extracellular fluid and the cytosol.[19] Electrolytes enter and leave cells through proteins in the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules.[20]
The transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant.[21][22] These metals are used in some proteins as cofactors and are essential for the activity of enzymes such as catalase and oxygen-carrier proteins such as hemoglobin.[23] These cofactors are bound tightly to a specific protein; although enzyme cofactors can be modified during catalysis, cofactors always return to their original state after catalysis has taken place. The metal micronutrients are taken up into organisms by specific transporters and bound to storage proteins such as ferritin or metallothionein when not being used.[24][25]
# Catabolism
Catabolism is the set of metabolic processes that release energy. These include breaking down and oxidising food molecules as well as reactions that trap the energy in sunlight. The purpose of these catabolic reactions is to provide the energy and components needed by anabolic reactions. The exact nature of these catabolic reactions differ from organism to organism, with organic molecules being used as a source of energy in organotrophs, while lithotrophs use inorganic substrates and phototrophs capture sunlight as chemical energy. However, all these different forms of metabolism depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules, water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulphate.[26] In animals these reactions involve complex organic molecules being broken down to simpler molecules, such as carbon dioxide and water. In photosynthetic organisms such as plants and cyanobacteria, these electron-transfer reactions do not release energy, but are used as a way of storing energy absorbed from sunlight.[6]
The most common set of catabolic reactions in animals can be separated into three main stages. In the first, large organic molecules such as proteins, polysaccharides or lipids are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to yet smaller molecules, usually acetyl coenzyme A (CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by reducing the coenzyme nicotinamide adenine dinucleotide (NAD+) into NADH.
## Digestion
Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and need to be broken into their smaller units before they can be used in cell metabolism. Several common classes of enzymes digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into monosaccharides.
Microbes simply secrete digestive enzymes into their surroundings,[27][28] while animals only secrete these enzymes from specialized cells in their guts.[29] The amino acids or sugars released by these extracellular enzymes are then pumped into cells by specific active transport proteins.[30][31]
## Energy from organic compounds
Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells once they have been digested into monosaccharides.[32] Once inside, the major route of breakdown is glycolysis, where sugars such as glucose and fructose are converted into pyruvate and some ATP is generated.[33] Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA and fed into the citric acid cycle. Although some more ATP is generated in the citric acid cycle, the most important product is NADH, which is made from NAD+ as the acetyl-CoA is oxidized. This oxidation releases carbon dioxide as a waste product. In anaerobic conditions, glycolysis produces lactate, through the enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for re-use in glycolysis. An alternative route for glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose sugars such as ribose, the sugar component of nucleic acids.
Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their structures.
Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as a source of energy.[34] The oxidation pathway starts with the removal of the amino group by a transaminase. The amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms α-ketoglutarate.[35] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis (discussed below).[36]
## Oxidative phosphorylation
In oxidative phosphorylation, the electrons removed from food molecules in pathways such as the citric acid cycle are transferred to oxygen and the energy released used to make ATP. This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are found in the cell's inner membrane.[37] These proteins use the energy released from passing electrons from reduced molecules like NADH onto oxygen to pump protons across a membrane.[38]
Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates a electrochemical gradient.[39] This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase. The flow of protons makes the stalk subunit rotate, causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate - turning it into ATP.[14]
## Energy from inorganic compounds
Chemolithotrophy is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds. These organisms can use hydrogen,[40] reduced sulfur compounds (such as sulfide, hydrogen sulfide and thiosulfate),[41] ferrous iron (FeII)[42] or ammonia[43] as sources of reducing power and they gain energy from the oxidation of these compounds with electron acceptors such as oxygen or nitrite.[44] These microbial processes are important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for soil fertility.[45][46]
## Energy from light
The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists. This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can however operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching between carbon fixation and the fermentation of organic compounds.[47][48]
The capture of solar energy is a process that is similar in principle to oxidative phosphorylation, as it involves energy being stored as a proton concentration gradient and this proton motive force then driving ATP synthesis.[14] The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic reaction centres. These structures are classed into two types depending on the type of photosynthetic pigment present, with most photosynthetic bacteria only having one type of reaction center, while plants and cyanobacteria have two.[49]
In plants, photosystem II uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump protons across the thylakoid membrane in the chloroplast.[50] These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through photosystem I and can then either be used to reduce the coenzyme NADP+, for use in the Calvin cycle which is discussed below, or recycled for further ATP generation.[51]
# Anabolism
Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed step-by-step from small and simple precursors. Anabolism involves three basic stages. Firstly, the production of precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic acids.
Organisms differ in how many of the molecules in their cells they can construct for themselves. Autotrophs such as plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions.
## Carbon fixation
Photosynthesis is the synthesis of glucose from sunlight, carbon dioxide (CO2) and water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the photosynthetic reaction centres, as described above, to convert CO2 into glycerate 3-phosphate, which can then be converted into glucose. This carbon-fixation reaction is carried out by the enzyme RuBisCO as part of the Calvin – Benson cycle.[52] Three types of photosynthesis occur in plants, C3 carbon fixation, C4 carbon fixation and CAM photosynthesis. These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and CAM photosynthesis incorporate the CO2 into other compounds first, as adaptations to deal with intense sunlight and dry conditions.[53]
In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin – Benson cycle, a reversed citric acid cycle,[54] or the carboxylation of acetyl-CoA.[55][56] Prokaryotic chemoautotrophs also fix CO2 through the Calvin – Benson cycle, but use energy from inorganic compounds to drive the reaction.[57]
## Carbohydrates and glycans
In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis.[33] However, this pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately and prevents both pathways from running simultaneously in a futile cycle.[58][59]
Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate.[60] As a result, after long-term starvation, vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot metabolize fatty acids.[61] In other organisms such as plants and bacteria, this metabolic problem is solved using the glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate, where it can be used for the production of glucose.[62][60]
Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-glucose) to an acceptor hydroxyl group on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the polysaccharides produced can have straight or branched structures.[63] The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called oligosaccharyltransferases.[64][65]
## Fatty acids, isoprenoids and steroids
Fatty acids are made by fatty acid synthases that polymerize and reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions that add the actyl group, reduce it to the alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty acid synthase reactions are carried out by a single multifunctional type I protein,[66] while in plant plastids and bacteria separate type II enzymes perform each step in the pathway.[67][68]
Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products.[69] These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate.[70] These precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these compounds from acetyl-CoA,[71] while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.[72][70] One important reaction that uses these activated isoprene donors is steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed into a set of rings to make lanosterol.[73] Lanosterol can then be converted into other steroids such as cholesterol and ergosterol.[74][73]
## Proteins
Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can synthesize only the ten nonessential amino acids.[6] Thus, the essential amino acids must be obtained from food. All amino acids are synthesized from intermediates in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid.[75]
Amino acids are made into proteins by being joined together in a chain by peptide bonds. Each different protein has a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase.[76] This aminoacyl-tRNA is then a substrate for the ribosome, which joins the amino acid onto the elongating protein chain, using the sequence information in a messenger RNA.[77]
## Nucleotide synthesis and salvage
Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy.[78] Consequently, most organisms have efficient systems to salvage preformed nucleotides.[78][79] Purines are synthesized as nucleosides (bases attached to ribose). Both adenine and guanine are made from the precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.[80]
# Xenobiotics and redox metabolism
All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called xenobiotics.[81] Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases,[82] UDP-glucuronosyltransferasess,[83] and glutathione S-transferases.[84] This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial biodegradation of pollutants and the bioremediation of contaminated land and oil spills.[85] Many of these microbial reactions are shared with multicellular organisms, but due to their incredible diversity, microbes are able to deal with a far wider range of xenobiotics than multicellular organisms and can degrade even persistent organic pollutants such as organochloride compounds.[86]
A related problem for aerobic organisms is oxidative stress.[87] Here, processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide.[88] These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases.[89][90]
# Thermodynamics of living organisms
Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second law of thermodynamics states that in any closed system, the amount of entropy (disorder) will tend to increase. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are open systems that exchange matter and energy with their surroundings. Thus living systems are not in equilibrium, but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the entropy of their environments.[91] The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder.[92]
# Regulation and control
As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells, a condition called homeostasis.[93][94] Metabolic regulation also allows organisms to respond to signals and interact actively with their environments.[95] Two closely-linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux through the pathway).[96] For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway.[97]
There are multiple levels of metabolic regulation. In intrinsic regulation, the metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the flux through the pathway to compensate.[96] This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway.[98] Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in the form of soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface.[99] These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins.[100]
A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin.[101] Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen.[102] The metabolism of glycogen is controlled by activity of phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes.[103]
# Evolution
The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all three domains of living things and were present in the last universal ancestor.[104][2] This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism.[105][106] The retention of these ancient pathways during later evolution may be the result of these reactions being an optimal solution to their particular metabolic problems, with pathways such as glycolysis and the citric acid cycle producing their end products highly efficiently and in a minimal number of steps.[3][4]
The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, with previous metabolic pathways being part of the ancient RNA world.[107]
Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway.[108] The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions being created from pre-existing steps in the pathway.[109] Another possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and perform similar functions on different molecules.[110]
The evolution of organisms can also produce the loss of metabolic pathways. For example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids, nucleotides and carbohydrates may instead be scavenged from the host.[111] Similar reduced metabolic capabilities are seen in endosymbiotic organisms.[112]
# Investigation and manipulation
Classically, metabolism is studied by a reductionist approach that focuses on a single metabolic pathway. Particularly valuable is the use of radioactive tracers at the whole-organism, tissue and cellular levels, which define the paths from precursors to final products by identifying radioactively-labelled intermediates and products.[113] The enzymes that catalyze these chemical reactions can then be purified and their kinetics and responses to inhibitors investigated. A parallel approach is to identify the small molecules in a cell or tissue; the complete set of these molecules is called the metabolome. Overall, these studies give a good view of the structure and function of simple metabolic pathways, but are inadequate when applied to more complex systems such as the metabolism of a complete cell.[114]
An idea of the complexity of the metabolic networks in cells that contain thousands of different enzymes is given by the figure showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide lists containing anything up to 45,000 genes.[115] However, it is now possible to use this genomic data to reconstruct complete networks of biochemical reactions and produce more holistic mathematical models that may explain and predict their behavior.[116] These models are especially powerful when used to integrate the pathway and metabolite data obtained through classical methods with data on gene expression from proteomic and DNA microarray studies.[117]
A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants or bacteria are genetically-modified to make them more useful in biotechnology and aid the production of drugs such as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid.[118] These genetic modifications usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of wastes.[119]
# History
The term metabolism is derived from the Greek Μεταβολισμός – "Metabolismos" for "change", or "overthrow".[120] The history of the scientific study of metabolism spans 400 years and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medecina.[121] He described how he weighed himself before and after eating, sleeping, working, sex, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called "insensible perspiration".
In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue.[122] In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called "ferments". He wrote that "alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells."[123] This discovery, along with the publication by Friedrich Wöhler in 1828 of the chemical synthesis of urea,[124] proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.
It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry.[125] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism.[126] He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle.[127][62] Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells. | https://www.wikidoc.org/index.php/Cellular_metabolism | |
037c16f6cd93d69c07380cb94b7ed6de47dbf7dd | wikidoc | Exocytosis | Exocytosis
Exocytosis (ek-soh-sy-TOH-sis) is the process by which a cell directs secretory vesicles to the cell membrane. These membrane-bound vesicles contain soluble proteins to be secreted to the extracellular environment, as well as membrane proteins and lipids that are sent to become components of the cell membrane.
# Types
In multicellular organisms there are two types of exocytosis:
1) Ca2+ triggered non-constitutive and
2) non Ca2+ triggered constitutive.
Exocytosis in neuronal chemical synapses is Ca2+ triggered and serves interneuronal signalling. Constitutive exocytosis is performed by all cells and serves the release of components of the extracellular matrix, or just delivery of newly-synthesized membrane proteins that are incorporated in the plasma membrane after the fusion of the transport vesicle.
# Functions
Exocytosis is needed by cells for secretion of proteins like enzymes, peptide hormones and antibodies from cells, turnover of plasma membrane, release of neurotransmitter from presynaptic neurons, placement of integral membrane proteins, acrosome reaction during fertilization, antigen presentation during the immune response and recycling of plasma membrane bound receptors.
Exocytosis is important in cellular signaling. In neuronal communication both chemical and electrical information needs to be sent throughout the cell. Exocytosis sends and converts the electrical information into chemical information. Within the neural cells, the information is electrical. In the synapse, after exocytosis has occurred, the neurotransmitters are released, and the information is chemical. The release of the neurotransmitter can either be excitatory (causing activity from the target cell) or inhibitory (preventing activity by the target cell).
# Steps
Five steps are involved in exocytosis:
## Vesicle trafficking
Certain vesicle-trafficking steps require the translocation of a vesicle over a significant distance. For example, vesicles that carry proteins from the Golgi apparatus to the cell surface are likely to use motor proteins and a cytoskeletal track to get close to their target before tethering would be appropriate. Both the actin- and the microtubule-based cytoskeletons are implicated in these processes, along with several motor proteins. Once the vesicles reach their targets, they come into contact with tethering factors that can restrain them.
## Vesicle tethering
It is useful to distinguish between the initial, loose tethering of vesicles with their targets from the more stable, docking interactions. Tethering involves links over distances of more than about half the diameter of a vesicle from a given membrane surface (>25 nm). Tethering interactions are likely to be involved in concentrating synaptic vesicles at the synapse.
## Vesicle docking
The term docking refers to the holding of two membranes within a bilayer's distance of one another (<5-10 nm). Stable docking probably represents several distinct, molecular states: the molecular interactions underlying the close and tight association of a vesicle with its target may include the molecular rearrangements needed to trigger bilayer fusion. A common feature of many proteins that function in vesicle tethering and docking is their propensity to form highly extended, coiled-coil structures. Tethering and docking of a transport vesicle at the target membrane precedes the formation of a tight core SNARE complex.
## Vesicle priming
In neuronal exocytosis, the term priming has been used to include all of the molecular rearrangements and ATP-dependent protein and lipid modifications that take place after initial docking of a synaptic vesicle but before exocytosis, such that the influx of calcium ions is all that is needed to trigger nearly instantaneous neurotransmitter release. In other cell types, whose secretion is constitutive (i.e. continuous, calcium ion independent, non-triggered) there is no priming.
## Vesicle fusion
The vesicle fusion is driven by SNARE proteins process of merging the vesicle membrane with the target one resulting in release of large biomolecules in the extracellular space (or in case of neurons in the synaptic cleft).
- The surface of the plasma membrane increases (by the surface of the fused vesicle). This is important for the regulation of cell size, e.g., during cell growth.
- The substances within the vesicle are released into the exterior. These might be waste products or toxins, or signalling molecules like hormones or neurotransmitters during synaptic transmission.
- Proteins embedded in the vesicle membrane are now part of the plasma membrane. The side of the protein that was facing the inside of the vesicle now faces the outside of the cell. This mechanism is important for the regulation of transmembrane receptors and transporters. | Exocytosis
Exocytosis (ek-soh-sy-TOH-sis) is the process by which a cell directs secretory vesicles to the cell membrane. These membrane-bound vesicles contain soluble proteins to be secreted to the extracellular environment, as well as membrane proteins and lipids that are sent to become components of the cell membrane.
# Types
In multicellular organisms there are two types of exocytosis:
1) Ca2+ triggered non-constitutive and
2) non Ca2+ triggered constitutive.
Exocytosis in neuronal chemical synapses is Ca2+ triggered and serves interneuronal signalling. Constitutive exocytosis is performed by all cells and serves the release of components of the extracellular matrix, or just delivery of newly-synthesized membrane proteins that are incorporated in the plasma membrane after the fusion of the transport vesicle.
# Functions
Exocytosis is needed by cells for secretion of proteins like enzymes, peptide hormones and antibodies from cells, turnover of plasma membrane, release of neurotransmitter from presynaptic neurons, placement of integral membrane proteins, acrosome reaction during fertilization, antigen presentation during the immune response and recycling of plasma membrane bound receptors.
Exocytosis is important in cellular signaling. In neuronal communication both chemical and electrical information needs to be sent throughout the cell. Exocytosis sends and converts the electrical information into chemical information. Within the neural cells, the information is electrical. In the synapse, after exocytosis has occurred, the neurotransmitters are released, and the information is chemical. The release of the neurotransmitter can either be excitatory (causing activity from the target cell) or inhibitory (preventing activity by the target cell).
# Steps
Five steps are involved in exocytosis:
## Vesicle trafficking
Certain vesicle-trafficking steps require the translocation of a vesicle over a significant distance. For example, vesicles that carry proteins from the Golgi apparatus to the cell surface are likely to use motor proteins and a cytoskeletal track to get close to their target before tethering would be appropriate. Both the actin- and the microtubule-based cytoskeletons are implicated in these processes, along with several motor proteins. Once the vesicles reach their targets, they come into contact with tethering factors that can restrain them.
## Vesicle tethering
It is useful to distinguish between the initial, loose tethering of vesicles with their targets from the more stable, docking interactions. Tethering involves links over distances of more than about half the diameter of a vesicle from a given membrane surface (>25 nm). Tethering interactions are likely to be involved in concentrating synaptic vesicles at the synapse.
## Vesicle docking
The term docking refers to the holding of two membranes within a bilayer's distance of one another (<5-10 nm). Stable docking probably represents several distinct, molecular states: the molecular interactions underlying the close and tight association of a vesicle with its target may include the molecular rearrangements needed to trigger bilayer fusion. A common feature of many proteins that function in vesicle tethering and docking is their propensity to form highly extended, coiled-coil structures. Tethering and docking of a transport vesicle at the target membrane precedes the formation of a tight core SNARE complex.
## Vesicle priming
In neuronal exocytosis, the term priming has been used to include all of the molecular rearrangements and ATP-dependent protein and lipid modifications that take place after initial docking of a synaptic vesicle but before exocytosis, such that the influx of calcium ions is all that is needed to trigger nearly instantaneous neurotransmitter release. In other cell types, whose secretion is constitutive (i.e. continuous, calcium ion independent, non-triggered) there is no priming.
## Vesicle fusion
The vesicle fusion is driven by SNARE proteins process of merging the vesicle membrane with the target one resulting in release of large biomolecules in the extracellular space (or in case of neurons in the synaptic cleft).
- The surface of the plasma membrane increases (by the surface of the fused vesicle). This is important for the regulation of cell size, e.g., during cell growth.
- The substances within the vesicle are released into the exterior. These might be waste products or toxins, or signalling molecules like hormones or neurotransmitters during synaptic transmission.
- Proteins embedded in the vesicle membrane are now part of the plasma membrane. The side of the protein that was facing the inside of the vesicle now faces the outside of the cell. This mechanism is important for the regulation of transmembrane receptors and transporters.
# External links
- Template:McGrawHillAnimation
- Exocytosis at the US National Library of Medicine Medical Subject Headings (MeSH) | https://www.wikidoc.org/index.php/Cellular_secretion | |
2e90f1e166593bed8be70e9096aaefd87b955d99 | wikidoc | Centimetre | Centimetre
A centimetre (American spelling: centimeter, symbol cm) is a unit of length in the metric system, equal to one hundredth of a metre, which is the current SI base unit of length. Centi is the SI prefix for a factor of 10^{-2}. Hence a centimetre can be written as 10×10^{-3} m (engineering notation) or 1 E-2 m (scientific E notation) — meaning 10 × 1 mm or 1 m / 100 respectively. The centimetre is the base unit of length in the now deprecated centimetre-gram-second system of units.
Though for many physical quantities, SI prefixes for factors of 103 - like milli and kilo - are often preferred by technicians, the centimetre remains a practical unit of length for many everyday measurements. A centimetre is approximately the width of the fingernail of an adult person.
# Equivalence to other units of length
1 centimetre is equal to:
- 0.01 metres, which can be represented by 1.00 E-2 m (1 metre is equal to 100 centimeters)
- about 0.393700787401575 inches (1 inch is equal to 2.54 centimetres exactly)
1 cubic centimetre is equal to 1 millilitre, under the current SI system of units.
# Uses of centimetre
In addition to its use in the measurement of length, the centimeter is used:
- sometimes, to report the level of rainfall as measured by a rain gauge
- in the CGS system, the centimetre is used to measure capacitance, where 1 cm of capacitance = 1.113×10^{-12} Farad
- in Canadian maps, centimetres are used to make conversions from map scale to real world scale (kilometers)
# Unicode symbols
For the purposes of compatibility with Chinese, Japanese and Korean (CJK) characters, Unicode has symbols for:
- centimetre (cm) - code 339D
- square centimetre (㎠) - code 33A0
- cubic centimetre (㎤) - code 33A4
They are useful only with East Asian fixed-width CJK fonts, because they are equal in size to one Chinese character. | Centimetre
Template:Unit of length
A centimetre (American spelling: centimeter, symbol cm) is a unit of length in the metric system, equal to one hundredth of a metre, which is the current SI base unit of length. Centi is the SI prefix for a factor of 10<math>^{-2}</math>.[1] Hence a centimetre can be written as 10×10<math>^{-3}</math> m (engineering notation) or 1 E-2 m (scientific E notation) — meaning 10 × 1 mm or 1 m / 100 respectively. The centimetre is the base unit of length in the now deprecated centimetre-gram-second system of units.
Though for many physical quantities, SI prefixes for factors of 103 - like milli and kilo - are often preferred by technicians, the centimetre remains a practical unit of length for many everyday measurements. A centimetre is approximately the width of the fingernail of an adult person.
# Equivalence to other units of length
1 centimetre is equal to:
- 0.01 metres, which can be represented by 1.00 E-2 m (1 metre is equal to 100 centimeters)
- about 0.393700787401575 inches (1 inch is equal to 2.54 centimetres exactly) [2]
1 cubic centimetre is equal to 1 millilitre, under the current SI system of units.
# Uses of centimetre
In addition to its use in the measurement of length, the centimeter is used:
- sometimes, to report the level of rainfall as measured by a rain gauge [3]
- in the CGS system, the centimetre is used to measure capacitance, where 1 cm of capacitance = 1.113×10<math>^{-12}</math> Farad [4]
- in Canadian maps, centimetres are used to make conversions from map scale to real world scale (kilometers)
# Unicode symbols
For the purposes of compatibility with Chinese, Japanese and Korean (CJK) characters, Unicode has symbols for: [5]
- centimetre (cm) - code 339D
- square centimetre (㎠) - code 33A0
- cubic centimetre (㎤) - code 33A4
They are useful only with East Asian fixed-width CJK fonts, because they are equal in size to one Chinese character. | https://www.wikidoc.org/index.php/Centimeter | |
b6570b596408e10f5c28ec042b509a5c99d75419 | wikidoc | Centrifuge | Centrifuge
A centrifuge is a piece of equipment, generally driven by a motor, that puts an object in rotation around a fixed axis, applying force perpendicular to the axis. The centrifuge works using the sedimentation principle, where the centripetal acceleration is used to separate substances of greater and lesser density. There are many different kinds of centrifuges, including those for very specialised purposes. It can be used for viable counts, when shaking the culture e.g. yeast, out of suspension.
# Theory
Protocols for centrifugation typically specify the amount of acceleration to be applied to the sample, rather than specifying a rotational speed such as revolutions per minute. The acceleration is often quoted in multiples of g, the standard acceleration due to gravity at the Earth's surface. This distinction is important because two rotors with different diameters running at the same rotational speed will subject samples to different accelerations.
The acceleration can be calculated as the product of the radius and the square of the angular velocity.
# History and predecessors
English military engineer Laval (1707-1751) invented a whirling arm apparatus to determine drag, and Antonin Prandl invented the first centrifuge in order to separate cream from milk to make churning butter much easier.
# Types and uses
There are basically four types of centrifuge:
- Tabletop/clinical/desktop centrifuge or microcentrifuge
- High-speed centrifuge
- Cooling centrifuge
- Ultracentrifuge
## Laboratory centrifuge
Simple centrifuges are used in chemistry, biology, and biochemistry for isolating and separating suspensions. They vary widely in speed and capacity. They usually comprise a rotor containing two, four, six, or many more numbered wells within which the samples containing centrifuge tips may be placed.
## Isotope separation
Other centrifuges, the first being the Zippe-type centrifuge, separate isotopes, and these kinds of centrifuges are in use in nuclear power and nuclear weapon programs.
Gas centrifuges are used in uranium enrichment. The heavier isotope of uranium (uranium-238) in the uranium hexafluoride gas tend to concentrate at the walls of the centrifuge as it spins, while the desired uranium-235 isotope is extracted and concentrated with a scoop selectively placed inside the centrifuge. It takes many thousands of centrifuges to enrich uranium enough for use in a nuclear reactor (around 3.5% enrichment), and many thousands more to enrich it to atomic bomb-grade (around 90% enrichment).
## Aeronautics and astronautics
Human Centrifuges are exceptionally large centrifuges that test the reactions and tolerance of pilots and astronauts to acceleration above those experienced in the Earth's gravity.
The US Air Force at Holloman Air Force Base, NM operates a human centrifuge. The centrifuge at Holloman AFB is operated by the aerospace physiology department for the purpose of training and evaluating prospective fighter pilots for high-g flight in Air Force fighter aircraft. It is important to note that the centrifuge at Holloman AFB is unrealistic in that it is far more difficult for a pilot to tolerate the high-g environment in the centrifuge than in a real fighter aircraft. This well-known fact is based on countless accounts from experienced operational fighter pilots.
The use of large centrifuges to simulate a feeling of gravity has been proposed for future long-duration space missions. Exposure to this simulated gravity would prevent or reduce the bone decalcification and muscle atrophy that affect individuals exposed to long periods of freefall. An example of this can be seen in the film 2001: A Space Odyssey (film)|2001: A Space Odyssey.
## Commercial applications
- Standalone centrifuges for drying (hand-washed) clothes - usually with a water outlet.
- Centrifuges are used in the attraction Mission: SPACE, located at Epcot in Walt Disney World, which propels riders using a combination of a centrifuge and a motion simulator to simulate the feeling of going into space.
- In soil mechanics, centrifuges utilize centrifugal acceleration to match soil stresses in a scale model to those found in reality.
- Large industrial centrifuges are commonly used in water and wastewater treatment to dry sludges. The resulting dry product is often termed cake, and the water leaving a centrifuge after most of the solids have been removed is called centrate.
# Calculating relative centrifugal force (RCF)
Relative centrifugal force is the measurement of the force applied to a sample within a centrifuge. This can be calculated from the speed (RPM) and the rotational radius (cm) using the following calculation.
where | Centrifuge
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A centrifuge is a piece of equipment, generally driven by a motor, that puts an object in rotation around a fixed axis, applying force perpendicular to the axis. The centrifuge works using the sedimentation principle, where the centripetal acceleration is used to separate substances of greater and lesser density. There are many different kinds of centrifuges, including those for very specialised purposes. It can be used for viable counts, when shaking the culture e.g. yeast, out of suspension.
# Theory
Protocols for centrifugation typically specify the amount of acceleration to be applied to the sample, rather than specifying a rotational speed such as revolutions per minute. The acceleration is often quoted in multiples of g, the standard acceleration due to gravity at the Earth's surface. This distinction is important because two rotors with different diameters running at the same rotational speed will subject samples to different accelerations.
The acceleration can be calculated as the product of the radius and the square of the angular velocity.
# History and predecessors
English military engineer Laval (1707-1751) invented a whirling arm apparatus to determine drag, and Antonin Prandl invented the first centrifuge in order to separate cream from milk to make churning butter much easier.
# Types and uses
There are basically four types of centrifuge:
- Tabletop/clinical/desktop centrifuge or microcentrifuge
- High-speed centrifuge
- Cooling centrifuge
- Ultracentrifuge
## Laboratory centrifuge
Simple centrifuges are used in chemistry, biology, and biochemistry for isolating and separating suspensions. They vary widely in speed and capacity. They usually comprise a rotor containing two, four, six, or many more numbered wells within which the samples containing centrifuge tips may be placed.
## Isotope separation
Other centrifuges, the first being the Zippe-type centrifuge, separate isotopes, and these kinds of centrifuges are in use in nuclear power and nuclear weapon programs.
Gas centrifuges are used in uranium enrichment. The heavier isotope of uranium (uranium-238) in the uranium hexafluoride gas tend to concentrate at the walls of the centrifuge as it spins, while the desired uranium-235 isotope is extracted and concentrated with a scoop selectively placed inside the centrifuge. It takes many thousands of centrifuges to enrich uranium enough for use in a nuclear reactor (around 3.5% enrichment), and many thousands more to enrich it to atomic bomb-grade (around 90% enrichment).
## Aeronautics and astronautics
Human Centrifuges are exceptionally large centrifuges that test the reactions and tolerance of pilots and astronauts to acceleration above those experienced in the Earth's gravity.
The US Air Force at Holloman Air Force Base, NM operates a human centrifuge. The centrifuge at Holloman AFB is operated by the aerospace physiology department for the purpose of training and evaluating prospective fighter pilots for high-g flight in Air Force fighter aircraft. It is important to note that the centrifuge at Holloman AFB is unrealistic in that it is far more difficult for a pilot to tolerate the high-g environment in the centrifuge than in a real fighter aircraft. This well-known fact is based on countless accounts from experienced operational fighter pilots.
The use of large centrifuges to simulate a feeling of gravity has been proposed for future long-duration space missions. Exposure to this simulated gravity would prevent or reduce the bone decalcification and muscle atrophy that affect individuals exposed to long periods of freefall. An example of this can be seen in the film 2001: A Space Odyssey (film)|2001: A Space Odyssey.
## Commercial applications
- Standalone centrifuges for drying (hand-washed) clothes - usually with a water outlet.
- Centrifuges are used in the attraction Mission: SPACE, located at Epcot in Walt Disney World, which propels riders using a combination of a centrifuge and a motion simulator to simulate the feeling of going into space.
- In soil mechanics, centrifuges utilize centrifugal acceleration to match soil stresses in a scale model to those found in reality.
- Large industrial centrifuges are commonly used in water and wastewater treatment to dry sludges. The resulting dry product is often termed cake, and the water leaving a centrifuge after most of the solids have been removed is called centrate.
# Calculating relative centrifugal force (RCF)
Relative centrifugal force is the measurement of the force applied to a sample within a centrifuge. This can be calculated from the speed (RPM) and the rotational radius (cm) using the following calculation.
where | https://www.wikidoc.org/index.php/Centrifuge | |
357b3003478886e66a2847f15a45146a889f57bc | wikidoc | Centrosome | Centrosome
The centrosome is the main microtubule organizing center (MTOC) of the cell as well as a regulator of cell-cycle progression. It was discovered in 1888 by Theodor Boveri and was described as the 'special organ of cell division.' Although the centrosome has a key role in efficient mitosis, it has been recently shown that it is not necessary.
Centrosomes are composed of two orthogonally arranged centrioles surrounded by an amorphous mass of pericentriolar material (PCM). The PCM contains proteins responsible for microtubule nucleation and anchoring including γ-tubulin, pericentrin and ninein. Each centriole generally comprises nine triplet microtubule blades in a pinwheel structure as well as centrin, cenexin and tektin.
# Roles of the centrosome
Centrosomes are often associated with the nuclear membrane during interphase of the cell cycle. In mitosis the nuclear membrane breaks down and the centrosome nucleated microtubules can interact with the chromosomes to build the mitotic spindle.
The mother centriole, the one that was inherited from the mother cell, also has a central role in making cilia and flagella.
The centrosome is duplicated only once per cell cycle so that each daughter cell inherits one centrosome, containing two centrioles. The centrosome replicates during the S phase of the cell cycle. During the prophase of mitosis, the centrosomes migrate to opposite poles of the cell. The mitotic spindle then forms between the two centrosomes. Upon division, each daughter cell receives one centrosome. Aberrant numbers of centrosomes in a cell have been associated with cancer.
Interestingly, centrosomes are not required for the progression of mitosis. When the centrosomes are irradiated by a laser, mitosis proceeds normally with a morphologically normal spindle. Moreover, development of the fruit fly Drosophila is largely normal when centrioles are absent due to a mutation in a gene required for their duplication. In the absence of the centrosome the microtubules of the spindle are focused by motors allowing the formation of a bipolar spindle. Many cells can completely undergo interphase without centrosomes.
File:Molly Sheehan Wikipedia 1.jpg
Figure 1: Role of the centrosome in cell cycle progression.
Although centrosomes are not required for mitosis or survival of the cell, they are required for survival of the organism. Acentrosomal cells lack radial arrays of astral microtubules. They are also defective in spindle positioning and in ability to establish a central localization site in cytokinesis. The function of centrosome in this context is hypothesized to ensure the fidelity of cell division as it is not necessary but greatly increases the efficacy. Some cell types arrest in the following cell cycle when centrosomes are absent. This is not a universal phenomenon.
When the nematode C. elegans egg is fertilized the sperm delivers a pair of centrioles. These centrioles will form the centrosomes which will direct the first cell division of the zygote and this will determine its polarity. It is not yet clear whether the role of the centrosome in polarity determination is microtubule dependent or independent.
# Centrosome Genome
Recent research in 2006 indicates that centrosomes may have their own genome, previously known only in nuclei, mitochondria and chloroplasts. Unlike the latter, it is RNA-based rather than DNA-based, and apparently includes an RNA sequence capable of duplicating the centrosome genome. The putative centrosome genome RNA sequences were purified from surf clam eggs, were found in "few to no" other places in the cell, and do not appear in existing genome databases.
The existence of nucleotides associated with the centrosome remains controversial. Many studies have investigated whether nucleotides associate with the centrosome with varying results. | Centrosome
The centrosome is the main microtubule organizing center (MTOC) of the cell as well as a regulator of cell-cycle progression. It was discovered in 1888 by Theodor Boveri and was described as the 'special organ of cell division.' Although the centrosome has a key role in efficient mitosis, it has been recently shown that it is not necessary.
Centrosomes are composed of two orthogonally arranged centrioles surrounded by an amorphous mass of pericentriolar material (PCM). The PCM contains proteins responsible for microtubule nucleation and anchoring[1] including γ-tubulin, pericentrin and ninein. Each centriole generally comprises nine triplet microtubule blades in a pinwheel structure as well as centrin, cenexin and tektin[2].
# Roles of the centrosome
Centrosomes are often associated with the nuclear membrane during interphase of the cell cycle. In mitosis the nuclear membrane breaks down and the centrosome nucleated microtubules can interact with the chromosomes to build the mitotic spindle.
The mother centriole, the one that was inherited from the mother cell, also has a central role in making cilia and flagella[2].
The centrosome is duplicated only once per cell cycle so that each daughter cell inherits one centrosome, containing two centrioles. The centrosome replicates during the S phase of the cell cycle. During the prophase of mitosis, the centrosomes migrate to opposite poles of the cell. The mitotic spindle then forms between the two centrosomes. Upon division, each daughter cell receives one centrosome. Aberrant numbers of centrosomes in a cell have been associated with cancer.
Interestingly, centrosomes are not required for the progression of mitosis. When the centrosomes are irradiated by a laser, mitosis proceeds normally with a morphologically normal spindle. Moreover, development of the fruit fly Drosophila is largely normal when centrioles are absent due to a mutation in a gene required for their duplication[3]. In the absence of the centrosome the microtubules of the spindle are focused by motors allowing the formation of a bipolar spindle. Many cells can completely undergo interphase without centrosomes[2].
File:Molly Sheehan Wikipedia 1.jpg
Figure 1: Role of the centrosome in cell cycle progression[4].
Although centrosomes are not required for mitosis or survival of the cell, they are required for survival of the organism. Acentrosomal cells lack radial arrays of astral microtubules. They are also defective in spindle positioning and in ability to establish a central localization site in cytokinesis. The function of centrosome in this context is hypothesized to ensure the fidelity of cell division as it is not necessary but greatly increases the efficacy. Some cell types arrest in the following cell cycle when centrosomes are absent. This is not a universal phenomenon.
When the nematode C. elegans egg is fertilized the sperm delivers a pair of centrioles. These centrioles will form the centrosomes which will direct the first cell division of the zygote and this will determine its polarity. It is not yet clear whether the role of the centrosome in polarity determination is microtubule dependent or independent.
# Centrosome Genome
Recent research in 2006[5] indicates that centrosomes may have their own genome, previously known only in nuclei, mitochondria and chloroplasts. Unlike the latter, it is RNA-based rather than DNA-based, and apparently includes an RNA sequence capable of duplicating the centrosome genome. The putative centrosome genome RNA sequences were purified from surf clam eggs, were found in "few to no" other places in the cell, and do not appear in existing genome databases.
The existence of nucleotides associated with the centrosome remains controversial. Many studies have investigated whether nucleotides associate with the centrosome with varying results. | https://www.wikidoc.org/index.php/Centrosome | |
9c7f3b24a692c74edeed0456b7a6191412f538ee | wikidoc | Cephalexin | Cephalexin
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# Black Box Warning
# Overview
Cephalexin is a 1st generation cephalosporin that is FDA approved for the {{{indicationType}}} of respiratory tract infections caused by s. pneumoniae and s. pyogenes, otitis media, skin and skin structure infections, bone infections, genitourinary tract infections. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Respiratory tract infections caused by S. pneumoniae and S. pyogenes (Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cephalexin is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cephalexin in the subsequent prevention of rheumatic fever are not available at present.)
- Otitis media due to S. pneumoniae, H. influenzae, staphylococci, streptococci and M. catarrhalis
- Skin and skin structure infections caused by staphylococci and/or streptococci
- Bone infections caused by staphylococci and/or P. mirabilis
- Genitourinary tract infections, including acute prostatitis, caused by E. coli, P. mirabilis, and K. pneumoniae
- Cephalexin is administered orally.
- The adult dosage ranges from 1 to 4 g daily in divided doses. The usual adult dose is 250 mg every 6 hours. For the following infections, a dosage of 500 mg may be administered every 12 hours: streptococcal pharyngitis, skin and skin structure infections, and uncomplicated cystitis in patients over 15 years of age. Cystitis therapy should be continued for 7 to 14 days. For more severe infections or those caused by less susceptible organisms, larger doses may be needed. If daily doses of cephalexin greater than 4 g are required, parenteral cephalosporins, in appropriate doses, should be considered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American Heart Association
- Class of Recommendation: Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Cephalexin 2 g orally
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cephalexin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Respiratory tract infections caused by S. pneumoniae and S. pyogenes (Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cephalexin is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cephalexin in the subsequent prevention of rheumatic fever are not available at present.)
- Otitis media due to S. pneumoniae, H. influenzae, staphylococci, streptococci and M. catarrhalis
- Skin and skin structure infections caused by staphylococci and/or streptococci
- Bone infections caused by staphylococci and/or P. mirabilis
- Genitourinary tract infections, including acute prostatitis, caused by E. coli, P. mirabilis, and K. pneumoniae
- The usual recommended daily dosage for pediatric patients is 25 to 50 mg/kg in divided doses. For streptococcal pharyngitis in patients over 1 year of age and for skin and skin structure infections, the total daily dose may be divided and administered every 12 hours.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: American Heart Association
- Class of Recommendation: Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Cephalexin- 50 mg/kg orally
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cephalexin in pediatric patients.
# Contraindications
- Cephalexin is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
# Warnings
- BEFORE CEPHALEXIN THERAPY IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS AND PENICILLIN. CEPHALOSPORIN C DERIVATIVES SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS.
- SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.
- There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and the cephalosporins. Patients have been reported to have had severe reactions (including anaphylaxis) to both drugs.
- Any patient who has demonstrated some form of allergy, particularly to drugs, should receive antibiotics cautiously. No exception should be made with regard to cephalexin.
- Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cephalexin, and may range from mild to life threatening. Therefore, it is important to consider this diagnosis in patients with diarrhea subsequent to the administration of antibacterial agents.
- Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis.
- After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
- Usage in Pregnancy — Safety of this product for use during pregnancy has not been established.
### Precautions
- General
- Prescribing cephalexin capsules and cephalexin for oral suspension in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Patients should be followed carefully so that any side effects or unusual manifestations of drug idiosyncrasy may be detected. If an allergic reaction to cephalexin occurs, the drug should be discontinued and the patient treated with the usual agents (e.g., epinephrine or other pressor amines, antihistamines, or corticosteroids).
- Prolonged use of cephalexin may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
- Positive direct Coombs’ tests have been reported during treatment with the cephalosporin antibiotics. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs’ testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognized that a positive Coombs’ test may be due to the drug.
- Cephalexin should be administered with caution in the presence of markedly impaired renal function. Under such conditions, careful clinical observation and laboratory studies should be made because safe dosage may be lower than that usually recommended.
- Indicated surgical procedures should be performed in conjunction with antibiotic therapy.
- As a result of administration of cephalexin, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict’s and Fehling’s solutions and also with Clinitest® tablets.
- As with other β-lactams, the renal excretion of cephalexin is inhibited by probenecid.
- Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
# Adverse Reactions
## Clinical Trials Experience
- Gastrointestinal — Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. Nausea and vomiting have been reported rarely. The most frequent side effect has been diarrhea. It was very rarely severe enough to warrant cessation of therapy. Dyspepsia, gastritis, and abdominal pain have also occurred. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely.
- Hypersensitivity — Allergic reactions in the form of rash, urticaria, angioedema, and, rarely, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been observed. These reactions usually subsided upon discontinuation of the drug. In some of these reactions, supportive therapy may be necessary. Anaphylaxis has also been reported.
- Other reactions have included genital and anal pruritus, genital moniliasis, vaginitis and vaginal discharge, dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis, and joint disorder. Reversible interstitial nephritis has been reported rarely. Eosinophilia, neutropenia, thrombocytopenia, and slight elevations in AST and ALT have been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Cephalexin in the drug label.
# Drug Interactions
There is limited information regarding Cephalexin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- The daily oral administration of cephalexin to rats in doses of 250 or 500 mg/kg prior to and during pregnancy, or to rats and mice during the period of organogenesis only, had no adverse effect on fertility, fetal viability, fetal weight, or litter size. Note that the safety of cephalexin during pregnancy in humans has not been established.
- Cephalexin showed no enhanced toxicity in weanling and newborn rats as compared with adult animals. Nevertheless, because the studies in humans cannot rule out the possibility of harm, cephalexin should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cephalexin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cephalexin during labor and delivery.
### Nursing Mothers
- The excretion of cephalexin in the milk increased up to 4 hours after a 500 mg dose; the drug reached a maximum level of 4 mcg/mL, then decreased gradually, and had disappeared 8 hours after administration. Caution should be exercised when cephalexin is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Cephalexin with respect to pediatric patients.
### Geriatic Use
- Published clinical studies in which the safety and efficacy of cephalexin in elderly patients was compared to that of younger patients included 433 patients who were 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Cephalexin is known to substantially excreted by the kidney, and the risk of toxic relations to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Cephalexin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cephalexin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cephalexin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cephalexin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cephalexin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cephalexin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cephalexin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cephalexin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Signs and Symptoms — Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhea, and hematuria. If other symptoms are present, it is probably secondary to an underlying disease state, an allergic reaction, or toxicity due to ingestion of a second medication.
- The oral median lethal dose of cephalexin in rats is 5,000 mg/kg.
### Management
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
- Unless 5 to 10 times the normal dose of cephalexin has been ingested, gastrointestinal decontamination should not be necessary.
- Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.
- Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cephalexin; however, it would be extremely unlikely that one of these procedures would be indicated.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cephalexin in the drug label.
# Pharmacology
## Mechanism of Action
- Cephalexin is a bactericidal antimicrobial which works through inhibition of bacterial cell-wall synthesis. This occurs through binding to one or more penicillin binding proteins of actively dividing cells.
## Structure
- Cephalexin, USP is a semisynthetic cephalosporin antibiotic intended for oral administration. It is 7-(D-α-amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid monohydrate. Cephalexin has the molecular formula C16H17N3O4SH2O and the molecular weight is 365.41.
- Cephalexin has the following structural formula:
- The nucleus of cephalexin is related to that of other cephalosporin antibiotics. The compound is a zwitterion; i.e., the molecule contains both a basic and an acidic group. The isoelectric point of cephalexin in water is approximately 4.5 to 5.
- The crystalline form of cephalexin which is available is a monohydrate. It is a white crystalline solid having a bitter taste. Solubility in water is low at room temperature; 1 or 2 mg/mL may be dissolved readily, but higher concentrations are obtained with increasing difficulty.
- The cephalosporins differ from penicillins in the structure of the bicyclic ring system. Cephalexin has a D-phenylglycyl group as substituent at the 7-amino position and an unsubstituted methyl group at the 3-position.
- Each capsule for oral administration, contains cephalexin monohydrate equivalent to 250 mg (720 µmol) or 500 mg (1,439 µmol) of cephalexin.
- In addition, each capsule contains the following inactive ingredients: D&C Yellow No. 10, edible printing ink with black iron oxide, FD&C Green No. 3, FD&C Yellow No. 6, gelatin, lactose monohydrate, magnesium stearate and titanium dioxide.
- Also, the 500 mg strength capsule contains FD&C Blue No.1.
- After mixing, each 5 mL of Cephalexin for Oral Suspension will contain cephalexin monohydrate equivalent to 125 mg (360 µmol) or 250 mg (720 µmol) cephalexin. The suspensions also contain colloidal silicon dioxide, FD&C Red No. 40, sodium benzoate, strawberry flavor, sucrose and xanthan gum.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cephalexin in the drug label.
## Pharmacokinetics
- Human Pharmacology
- Cephalexin is acid stable and may be given without regard to meals. It is rapidly absorbed after oral administration. Following doses of 250 mg, 500 mg, and 1 g, average peak serum levels of approximately 9, 18, and 32 mcg/mL respectively were obtained at 1 hour. Measurable levels were present 6 hours after administration. Cephalexin is excreted in the urine by glomerular filtration and tubular secretion. Studies showed that over 90% of the drug was excreted unchanged in the urine within 8 hours. During this period, peak urine concentrations following the 250 mg, 500 mg, and 1 g doses were approximately 1,000, 2,200, and 5,000 mcg/mL respectively.
- In vitro tests demonstrate that the cephalosporins are bactericidal because of their inhibition of cell-wall synthesis. Cephalexin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.
- Aerobes, Gram-positive:
- Staphylococcus aureus (including penicillinase-producing strains)
- Staphylococcus epidermidis (penicillin-susceptible strains)
- Streptococcus pneumoniae
- Streptococcus pyogenes
- Aerobes, Gram-negative:
- Escherichia coli
- Haemophilus influenzae
- Klebsiella pneumoniae
- Moraxella (Branhamella) catarrhalis
- Proteus mirabilis
- Note — Methicillin-resistant staphylococci and most strains of enterococci (Enterococcus faecalis ) are resistant to cephalosporins, including cephalexin. It is not active against most strains of Enterobacter spp, Morganella morganii, and Proteus vulgaris. It has no activity against Pseudomonas spp or Acinetobacter calcoaceticus.
- Diffusion techniques:
- Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure1 that has been recommended for use with disks to test the susceptibility of microorganisms to cephalexin uses the 30 mcg cephalothin disk. Interpretation involves correlation of the diameter obtained in the disk test with the minimal inhibitory concentration (MIC) for cephalexin.
- Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg cephalothin disk should be interpreted according to the following criteria:
- A report of “Susceptible” indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. A report of “Intermediate” indicates that the result should be considered equivocal, and, if microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.
- Measurement of MIC or MBC and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections.
- Standardized susceptibility test procedures require the use of laboratory control microorganisms. The 30 mcg cephalothin disk should provide the following zone diameters in these laboratory test quality control strains:
- Dilution techniques:
- Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method2 (broth, agar, microdilution) or equivalent with cephalothin powder. The MIC values obtained should be interpreted according to the following criteria:
- Interpretation should be as stated above for results using diffusion techniques.
- As with standard diffusion techniques, dilution methods require the use of laboratory control microorganisms. Standard cephalothin powder should provide the following MIC values:
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Cephalexin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Cephalexin in the drug label.
# How Supplied
- Cephalexin For Oral Suspension, USP is available in:
- The 125 mg per 5 mL oral suspension- is pink in color with a strawberry flavor and is available as follows:
100 mL Bottles NDC 63304-958-01
200 mL Bottles NDC 63304-958-02
- 100 mL Bottles NDC 63304-958-01
- 200 mL Bottles NDC 63304-958-02
- The 250 mg per 5 mL oral suspension- is pink in color with a strawberry flavor and is available as follows:
100 mL Bottles NDC 63304-959-01
200 mL Bottles NDC 63304-959-02
- 100 mL Bottles NDC 63304-959-01
- 200 mL Bottles NDC 63304-959-02
- After mixing, store in a refrigerator. May be kept for 14 days without significant loss of potency. Shake well before using. Keep tightly closed.
- Cephalexin Capsules, USP are available in:
- 250 mg dark green and white, size 2, printed “RX656” on both cap and body.
(28s) NDC 63304-656-27
(100s) NDC 63304-656-01
(500s) NDC 63304-656-05
- (28s) NDC 63304-656-27
- (100s) NDC 63304-656-01
- (500s) NDC 63304-656-05
- 500 mg, dark green and light green, size 0, printed “RX657” on both cap and body.
(28s) NDC 63304-657-27
(100s) NDC 63304-657-01
(500s) NDC 63304-657-05
- (28s) NDC 63304-657-27
- (100s) NDC 63304-657-01
- (500s) NDC 63304-657-05
- The bottle packages contain desiccant.
- Dispense in tight, light-resistant container.
- Store at 20 – 25° C (68 – 77° F).
## Storage
There is limited information regarding Cephalexin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including cephalexin capsules and cephalexin for oral suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cephalexin capsules and cephalexin for oral suspension is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cephalexin capsules and cephalexin for oral suspension or other antibacterial drugs in the future.
# Precautions with Alcohol
- Alcohol-Cephalexin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CEPHALEXIN®
# Look-Alike Drug Names
- Keflex® — Keppra®
- Keflex® — Valtrex®
# Drug Shortage Status
# Price | Cephalexin
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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# Black Box Warning
# Overview
Cephalexin is a 1st generation cephalosporin that is FDA approved for the {{{indicationType}}} of respiratory tract infections caused by s. pneumoniae and s. pyogenes, otitis media, skin and skin structure infections, bone infections, genitourinary tract infections. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Respiratory tract infections caused by S. pneumoniae and S. pyogenes (Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cephalexin is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cephalexin in the subsequent prevention of rheumatic fever are not available at present.)
- Otitis media due to S. pneumoniae, H. influenzae, staphylococci, streptococci and M. catarrhalis
- Skin and skin structure infections caused by staphylococci and/or streptococci
- Bone infections caused by staphylococci and/or P. mirabilis
- Genitourinary tract infections, including acute prostatitis, caused by E. coli, P. mirabilis, and K. pneumoniae
- Cephalexin is administered orally.
- The adult dosage ranges from 1 to 4 g daily in divided doses. The usual adult dose is 250 mg every 6 hours. For the following infections, a dosage of 500 mg may be administered every 12 hours: streptococcal pharyngitis, skin and skin structure infections, and uncomplicated cystitis in patients over 15 years of age. Cystitis therapy should be continued for 7 to 14 days. For more severe infections or those caused by less susceptible organisms, larger doses may be needed. If daily doses of cephalexin greater than 4 g are required, parenteral cephalosporins, in appropriate doses, should be considered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American Heart Association
- Class of Recommendation: Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Cephalexin 2 g orally
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cephalexin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Respiratory tract infections caused by S. pneumoniae and S. pyogenes (Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Cephalexin is generally effective in the eradication of streptococci from the nasopharynx; however, substantial data establishing the efficacy of cephalexin in the subsequent prevention of rheumatic fever are not available at present.)
- Otitis media due to S. pneumoniae, H. influenzae, staphylococci, streptococci and M. catarrhalis
- Skin and skin structure infections caused by staphylococci and/or streptococci
- Bone infections caused by staphylococci and/or P. mirabilis
- Genitourinary tract infections, including acute prostatitis, caused by E. coli, P. mirabilis, and K. pneumoniae
- The usual recommended daily dosage for pediatric patients is 25 to 50 mg/kg in divided doses. For streptococcal pharyngitis in patients over 1 year of age and for skin and skin structure infections, the total daily dose may be divided and administered every 12 hours.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: American Heart Association
- Class of Recommendation: Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Cephalexin* 50 mg/kg orally
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cephalexin in pediatric patients.
# Contraindications
- Cephalexin is contraindicated in patients with known allergy to the cephalosporin group of antibiotics.
# Warnings
- BEFORE CEPHALEXIN THERAPY IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO CEPHALOSPORINS AND PENICILLIN. CEPHALOSPORIN C DERIVATIVES SHOULD BE GIVEN CAUTIOUSLY TO PENICILLIN-SENSITIVE PATIENTS.
- SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.
- There is some clinical and laboratory evidence of partial cross-allergenicity of the penicillins and the cephalosporins. Patients have been reported to have had severe reactions (including anaphylaxis) to both drugs.
- Any patient who has demonstrated some form of allergy, particularly to drugs, should receive antibiotics cautiously. No exception should be made with regard to cephalexin.
- Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cephalexin, and may range from mild to life threatening. Therefore, it is important to consider this diagnosis in patients with diarrhea subsequent to the administration of antibacterial agents.
- Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis.
- After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
- Usage in Pregnancy — Safety of this product for use during pregnancy has not been established.
### Precautions
- General
- Prescribing cephalexin capsules and cephalexin for oral suspension in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
- Patients should be followed carefully so that any side effects or unusual manifestations of drug idiosyncrasy may be detected. If an allergic reaction to cephalexin occurs, the drug should be discontinued and the patient treated with the usual agents (e.g., epinephrine or other pressor amines, antihistamines, or corticosteroids).
- Prolonged use of cephalexin may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.
- Positive direct Coombs’ tests have been reported during treatment with the cephalosporin antibiotics. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs’ testing of newborns whose mothers have received cephalosporin antibiotics before parturition, it should be recognized that a positive Coombs’ test may be due to the drug.
- Cephalexin should be administered with caution in the presence of markedly impaired renal function. Under such conditions, careful clinical observation and laboratory studies should be made because safe dosage may be lower than that usually recommended.
- Indicated surgical procedures should be performed in conjunction with antibiotic therapy.
- As a result of administration of cephalexin, a false-positive reaction for glucose in the urine may occur. This has been observed with Benedict’s and Fehling’s solutions and also with Clinitest® tablets.
- As with other β-lactams, the renal excretion of cephalexin is inhibited by probenecid.
- Broad-spectrum antibiotics should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
# Adverse Reactions
## Clinical Trials Experience
- Gastrointestinal — Symptoms of pseudomembranous colitis may appear either during or after antibiotic treatment. Nausea and vomiting have been reported rarely. The most frequent side effect has been diarrhea. It was very rarely severe enough to warrant cessation of therapy. Dyspepsia, gastritis, and abdominal pain have also occurred. As with some penicillins and some other cephalosporins, transient hepatitis and cholestatic jaundice have been reported rarely.
- Hypersensitivity — Allergic reactions in the form of rash, urticaria, angioedema, and, rarely, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been observed. These reactions usually subsided upon discontinuation of the drug. In some of these reactions, supportive therapy may be necessary. Anaphylaxis has also been reported.
- Other reactions have included genital and anal pruritus, genital moniliasis, vaginitis and vaginal discharge, dizziness, fatigue, headache, agitation, confusion, hallucinations, arthralgia, arthritis, and joint disorder. Reversible interstitial nephritis has been reported rarely. Eosinophilia, neutropenia, thrombocytopenia, and slight elevations in AST and ALT have been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Cephalexin in the drug label.
# Drug Interactions
There is limited information regarding Cephalexin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- The daily oral administration of cephalexin to rats in doses of 250 or 500 mg/kg prior to and during pregnancy, or to rats and mice during the period of organogenesis only, had no adverse effect on fertility, fetal viability, fetal weight, or litter size. Note that the safety of cephalexin during pregnancy in humans has not been established.
- Cephalexin showed no enhanced toxicity in weanling and newborn rats as compared with adult animals. Nevertheless, because the studies in humans cannot rule out the possibility of harm, cephalexin should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cephalexin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cephalexin during labor and delivery.
### Nursing Mothers
- The excretion of cephalexin in the milk increased up to 4 hours after a 500 mg dose; the drug reached a maximum level of 4 mcg/mL, then decreased gradually, and had disappeared 8 hours after administration. Caution should be exercised when cephalexin is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Cephalexin with respect to pediatric patients.
### Geriatic Use
- Published clinical studies in which the safety and efficacy of cephalexin in elderly patients was compared to that of younger patients included 433 patients who were 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Cephalexin is known to substantially excreted by the kidney, and the risk of toxic relations to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Cephalexin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cephalexin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cephalexin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cephalexin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cephalexin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cephalexin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cephalexin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cephalexin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Signs and Symptoms — Symptoms of oral overdose may include nausea, vomiting, epigastric distress, diarrhea, and hematuria. If other symptoms are present, it is probably secondary to an underlying disease state, an allergic reaction, or toxicity due to ingestion of a second medication.
- The oral median lethal dose of cephalexin in rats is 5,000 mg/kg.
### Management
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.
- Unless 5 to 10 times the normal dose of cephalexin has been ingested, gastrointestinal decontamination should not be necessary.
- Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.
- Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of cephalexin; however, it would be extremely unlikely that one of these procedures would be indicated.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cephalexin in the drug label.
# Pharmacology
## Mechanism of Action
- Cephalexin is a bactericidal antimicrobial which works through inhibition of bacterial cell-wall synthesis. This occurs through binding to one or more penicillin binding proteins of actively dividing cells.
## Structure
- Cephalexin, USP is a semisynthetic cephalosporin antibiotic intended for oral administration. It is 7-(D-α-amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid monohydrate. Cephalexin has the molecular formula C16H17N3O4S•H2O and the molecular weight is 365.41.
- Cephalexin has the following structural formula:
- The nucleus of cephalexin is related to that of other cephalosporin antibiotics. The compound is a zwitterion; i.e., the molecule contains both a basic and an acidic group. The isoelectric point of cephalexin in water is approximately 4.5 to 5.
- The crystalline form of cephalexin which is available is a monohydrate. It is a white crystalline solid having a bitter taste. Solubility in water is low at room temperature; 1 or 2 mg/mL may be dissolved readily, but higher concentrations are obtained with increasing difficulty.
- The cephalosporins differ from penicillins in the structure of the bicyclic ring system. Cephalexin has a D-phenylglycyl group as substituent at the 7-amino position and an unsubstituted methyl group at the 3-position.
- Each capsule for oral administration, contains cephalexin monohydrate equivalent to 250 mg (720 µmol) or 500 mg (1,439 µmol) of cephalexin.
- In addition, each capsule contains the following inactive ingredients: D&C Yellow No. 10, edible printing ink with black iron oxide, FD&C Green No. 3, FD&C Yellow No. 6, gelatin, lactose monohydrate, magnesium stearate and titanium dioxide.
- Also, the 500 mg strength capsule contains FD&C Blue No.1.
- After mixing, each 5 mL of Cephalexin for Oral Suspension will contain cephalexin monohydrate equivalent to 125 mg (360 µmol) or 250 mg (720 µmol) cephalexin. The suspensions also contain colloidal silicon dioxide, FD&C Red No. 40, sodium benzoate, strawberry flavor, sucrose and xanthan gum.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cephalexin in the drug label.
## Pharmacokinetics
- Human Pharmacology
- Cephalexin is acid stable and may be given without regard to meals. It is rapidly absorbed after oral administration. Following doses of 250 mg, 500 mg, and 1 g, average peak serum levels of approximately 9, 18, and 32 mcg/mL respectively were obtained at 1 hour. Measurable levels were present 6 hours after administration. Cephalexin is excreted in the urine by glomerular filtration and tubular secretion. Studies showed that over 90% of the drug was excreted unchanged in the urine within 8 hours. During this period, peak urine concentrations following the 250 mg, 500 mg, and 1 g doses were approximately 1,000, 2,200, and 5,000 mcg/mL respectively.
- In vitro tests demonstrate that the cephalosporins are bactericidal because of their inhibition of cell-wall synthesis. Cephalexin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.
- Aerobes, Gram-positive:
- Staphylococcus aureus (including penicillinase-producing strains)
- Staphylococcus epidermidis (penicillin-susceptible strains)
- Streptococcus pneumoniae
- Streptococcus pyogenes
- Aerobes, Gram-negative:
- Escherichia coli
- Haemophilus influenzae
- Klebsiella pneumoniae
- Moraxella (Branhamella) catarrhalis
- Proteus mirabilis
- Note — Methicillin-resistant staphylococci and most strains of enterococci (Enterococcus faecalis [formerly Streptococcus faecalis]) are resistant to cephalosporins, including cephalexin. It is not active against most strains of Enterobacter spp, Morganella morganii, and Proteus vulgaris. It has no activity against Pseudomonas spp or Acinetobacter calcoaceticus.
- Diffusion techniques:
- Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure1 that has been recommended for use with disks to test the susceptibility of microorganisms to cephalexin uses the 30 mcg cephalothin disk. Interpretation involves correlation of the diameter obtained in the disk test with the minimal inhibitory concentration (MIC) for cephalexin.
- Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg cephalothin disk should be interpreted according to the following criteria:
- A report of “Susceptible” indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. A report of “Intermediate” indicates that the result should be considered equivocal, and, if microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.
- Measurement of MIC or MBC and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections.
- Standardized susceptibility test procedures require the use of laboratory control microorganisms. The 30 mcg cephalothin disk should provide the following zone diameters in these laboratory test quality control strains:
- Dilution techniques:
- Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method2 (broth, agar, microdilution) or equivalent with cephalothin powder. The MIC values obtained should be interpreted according to the following criteria:
- Interpretation should be as stated above for results using diffusion techniques.
- As with standard diffusion techniques, dilution methods require the use of laboratory control microorganisms. Standard cephalothin powder should provide the following MIC values:
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Cephalexin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Cephalexin in the drug label.
# How Supplied
- Cephalexin For Oral Suspension, USP is available in:
- The 125 mg per 5 mL oral suspension* is pink in color with a strawberry flavor and is available as follows:
100 mL Bottles NDC 63304-958-01
200 mL Bottles NDC 63304-958-02
- 100 mL Bottles NDC 63304-958-01
- 200 mL Bottles NDC 63304-958-02
- The 250 mg per 5 mL oral suspension* is pink in color with a strawberry flavor and is available as follows:
100 mL Bottles NDC 63304-959-01
200 mL Bottles NDC 63304-959-02
- 100 mL Bottles NDC 63304-959-01
- 200 mL Bottles NDC 63304-959-02
- After mixing, store in a refrigerator. May be kept for 14 days without significant loss of potency. Shake well before using. Keep tightly closed.
- Cephalexin Capsules, USP are available in:
- 250 mg dark green and white, size 2, printed “RX656” on both cap and body.
(28s) NDC 63304-656-27
(100s) NDC 63304-656-01
(500s) NDC 63304-656-05
- (28s) NDC 63304-656-27
- (100s) NDC 63304-656-01
- (500s) NDC 63304-656-05
- 500 mg, dark green and light green, size 0, printed “RX657” on both cap and body.
(28s) NDC 63304-657-27
(100s) NDC 63304-657-01
(500s) NDC 63304-657-05
- (28s) NDC 63304-657-27
- (100s) NDC 63304-657-01
- (500s) NDC 63304-657-05
- The bottle packages contain desiccant.
- Dispense in tight, light-resistant container.
- Store at 20 – 25° C (68 – 77° F).
## Storage
There is limited information regarding Cephalexin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including cephalexin capsules and cephalexin for oral suspension should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cephalexin capsules and cephalexin for oral suspension is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cephalexin capsules and cephalexin for oral suspension or other antibacterial drugs in the future.
# Precautions with Alcohol
- Alcohol-Cephalexin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CEPHALEXIN®[2]
# Look-Alike Drug Names
- Keflex® — Keppra®[3]
- Keflex® — Valtrex®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cephalexin | |
62ef4186efb54e13db13461a668f2bdaab0801bb | wikidoc | Pelvimetry | Pelvimetry
# Background
Pelvimetry is the assessment of the female pelvis in relation to the birth of a baby. Traditional obstetrical services relied heavily on pelvimetry in the conduct of delivery in order to decide if natural or operative vaginal delivery was possible or if and when to use a cesarean section. With the increased safety of modern cesarean section and increased medico legal concerns about use of operative vaginal delivery, the threshold to perform a cesarean section has decreased and the need for pelvimetry diminished.
# Use
Pelvimetry used to be performed routinely to discern if spontaneous labour was medically advisable. Women whose pelvises were deemed too small received caesarean sections instead of birthing naturally. Research indicates that pelvimetry is not a useful diagnostic tool for CPD (see below) and that in all cases spontaneous labour and birthing should be facilitated. See Blackadar & Viera, 2003, p505
A woman's pelvis loosens up before birth (with the help of hormones), and an upright and/or squatting woman can birth a considerably larger baby. A woman in the lithotomy (lying on her back, head of bed elevated) is more than likely not going to push a larger than average baby out, due to the size of outlet that this position creates. Since obstetricians continue to place women in this position for their requirement of 'access', not considering the birthing mother's needs to be in a better position to open her pelvis, it is more likely that women will be given the diagnosis that their pelvis is too small to birth their baby.
# Cephalo-pelvic disproportion: CPD
Cephalo-pelvic disproportion exists when the capacity of the pelvis is inadequate to allow the fetus to negotiate the birth canal. This may be due to a small pelvis, a nongynecoid (see below) pelvic formation, or a large fetus, and combinations of these. Certain medical conditions may distort pelvic bones, such as rickets or a pelvic fracture, and lead to CPD.
### Contraindicated medications
Cephalo-pelvic disproportion is considered an absolute contraindication to the use of the following medications:
- Oxytocin
# Terminology
The terms used in pelvimetry are commonly used in obstetrics. Clinical pelvimetry attempts to assess the pelvis by clinical examination. Pelvimetry can also be done by radiography and MRI.
## Pelvic planes
- Pelvic inlet: The line between the narrowest bony points formed by the sacral promontory and the inner pubic arch is termed obstetrical conjugate: It should be 11.5 cm or more. This anteroposterior line at the inlet is 2 cm less than the diagonal conjugate (distance from undersurface of pubic arch to sacral promontory). The transverse diameter of the pelvic inlet measures 13.5 cm.
- Midpelvis: The line between the narrowest bone points connects the ischial spines; it typically exceeds 12 cm.
- Pelvic outlet: The distance between the ischial tuberosities (normally > 10 cm), and the angulation of the pubic arch.
## Pelvic types
Traditional obstetrics characterizes four types of pelvises:
- Gynecoid: Ideal shape, with round to slightly oval (obstetrical inlet slightly less transverse) inlet: best chances for normal vaginal delivery.
- Android: triangular inlet, and prominent ischial spines, more angulated pubic arch.
- Anthropoid: inlet transverse is greater than inlet obstetrical diameter.
- Platypelloid: Flat inlet with shortened obstetrical diameter.
## Fetal relationship
- Engagement: The fetal is engaged if the widest leading part (typically the widest circumference of the head) is negotiating the inlet.
- Station: Relationship of the leading bony part of the fetus to the maternal ischial spines. If at the level of the spines it is at “0(zero)” station, if it passed it by 2 cm it is at “+2” station.
- Attitude: Relationship of fetal head to spine: flexed, neutral (“military”), or extended attitudes are possible.
- Position: Relationship of presenting part to maternal pelvis, i.e. ROP=right occiput posterior, or LOA=left occiput anterior.
- Presentation: Relationship between the leading fetal part and the pelvic inlet: cephalic, breech, or shoulder presentation.
- Lie: Relationship between the longitudinal axis of fetus and mother: longitudinal, oblique, and transverse.
- Caput or Caput succedaneum: edema typically formed by the tissue overlying the fetal skull during the vaginal birthing process. | Pelvimetry
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Pelvimetry is the assessment of the female pelvis in relation to the birth of a baby. Traditional obstetrical services relied heavily on pelvimetry in the conduct of delivery in order to decide if natural or operative vaginal delivery was possible or if and when to use a cesarean section. With the increased safety of modern cesarean section and increased medico legal concerns about use of operative vaginal delivery, the threshold to perform a cesarean section has decreased and the need for pelvimetry diminished.
# Use
Pelvimetry used to be performed routinely to discern if spontaneous labour was medically advisable. Women whose pelvises were deemed too small received caesarean sections instead of birthing naturally. Research indicates that pelvimetry is not a useful diagnostic tool for CPD (see below) and that in all cases spontaneous labour and birthing should be facilitated. See Blackadar & Viera, 2003, p505
A woman's pelvis loosens up before birth (with the help of hormones), and an upright and/or squatting woman can birth a considerably larger baby. A woman in the lithotomy (lying on her back, head of bed elevated) is more than likely not going to push a larger than average baby out, due to the size of outlet that this position creates. Since obstetricians continue to place women in this position for their requirement of 'access', not considering the birthing mother's needs to be in a better position to open her pelvis, it is more likely that women will be given the diagnosis that their pelvis is too small to birth their baby.
# Cephalo-pelvic disproportion: CPD
Cephalo-pelvic disproportion exists when the capacity of the pelvis is inadequate to allow the fetus to negotiate the birth canal. This may be due to a small pelvis, a nongynecoid (see below) pelvic formation, or a large fetus, and combinations of these. Certain medical conditions may distort pelvic bones, such as rickets or a pelvic fracture, and lead to CPD.
### Contraindicated medications
Cephalo-pelvic disproportion is considered an absolute contraindication to the use of the following medications:
- Oxytocin
# Terminology
The terms used in pelvimetry are commonly used in obstetrics. Clinical pelvimetry attempts to assess the pelvis by clinical examination. Pelvimetry can also be done by radiography and MRI.
## Pelvic planes
- Pelvic inlet: The line between the narrowest bony points formed by the sacral promontory and the inner pubic arch is termed obstetrical conjugate: It should be 11.5 cm or more. This anteroposterior line at the inlet is 2 cm less than the diagonal conjugate (distance from undersurface of pubic arch to sacral promontory). The transverse diameter of the pelvic inlet measures 13.5 cm.
- Midpelvis: The line between the narrowest bone points connects the ischial spines; it typically exceeds 12 cm.
- Pelvic outlet: The distance between the ischial tuberosities (normally > 10 cm), and the angulation of the pubic arch.
## Pelvic types
Traditional obstetrics characterizes four types of pelvises:
- Gynecoid: Ideal shape, with round to slightly oval (obstetrical inlet slightly less transverse) inlet: best chances for normal vaginal delivery.
- Android: triangular inlet, and prominent ischial spines, more angulated pubic arch.
- Anthropoid: inlet transverse is greater than inlet obstetrical diameter.
- Platypelloid: Flat inlet with shortened obstetrical diameter.
## Fetal relationship
- Engagement: The fetal is engaged if the widest leading part (typically the widest circumference of the head) is negotiating the inlet.
- Station: Relationship of the leading bony part of the fetus to the maternal ischial spines. If at the level of the spines it is at “0(zero)” station, if it passed it by 2 cm it is at “+2” station.
- Attitude: Relationship of fetal head to spine: flexed, neutral (“military”), or extended attitudes are possible.
- Position: Relationship of presenting part to maternal pelvis, i.e. ROP=right occiput posterior, or LOA=left occiput anterior.
- Presentation: Relationship between the leading fetal part and the pelvic inlet: cephalic, breech, or shoulder presentation.
- Lie: Relationship between the longitudinal axis of fetus and mother: longitudinal, oblique, and transverse.
- Caput or Caput succedaneum: edema typically formed by the tissue overlying the fetal skull during the vaginal birthing process. | https://www.wikidoc.org/index.php/Cephalo-pelvic_disproportion | |
8dc311cbf4e686f435be9010c2ab7a0a8a7e783a | wikidoc | Cephradine | Cephradine
# Overview
Cefradine (INN) (formerly cephradine BAN) is a first generation cephalosporin antibiotic.
# Indications
It has similar spectrum of activity to cefalexin.
RESPIRATORY TRACT INFECTIONS (e.g., tonsillitis, pharyngitis, and lobar pneumonia) caused by group A beta-hemolytic streptococci and S. pneumoniae (formerly D. pneumonia).
(Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Velosef is generally effective in the eradication of streptococci from the nasopharynx; substantial data establishing the efficacy of Velosef in the subsequent prevention of rheumatic fever are not available at present.)
OTITIS MEDIA caused by group A beta-hemolytic streptococci, S. pneumoniae (formerly D. pneumoniae), H. influenzae, and staphylococci.
SKIN AND SKIN STRUCTURE INFECTIONS caused by staphylococci (penicillin-susceptible and penicillin-resistant) and beta-hemolytic streptococci.
URINARY TRACT INFECTIONS, including prostatitis, caused by E. coli, P. mirabilis, Klebsiella species, and enterococci (S. faecalis). The high concentrations of cephradine achievable in the urinary tract will be effective against many strains of enterococci for which disc susceptibility studies indicate relative resistance. It is to be noted that among beta-lactam antibiotics, ampicillin is the drug of choice for enterococcal urinary tract (E. faecalis) infection.
# Formulations
Capsules containing 250 mg or 500 mg, Syrup containing 250 mg/5 ml, or vials for injection containing 500 mg or 1 g.
# Brand Names
International Brands Velocef, Infexin (by Merck Pvt, Ltd) Intracef (by Beximco Pharma) SEFRIL(The ACME laboratories Ltd., Bangladesh), REOCEF(Rephco Pharmaceuticals Ltd., Bangladesh). Lebac (by Square pharmaceuticals Ltd., Bangladesh) | Cephradine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cefradine (INN) (formerly cephradine BAN) is a first generation cephalosporin antibiotic.
# Indications
It has similar spectrum of activity to cefalexin.
RESPIRATORY TRACT INFECTIONS (e.g., tonsillitis, pharyngitis, and lobar pneumonia) caused by group A beta-hemolytic streptococci and S. pneumoniae (formerly D. pneumonia).
(Penicillin is the usual drug of choice in the treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever. Velosef is generally effective in the eradication of streptococci from the nasopharynx; substantial data establishing the efficacy of Velosef in the subsequent prevention of rheumatic fever are not available at present.)
OTITIS MEDIA caused by group A beta-hemolytic streptococci, S. pneumoniae (formerly D. pneumoniae), H. influenzae, and staphylococci.
SKIN AND SKIN STRUCTURE INFECTIONS caused by staphylococci (penicillin-susceptible and penicillin-resistant) and beta-hemolytic streptococci.
URINARY TRACT INFECTIONS, including prostatitis, caused by E. coli, P. mirabilis, Klebsiella species, and enterococci (S. faecalis). The high concentrations of cephradine achievable in the urinary tract will be effective against many strains of enterococci for which disc susceptibility studies indicate relative resistance. It is to be noted that among beta-lactam antibiotics, ampicillin is the drug of choice for enterococcal urinary tract (E. faecalis) infection.
# Formulations
Capsules containing 250 mg or 500 mg, Syrup containing 250 mg/5 ml, or vials for injection containing 500 mg or 1 g.
# Brand Names
International Brands Velocef, Infexin (by Merck Pvt, Ltd) Intracef (by Beximco Pharma) SEFRIL(The ACME laboratories Ltd., Bangladesh), REOCEF(Rephco Pharmaceuticals Ltd., Bangladesh). Lebac (by Square pharmaceuticals Ltd., Bangladesh) | https://www.wikidoc.org/index.php/Cephradine | |
5c048a5f659ca5547933fc96897847d38e1b146d | wikidoc | Miracidium | Miracidium
A miracidium is a small free-living larval stage of parasitic flatworms in the class Trematoda. It is released from eggs which are usually shed in the faeces of its vertebrate host. When an egg is immersed in water, its operculum liberates the miracidium, which swims using cilia to find the first host in its life cycle, a mollusc. Miracidia are transmission stages that do not feed and, if they do not find a molluscan host, do not survive much beyond 24 hours. It goes through various stages in its mollusc host; the details vary with species:-
- Miracidium: settles in the mollusc and becomes a sporocyst.
- Sporocyst: produces either more sporocysts, or rediae.
- Redia: produces either more rediae, or cercariae.
- Cercaria: This is somewhat like a small adult, but has a large swimming tail somewhat like a tadpole's (but without a notochord or backbone, as it is not a chordate). It finds and settles in a host, and becomes an adult, or a mesocercaria, or a metacercaria, according to species.
- Mesocercaria: A cercaria little modified but resting.
- Metacercaria: A cercaria encysted and resting.
- Adult.
With some species of Trematoda the cercaria develops into an adult in that host.
With other species of Trematoda (for example Ribeiroia) the cercaria encysts, and waits until the host is eaten by a third host, in whose gut it emerges and develops into an adult.
In its final host, it eventually lays eggs which are discharged in its host's faeces. From there the eggs hatch in the presence of free water and the miracidium stage of life is reached again. | Miracidium
A miracidium is a small free-living larval stage of parasitic flatworms in the class Trematoda. It is released from eggs which are usually shed in the faeces of its vertebrate host. When an egg is immersed in water, its operculum liberates the miracidium, which swims using cilia to find the first host in its life cycle, a mollusc. Miracidia are transmission stages that do not feed and, if they do not find a molluscan host, do not survive much beyond 24 hours. It goes through various stages in its mollusc host; the details vary with species:-
- Miracidium: settles in the mollusc and becomes a sporocyst.
- Sporocyst: produces either more sporocysts, or rediae.
- Redia: produces either more rediae, or cercariae.
- Cercaria: This is somewhat like a small adult, but has a large swimming tail somewhat like a tadpole's (but without a notochord or backbone, as it is not a chordate). It finds and settles in a host, and becomes an adult, or a mesocercaria, or a metacercaria, according to species.
- Mesocercaria: A cercaria little modified but resting.
- Metacercaria: A cercaria encysted and resting.
- Adult.
With some species of Trematoda the cercaria develops into an adult in that host.
With other species of Trematoda (for example Ribeiroia) the cercaria encysts, and waits until the host is eaten by a third host, in whose gut it emerges and develops into an adult.
In its final host, it eventually lays eggs which are discharged in its host's faeces. From there the eggs hatch in the presence of free water and the miracidium stage of life is reached again.
# External links
- A set of pages:-
http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life1.html
http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life2.html
http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life3.html
http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life4.html
http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life5.html
- http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life1.html
- http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life2.html
- http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life3.html
- http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life4.html
- http://www.path.cam.ac.uk/~schisto/OtherFlukes/Flukes_Gen/Fluke_Life5.html
cs:Miracidium
de:Miracidium
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Cercaria | |
c3014f2402797b8af21f2393478b8d4f389426a9 | wikidoc | Cerebritis | Cerebritis
# Overview
Cerebritis is an infection of the brain that normally leads to the formation of an abscess within the brain itself. It is the inflammation of the cerebrum, a structure within the brain, which performs a number of important functions, including most of the things which people associate with being human, such as memory and speech. It is also defined as a purulent nonencapsulated parenchymal infection of brain which is characterized by nonspecific features on CT (ill-defined low density area with peripheral enhancement) and cannot reliably be distinguished from neoplasms.
Cerebritis usually occurs as a result of an underlying condition, which causes the inflammation of the brain tissue. It is commonly found in patients with lupus. Lupus cerebritis may occur in adults and children. The duration of the central nervous system involvement may vary from a few minutes, as in classic migraine or a transient ischemic attack, to years, as in dementia. Resulting neurological deficits may be transient or permanent, occasionally resulting in death.
# Symptoms
The symptoms of cerebritis may range from mild to severe.
The severity of the symptoms varies based on the degree of swelling and on how elevated is the intracranial pressure. Mild symptoms include headaches, depression, anxiety and in some cases, memory loss. In some cases inflammation of brain can be seen if the brain or the nervous system is attacked as a result of problems with the immune system. The serious problems caused because of inflammation include headaches, seizures, vision problems, dizziness, behavior changes and even stroke.
Severe lupus cerebritis symptoms include psychosis, dementia, peripheral neuropathy, cerebellar ataxia (failure of muscular coordination, usually on one side of the body), and chorea (jerky, involuntary movements). Stroke incidence is 3-20% in systemic lupus patients, and is highest in the first five years of the disease. Peripheral neuropathy (carpal tunnel syndrome, for example) occurs in more than 20% of systemic lupus patients and cranial nerve palsies occur in 10-15%.
# Causes
Lupus systemic erythematosus is one of the most common causes of cerebritis as it is believed that more than half of the patients with lupus from the United States suffer from a degree or another of lupus cerebritis.
The exact pathophysiological process of lupus cerebritis is unknown. The proposed mechanisms are likely due to the assault of several autoimmune system changes, including the following:
- Circulating immune complexes. The immune complexes, which consist of DNA and anti-DNA, cause an inflammatory response as well as a disruption of the blood–brain barrier. These circulating complexes have been found trapped in the highly vascular choroid plexus of SLE patients upon autopsy. True vasculitis, however, is found only in about 10% of patients with cerebral lupus.
- Anti-neuronal antibodies. The three identified anti-neuronal antibodies postulated in CNS involvement are the lympho-cytotoxic antibodies (LCAs), which somehow react with brain tissue and interfere with the neuron's ability to respond. LCAs have a specific role and are found in both the serum and cerebrospinal fluid (CSF) of lupus patients with cerebritis. These antibodies also correlate with cognitive and visual spatial defects. Second, the anti-neuronal membrane antibodies are targeted directly to neuronal antigens. They, too, are found in the serum of SLE patients with cerebritis. And third, the intracytoplasmic antibodies target the constituents of the neuron cells and they are found in the CSF and serum. These antibodies are seen in 90% of SLE patients with psychosis.
- Antiphospholipid antibodies. The two antibodies implicated are anticardiolipin and lupus anticoagulant. Anticardiolipin antibodies attach to the endothelial lining of cells, causing endothelial damage, platelet aggregation, inflammation, and fibrosis.
- Cytokine release. The final mechanism of lupus cerebritis involves the cytokines. The cytokines trigger edema, endothelial thickening, and infiltration of neutrophils in brain tissue. Two cytokines, interferon alpha and interleukin-6, have been found in the CSF of SLE patients with psychosis.
However, it is not clear which mechanism is the actual cause of cerebritis in lupus patients. Specialists believe that all mechanisms may be present at the same time or they may act independently.
In very rare cases, cerebritis may occur as a result of a Klebsiella pneumoniae infection.
One other reason to develop cerebritis is an infection caused by bacteria, viruses, or other organisms. Infections can occur when infectious agents enter the brain through the sinuses or as a result of trauma. Some pathogens are also capable of passing over the blood–brain barrier and entering the brain through the bloodstream, despite the fact that the body has evolved defenses which are specifically designed to prevent this.
# Treatment
Lupus is a condition with no known cure. Lupus cerebritis however is treated by suppressing the autoimmune activity.
When it is caused by infections, treatment consists of medication that will primarily cure the infection. For inflammation, steroids can be used to bring down the swelling. If the swelling appears to have increased to a dangerous level, surgery may be needed to relieve pressure on the brain. The formation of an abscess also calls for surgery as it will be necessary to drain the abscess. | Cerebritis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cerebritis is an infection of the brain that normally leads to the formation of an abscess within the brain itself. It is the inflammation of the cerebrum, a structure within the brain, which performs a number of important functions, including most of the things which people associate with being human, such as memory and speech. It is also defined as a purulent nonencapsulated parenchymal infection of brain which is characterized by nonspecific features on CT (ill-defined low density area with peripheral enhancement) and cannot reliably be distinguished from neoplasms.[1]
Cerebritis usually occurs as a result of an underlying condition, which causes the inflammation of the brain tissue. It is commonly found in patients with lupus. Lupus cerebritis may occur in adults and children. The duration of the central nervous system involvement may vary from a few minutes, as in classic migraine or a transient ischemic attack, to years, as in dementia. Resulting neurological deficits may be transient or permanent, occasionally resulting in death.[2]
# Symptoms
The symptoms of cerebritis may range from mild to severe.[3]
The severity of the symptoms varies based on the degree of swelling and on how elevated is the intracranial pressure. Mild symptoms include headaches, depression, anxiety and in some cases, memory loss. In some cases inflammation of brain can be seen if the brain or the nervous system is attacked as a result of problems with the immune system. The serious problems caused because of inflammation include headaches, seizures, vision problems, dizziness, behavior changes and even stroke.[4]
Severe lupus cerebritis symptoms include psychosis, dementia, peripheral neuropathy, cerebellar ataxia (failure of muscular coordination, usually on one side of the body), and chorea (jerky, involuntary movements). Stroke incidence is 3-20% in systemic lupus patients, and is highest in the first five years of the disease. Peripheral neuropathy (carpal tunnel syndrome, for example) occurs in more than 20% of systemic lupus patients and cranial nerve palsies occur in 10-15%.[5]
# Causes
Lupus systemic erythematosus is one of the most common causes of cerebritis as it is believed that more than half of the patients with lupus from the United States suffer from a degree or another of lupus cerebritis.[6]
The exact pathophysiological process of lupus cerebritis is unknown. The proposed mechanisms are likely due to the assault of several autoimmune system changes, including the following:
- Circulating immune complexes. The immune complexes, which consist of DNA and anti-DNA, cause an inflammatory response as well as a disruption of the blood–brain barrier. These circulating complexes have been found trapped in the highly vascular choroid plexus of SLE patients upon autopsy. True vasculitis, however, is found only in about 10% of patients with cerebral lupus.[7]
- Anti-neuronal antibodies. The three identified anti-neuronal antibodies postulated in CNS involvement are the lympho-cytotoxic antibodies (LCAs), which somehow react with brain tissue and interfere with the neuron's ability to respond. LCAs have a specific role and are found in both the serum and cerebrospinal fluid (CSF) of lupus patients with cerebritis. These antibodies also correlate with cognitive and visual spatial defects. Second, the anti-neuronal membrane antibodies are targeted directly to neuronal antigens. They, too, are found in the serum of SLE patients with cerebritis. And third, the intracytoplasmic antibodies target the constituents of the neuron cells and they are found in the CSF and serum. These antibodies are seen in 90% of SLE patients with psychosis.[8]
- Antiphospholipid antibodies. The two antibodies implicated are anticardiolipin and lupus anticoagulant. Anticardiolipin antibodies attach to the endothelial lining of cells, causing endothelial damage, platelet aggregation, inflammation, and fibrosis.[9]
- Cytokine release. The final mechanism of lupus cerebritis involves the cytokines. The cytokines trigger edema, endothelial thickening, and infiltration of neutrophils in brain tissue. Two cytokines, interferon alpha and interleukin-6, have been found in the CSF of SLE patients with psychosis.[10]
However, it is not clear which mechanism is the actual cause of cerebritis in lupus patients. Specialists believe that all mechanisms may be present at the same time or they may act independently.
In very rare cases, cerebritis may occur as a result of a Klebsiella pneumoniae infection.[11]
One other reason to develop cerebritis is an infection caused by bacteria, viruses, or other organisms. Infections can occur when infectious agents enter the brain through the sinuses or as a result of trauma. Some pathogens are also capable of passing over the blood–brain barrier and entering the brain through the bloodstream, despite the fact that the body has evolved defenses which are specifically designed to prevent this.
# Treatment
Lupus is a condition with no known cure. Lupus cerebritis however is treated by suppressing the autoimmune activity.[12]
When it is caused by infections, treatment consists of medication that will primarily cure the infection. For inflammation, steroids can be used to bring down the swelling. If the swelling appears to have increased to a dangerous level, surgery may be needed to relieve pressure on the brain. The formation of an abscess also calls for surgery as it will be necessary to drain the abscess. | https://www.wikidoc.org/index.php/Cerebritis | |
c4c75ce08cad0c2be1f1626cfa6728f55892f172 | wikidoc | Certoparin | Certoparin
Certoparin (Sandoparin®, Embolex®, Novartis) is a low molecular weight heparin, primarily active against factor Xa. Like other low molecular weight heparins, it is used to prevent deep venous thrombosis.
Mechanism of action:
Certoparin is a low molecular weight heparin. Heparin and certoparin (anticoagulants) work by interfering with the body's natural blood clotting mechanism. This mechanism involves a series of complex pathways. Heparin and certoparin inactivate a compound in this pathway called thrombin, which plays an important role in blood clot formation. Therefore, heparin and certoparin prevent the formation of blood clots in the body and breakdown pre-existing blood clots. Certoparin has many advantages over normal heparin. These include a more effective anticoagulant effect and reduced risk of bleeding. Certoparin is given by injection under the skin, and is used for the treatment of blood clots in conditions such as deep vein thrombosis and pulmonary embolism and the prevention of blood clots following surgery.
Side effects:
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Because a side effect is stated here, it does not mean that all people using this medicine will experience that or any side effect.
Allergy to active ingredients (hypersensitivity)
Alteration in results of liver function tests
Thinning of the bones (osteoporosis) with long term use
Decrease in the number of platelets in the blood (thrombocytopenia)
Bleeding at injection site
The side effects listed above may not include all of the side effects reported by the drug's manufacturer. For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist. | Certoparin
Certoparin (Sandoparin®, Embolex®, Novartis) is a low molecular weight heparin, primarily active against factor Xa. Like other low molecular weight heparins, it is used to prevent deep venous thrombosis.
Template:Pharma-stub
Mechanism of action:
Certoparin is a low molecular weight heparin. Heparin and certoparin (anticoagulants) work by interfering with the body's natural blood clotting mechanism. This mechanism involves a series of complex pathways. Heparin and certoparin inactivate a compound in this pathway called thrombin, which plays an important role in blood clot formation. Therefore, heparin and certoparin prevent the formation of blood clots in the body and breakdown pre-existing blood clots. Certoparin has many advantages over normal heparin. These include a more effective anticoagulant effect and reduced risk of bleeding. Certoparin is given by injection under the skin, and is used for the treatment of blood clots in conditions such as deep vein thrombosis and pulmonary embolism and the prevention of blood clots following surgery.
Side effects:
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Because a side effect is stated here, it does not mean that all people using this medicine will experience that or any side effect.
Allergy to active ingredients (hypersensitivity)
Alteration in results of liver function tests
Thinning of the bones (osteoporosis) with long term use
Decrease in the number of platelets in the blood (thrombocytopenia)
Bleeding at injection site
The side effects listed above may not include all of the side effects reported by the drug's manufacturer. For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist. | https://www.wikidoc.org/index.php/Certoparin | |
c3beb9f537d0afa49925ce92d26c574abb302f8f | wikidoc | Ceruletide | Ceruletide
# Overview
Ceruletide (INN), also known as cerulein or caerulein, is a ten amino acid oligopeptide that stimulates smooth muscle and increases digestive secretions. Ceruletide is similar in action and composition to cholecystokinin. It stimulates gastric, biliary, and pancreatic secretion; and certain smooth muscle. It is used in paralytic ileus and as diagnostic aid in pancreatic malfunction. It is used to induce pancreatitis in experimental animal models.
Ceruletide was discovered and its structure elucidated in 1967 by Australian and Italian scientists from dried skins of the Australian green tree frog (Litoria caerulea, formerly Hyla caerulea). Its amino acid sequence is Pglu-Gln-Asp-Tyr-Thr-Gly-Trp-Met-Asp-Phe-NH2.
# Induction of pancreatitis
Ceruletide upregulates pancreatic acinar cell intercellular adhesion molecule-1 (ICAM-1) proteins through intracellular upregulation of NF-κB. Surface ICAM-1 in turn promotes neutrophil adhesion onto acinar cells enhancing pancreatic inflammation. In addition to promoting the inflammatory cell reaction to acinar cells, ceruletide induces pancreatitis through dysregulation of digestive enzyme production and cytoplasmic vacuolization, leading to acinar cell death and pancreatic edema. Ceruletide also activates NADPH oxidase, a source of reactive oxygen species contributing to inflammation, as well as the Janus kinase/signal transducer, another inflammation inducer. | Ceruletide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ceruletide (INN), also known as cerulein or caerulein, is a ten amino acid oligopeptide that stimulates smooth muscle and increases digestive secretions. Ceruletide is similar in action and composition to cholecystokinin. It stimulates gastric, biliary, and pancreatic secretion; and certain smooth muscle. It is used in paralytic ileus and as diagnostic aid in pancreatic malfunction. It is used to induce pancreatitis in experimental animal models.
Ceruletide was discovered and its structure elucidated in 1967 by Australian and Italian scientists from dried skins of the Australian green tree frog (Litoria caerulea, formerly Hyla caerulea). Its amino acid sequence is Pglu-Gln-Asp-Tyr[SO3H]-Thr-Gly-Trp-Met-Asp-Phe-NH2.[1][2]
# Induction of pancreatitis
Ceruletide upregulates pancreatic acinar cell intercellular adhesion molecule-1 (ICAM-1) proteins through intracellular upregulation of NF-κB. Surface ICAM-1 in turn promotes neutrophil adhesion onto acinar cells enhancing pancreatic inflammation.[3] In addition to promoting the inflammatory cell reaction to acinar cells, ceruletide induces pancreatitis through dysregulation of digestive enzyme production and cytoplasmic vacuolization, leading to acinar cell death and pancreatic edema. Ceruletide also activates NADPH oxidase, a source of reactive oxygen species contributing to inflammation, as well as the Janus kinase/signal transducer, another inflammation inducer.[4] | https://www.wikidoc.org/index.php/Ceruletide | |
50ab59df940cea546943d7e933a883c3f36b38ad | wikidoc | Cetrorelix | Cetrorelix
# 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
Cetrorelix is a Luteinizing Hormone Releasing Hormone Antagonist that is FDA approved for the treatment of inhibition of premature LH surges in women undergoing controlled ovarian stimulation. Common adverse reactions include Ovarian hyperstimulation syndrome, Nausea, Headache ..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Cetrotide® (cetrorelix acetate for injection) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian stimulation.
### Dosage
- Ovarian stimulation therapy with gonadotropins (FSH, hMG) is started on cycle Day 2 or 3. The dose of gonadotropins should be adjusted according to individual response. Cetrotide® (cetrorelix acetate for injection) 0.25 mg may be administered subcutaneously once daily during the early- to mid-follicular phase.
- Cetrotide® 0.25 mg is administered on either stimulation day 5 (morning or evening) or day 6 (morning) and continued daily until the day of hCG administration.
- When assessment by ultrasound shows a sufficient number of follicles of adequate size, hCG is administered to induce ovulation and final maturation of the oocytes. No hCG should be administered if the ovaries show an excessive response to the treatment with gonadotropins to reduce the chance of developing ovarian hyperstimulation syndrome (OHSS).
- Cetrotide® 0.25 mg can be administered by the patient herself after appropriate instructions by her doctor.
- Directions for using Cetrotide® 0.25 mg with the enclosed needles and pre-filled syringe:
- Wash hands thoroughly with soap and water.
- Flip off the plastic cover of the vial and wipe the aluminum ring and the rubber stopper with an alcohol swab.
- Twist the injection needle with the yellow mark (20 gauge) on the pre-filled syringe.
- Push the needle through the center of the rubber stopper of the vial and slowly inject the solvent into the vial.
- Leaving the syringe in the vial, gently swirl the vial until the solution is clear and without residues. Avoid forming bubbles.
- Draw the total contents of the vial into the syringe. If necessary, invert the vial and pull back the needle as far as needed to withdraw the entire contents of the vial.
- Replace the needle with the yellow mark by the injection needle with the grey mark (27 gauge).
- Invert the syringe and push the plunger until all air bubbles have been expelled.
- Choose an injection site in the lower abdominal area, preferably around, but staying at least one inch away from the navel. Choose a different injection site each day to minimize local irritation. Use the second alcohol swab to clean the skin at the injection site and allow alcohol to dry. Gently pinch up the skin surrounding the site of injection.
- Inject the prescribed dose as directed by your doctor, nurse or pharmacist.
- Use the syringe and needles only once. Dispose of the syringe and needles properly after use. If available, use a medical waste container for disposal.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cetrorelix in adult patients.
### Non–Guideline-Supported Use
- Uterine leiomyoma
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cetrorelix in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cetrorelix in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cetrorelix in pediatric patients.
# Contraindications
- Cetrotide® (cetrorelix acetate for injection) is contraindicated under the following conditions:
- Hypersensitivity to cetrorelix acetate, extrinsic peptide hormones or mannitol.
- Known hypersensitivity to GnRH or any other GnRH analogs.
- Known or suspected pregnancy, and lactation.
- Severe renal impairment
# Warnings
- Cetrotide® (cetrorelix acetate for injection) should be prescribed by physicians who are experienced in fertility treatment. Before starting treatment with Cetrotide®, pregnancy must be excluded
### Precautions
- Cases of hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been reported during post-marketing surveillance. A severe anaphylactic reaction associated with cough, rash, and hypotension, was observed in one patient after seven months of treatment with Cetrotide® (10 mg/day) in a study for an indication unrelated to infertility.
- Special care should be taken in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with Cetrotide® is not advised in women with severe allergic conditions.
- Prior to therapy with Cetrotide® (cetrorelix acetate for injection), patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed. Cetrotide® should not be prescribed if a patient is pregnant.
- If Cetrotide® is prescribed to patients for self-administration, information for proper use is given in the Patient Leaflet.
- After the exclusion of preexisting conditions, enzyme elevations (ALT, AST, GGT, alkaline phosphatase) were found in 1-2% of patients receiving Cetrotide® during controlled ovarian stimulation. The elevations ranged up to three times the upper limit of normal. The clinical significance of these findings was not determined.
- During stimulation with human menopausal gonadotropin, Cetrotide® had no notable effects on hormone levels aside from inhibition of LH surges.
# Adverse Reactions
## Clinical Trials Experience
- The safety of Cetrotide® (cetrorelix acetate for injection) in 949 patients undergoing controlled ovarian stimulation in clinical studies was evaluated. Women were between 19 and 40 years of age (mean: 32). 94.0% of them were Caucasian. Cetrotide® was given in doses ranging from 0.1 mg to 5 mg as either a single or multiple dose.
- Table 3 shows systemic adverse events, reported in clinical studies without regard to causality, from the beginning of Cetrotide® treatment until confirmation of pregnancy by ultrasound at an incidence ≥ 1% in Cetrotide® treated subjects undergoing COS.
- Local site reactions (e.g. redness, erythema, bruising, itching, swelling, and pruritus) were reported. Usually, they were of a transient nature, mild intensity and short duration. During post-marketing surveillance, rare cases of hypersensitivity reactions including anaphylactoid reactions have been reported.
- Two stillbirths were reported in Phase 3 studies of Cetrotide®.
- Clinical follow-up studies of 316 newborns of women administered Cetrotide® were reviewed. One infant of a set of twin neonates was found to have anencephaly at birth and died after four days. The other twin was normal. Developmental findings from ongoing baby follow-up included a child with a ventricular septal defect and another child with bilateral congenital glaucoma.
- Four pregnancies that resulted in therapeutic abortion in Phase 2 and Phase 3 controlled ovarian stimulation studies had major anomalies (diaphragmatic hernia, trisomy 21, Klinefelter syndrome, polymalformation, and trisomy 18). In three of these four cases, intracytoplasmic sperm injection (ICSI) was the fertilization method employed; in the fourth case, in vitro fertilization (IVF) was the method employed.
- The minor congenital anomalies reported include: supernumerary nipple, bilateral strabismus, imperforate hymen, congenital nevi, hemangiomata, and QT syndrome.
- The causal relationship between the reported anomalies and Cetrotide® is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.
## Postmarketing Experience
- During post-marketing surveillance, rare cases of hypersensitivity reactions including anaphylactoid reactions have been reported.
# Drug Interactions
- No formal drug interaction studies have been performed with Cetrotide®.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Cetrotide® is contraindicated in pregnant women.
- When administered to rats for the first seven days of pregnancy, cetrorelix acetate did not affect the development of the implanted conceptus at doses up to 38 μg/kg (approximately 1 times the recommended human therapeutic dose based on body surface area). However, a dose of 139 μg/kg (approximately 4 times the human dose) resulted in a resorption rate and a postimplantation loss of 100%. When administered from day 6 to near term to pregnant rats and rabbits, very early resorptions and total implantation losses were seen in rats at doses from 4.6 μg/kg (0.2 times the human dose) and in rabbits at doses from 6.8 μg/kg (0.4 times the human dose). In animals that maintained their pregnancy, there was no increase in the incidence of fetal abnormalities.
- The fetal resorption observed in animals is a logical consequence of the alteration in hormonal levels effected by the antigonadotrophic properties of Cetrotide®, which could result in fetal loss in humans as well. Therefore, this drug should not be used in pregnant women.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cetrorelix in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cetrorelix during labor and delivery.
### Nursing Mothers
- It is not known whether Cetrotide® is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Cetrotide® on lactation and/or the breast-fed child have not been determined, Cetrotide® should not be used by nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Cetrorelix with respect to pediatric patients.
### Geriatic Use
- Cetrotide® is not intended to be used in subjects aged 65 and over.
### Gender
There is no FDA guidance on the use of Cetrorelix with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cetrorelix with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cetrorelix in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cetrorelix in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cetrorelix in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cetrorelix in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- subcutaneous
### Monitoring
There is limited information regarding Monitoring of Cetrorelix in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cetrorelix in the drug label.
# Overdosage
- There have been no reports of overdosage with Cetrotide® 0.25 mg or 3 mg in humans. Single doses up to 120 mg Cetrotide® have been well tolerated in patients treated for other indications without signs of overdosage.
# Pharmacology
## Mechanism of Action
- GnRH induces the production and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the gonadotrophic cells of the anterior pituitary. Due to a positive estradiol (E2) feedback at midcycle, GnRH liberation is enhanced resulting in an LH-surge. This LH-surge induces the ovulation of the dominant follicle, resumption of oocyte meiosis and subsequently luteinization as indicated by rising progesterone levels.
- Cetrotide® competes with natural GnRH for binding to membrane receptors on pituitary cells and thus controls the release of LH and FSH in a dose-dependent manner. The onset of LH suppression is approximately one hour with the 3 mg dose and two hours with the 0.25 mg dose. This suppression is maintained by continuous treatment and there is a more pronounced effect on LH than on FSH. An initial release of endogenous gonadotropins has not been detected with Cetrotide®, which is consistent with an antagonist effect.
- The effects of Cetrotide® on LH and FSH are reversible after discontinuation of treatment. In women, Cetrotide® delays the LH-surge, and consequently ovulation, in a dose-dependent fashion. FSH levels are not affected at the doses used during controlled ovarian stimulation. Following a single 3 mg dose of Cetrotide®, duration of action of at least 4 days has been established. A dose of Cetrotide® 0.25 mg every 24 hours has been shown to maintain the effect.
## Structure
- Cetrotide® (cetrorelix acetate for injection) is a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic activity. Cetrorelix acetate is an analog of native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, and 10. The molecular formula is Acetyl-D-3-(2´-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3´-pyridyl)-alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide, and the molecular weight is 1431.06, calculated as the anhydrous free base. The structural formula is as follows:
- Cetrotide® (cetrorelix acetate for injection) 0.25 mg is a sterile lyophilized powder intended for subcutaneous injection after reconstitution with Sterile Water for Injection, USP (pH 5-8), that comes supplied in a 1.0 mL pre-filled syringe. Each vial of Cetrotide® 0.25 mg contains 0.26-0.27 mg cetrorelix acetate, equivalent to 0.25 mg cetrorelix, and 54.80 mg mannitol.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cetrorelix in the drug label.
## Pharmacokinetics
- The pharmacokinetic parameters of single and multiple doses of Cetrotide® (cetrorelix acetate for injection) in adult healthy female subjects are summarized in Table 1.
- Cetrotide® is rapidly absorbed following subcutaneous injection, maximal plasma concentrations being achieved approximately one to two hours after administration. The mean absolute bioavailability of Cetrotide® following subcutaneous administration to healthy female subjects is 85%.
- The volume of distribution of Cetrotide® following a single intravenous dose of 3 mg is about 1 l/kg. In vitro protein binding to human plasma is 86%.
- Cetrotide® concentrations in follicular fluid and plasma were similar on the day of oocyte pick-up in patients undergoing controlled ovarian stimulation. Following subcutaneous administration of Cetrotide® 0.25 mg and 3 mg, plasma concentrations of cetrorelix were below or in the range of the lower limit of quantitation on the day of oocyte pick-up and embryo transfer.
- After subcutaneous administration of 10 mg Cetrotide® to females and males, Cetrotide® and small amounts of (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples over 24 hours.
- In in vitro studies, Cetrotide® was stable against phase I- and phase II-metabolism. Cetrotide® was transformed by peptidases, and the (1-4) peptide was the predominant metabolite.
- Following subcutaneous administration of 10 mg cetrorelix to males and females, only unchanged cetrorelix was detected in urine. In 24 hours, cetrorelix and small amounts of the (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples. 2-4% of the dose was eliminated in the urine as unchanged cetrorelix, while 5-10% was eliminated as cetrorelix and the four metabolites in bile. Therefore, only 7-14% of the total dose was recovered as unchanged cetrorelix and metabolites in urine and bile up to 24 hours. The remaining portion of the dose may not have been recovered since bile and urine were not collected for a longer period of time.
- Pharmacokinetic investigations have not been performed either in subjects with impaired renal or liver function, or in the elderly, or in children.
- Pharmacokinetic differences in different races have not been determined.
- There is no evidence of differences in pharmacokinetic parameters for Cetrotide® between healthy subjects and patients undergoing controlled ovarian stimulation.
- No formal drug-drug interaction studies have been performed with Cetrotide®
## Nonclinical Toxicology
- Long-term carcinogenicity studies in animals have not been performed with cetrorelix acetate. Cetrorelix acetate was not genotoxic in vitro (Ames test, HPRT test, chromosome aberration test) or in vivo (chromosome aberration test, mouse micronucleus test). Cetrorelix acetate induced polyploidy in CHL-Chinese hamster lung fibroblasts, but not in V79-Chinese hamster lung fibroblasts, cultured peripheral human lymphocytes or in an in vitro micronucleus test in the CHL-cell line. Treatment with 0.46 mg/kg cetrorelix acetate for 4 weeks resulted in complete infertility in female rats which was reversed 8 weeks after cessation of treatment.
# Clinical Studies
- Seven hundred thirty two (732) patients were treated with Cetrotide® (cetrorelix acetate for injection) in five (two Phase 2 dose-finding and three Phase 3) clinical trials. The clinical trial population consisted of Caucasians (95.5%) and Black, Asian, Arabian and others (4.5%). Women were between 19 and 40 years of age (mean: 32). The studies excluded subjects with polycystic ovary syndrome (PCOS), subjects with low or no ovarian reserve, and subjects with stage III-IV endometriosis.
- Two dose regimens were investigated in these clinical trials, either a single dose per treatment cycle or multiple dosing. In the Phase 2 studies, a single dose of 3 mg was established as the minimal effective dose for the inhibition of premature LH surges with a protection period of at least 4 days. When Cetrotide® is administered in a multidose regimen, 0.25 mg was established as the minimal effective dose. The extent and duration of LH-suppression is dose dependent.
- In the Phase 3 program, efficacy of the single 3 mg dose regimen of Cetrotide® and the multiple 0.25 mg dose regimen of Cetrotide® was established separately in two adequate and well controlled clinical studies utilizing active comparators. A third non-comparative clinical study evaluated only the multiple 0.25 mg dose regimen of Cetrotide®. The ovarian stimulation treatment with recombinant FSH or human menopausal gonadotropin (hMG) was initiated on day 2 or 3 of a normal menstrual cycle. The dose of gonadotropins was administered according to the individual patient's disposition and response.
- In the single dose regimen study, Cetrotide® 3 mg was administered on the day of controlled ovarian stimulation when adequate estradiol levels (400 pg/mL) were obtained, usually on day 7 (range day 5-12). If hCG was not given within 4 days of the 3 mg dose of Cetrotide®, then 0.25 mg of Cetrotide® was administered daily beginning 96 hours after the 3 mg injection until and including the day of hCG administration.
- In the two multiple dose regimen studies, Cetrotide® 0.25 mg was started on day 5 or 6 of COS. Both gonadotropins and Cetrotide® were continued daily (multiple dose regimen) until the injection of human chorionic gonadotropin (hCG).
- Oocyte pick-up (OPU) followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) as well as embryo transfer (ET) were subsequently performed. The results for Cetrotide® are summarized below in Table 2.
- In addition to IVF and ICSI, one pregnancy was obtained after intrauterine insemination. In the five Phase 2 and Phase 3 clinical trials, 184 pregnancies have been reported out of a total of 732 patients (including 21 pregnancies following the replacement of frozen-thawed embryos).
- In the 3 mg regimen, 9 patients received an additional dose of 0.25 mg of Cetrotide® and two other patients received two additional doses of 0.25 mg Cetrotide®. The median number of days of Cetrotide® multiple dose treatment was 5 (range 1-15) in both studies.
- No drug related allergic reactions were reported from these clinical studies.
# How Supplied
- Cetrotide® (cetrorelix acetate for injection) 0.25 mg is available in a carton of one packaged tray (NDC 44087-1225-1).
- Each packaged tray contains: one glass vial containing 0.26 - 0.27 mg cetrorelix acetate (corresponding to 0.25 mg cetrorelix), one pre-filled glass syringe with 1 mL of Sterile Water for Injection, USP (pH 5-8), one 20 gauge needle (yellow), one 27 gauge needle (grey), and two alcohol swabs.
## Storage
- Store Cetrotide® 0.25 mg refrigerated, 2-8°C (36-46°F). Store the packaged tray in the outer carton in order to protect from light.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - CARTON
NDC 44087-1225-1
Cetrotide ® .25 mg
(cetrorelix acetate for injection)
Store refrigerated, 2-8°C (36-46°F).
One carton contains one packaged tray which contains:
1 vial with lyophilized powder for reconstitution
1 pre-filled syringe with diluent
1 20-gauge needle
1 27-gauge needle
2 alcohol swabs
Sterile - for subcutaneous use only
Rx only
### Ingredients and Appearance
# Patient Counseling Information
- Prior to therapy with Cetrotide® (cetrorelix acetate for injection), patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed (see ADVERSE REACTIONS). Cetrotide® should not be prescribed if a patient is pregnant.
- If Cetrotide® is prescribed to patients for self-administration, information for proper use is given in the Patient Leaflet
### PATIENT PACKAGE INSERT
- Active ingredient: cetrorelix acetate
- Cetrotide® blocks the effects of a natural hormone, called gonadotropin-releasing hormone (GnRH). GnRH controls the secretion of another hormone, called luteinizing hormone (LH), which induces ovulation during the menstrual cycle. During hormone treatment for ovarian stimulation, premature ovulation may lead to eggs that are not suitable for fertilization. Cetrotide® blocks such undesirable premature ovulation.
- Cetrotide® is used to prevent premature ovulation during controlled ovarian stimulation.
- Do not use Cetrotide® if you
- have kidney disease
- are allergic to cetrorelix acetate, mannitol or exogenous peptide hormones (medicines similar to Cetrotide®) or
- are pregnant, or think that you might be pregnant, or if you are breast-feeding.
- Consult your doctor before taking Cetrotide® if you have had severe allergic reactions.
- Ovarian stimulation therapy is started on cycle Day 2 or 3. Cetrotide® 0.25 mg is injected under the skin once daily , as directed by your physician. When an ultrasound examination shows that you are ready, another drug (hCG) is injected to induce ovulation.
- You may self-inject Cetrotide® after special instruction from your doctor.
- To fully benefit from Cetrotide®, please read carefully and follow the instructions given below, unless your doctor advises you otherwise.
- Cetrotide® is for injection under the skin of the lower abdominal area, preferably around, but staying at least one inch away from the belly button. Choose a different injection site each day to minimize local irritation.
- Dissolve Cetrotide® powder only with the water contained in the pre-filled syringe. Do not use a Cetrotide® solution if it contains particles or if it is not clear.
- Before you inject Cetrotide® yourself, please read the following instructions carefully:
### SPECIAL ADVICE
- Contact your doctor in case of overdosage immediately to check whether an adjustment of the further ovarian stimulation procedure is required.
- Mild and short lasting reactions may occur at the injection site like reddening, itching, and swelling. Nausea and headache have also been reported.
- Call your doctor if you have any side effect not mentioned in this leaflet or if you are unsure about the effect of this medicine.
- Store Cetrotide® in a cool dry place protected from excess moisture and heat.
- Store Cetrotide® 0.25 mg in the refrigerator at 2-8°C (36-46°F). Keep the packaged tray in the outer carton in order to protect it from light.
- Do not use the Cetrotide® powder or the pre-filled syringe after the expiration date, which is printed on the labels and on the carton, and dispose of the vial and the syringe properly.
- The solution should be used immediately after preparation.
- If you suspect that you may have taken more than the prescribed dose of this medicine, contact your doctor immediately. This medicine was prescribed for your particular condition. Do not use it for another condition or give the drug to others.
- This leaflet provides a summary of the information about Cetrotide®. Medicines are sometimes prescribed for uses other than those listed in the Leaflet. If you have any questions or concerns, or want more information about Cetrotide®, contact your doctor or pharmacist.
# Precautions with Alcohol
- Alcohol-Cetrorelix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cetrotide®
# Look-Alike Drug Names
There is limited information regarding Cetrorelix Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cetrorelix
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Overview
Cetrorelix is a Luteinizing Hormone Releasing Hormone Antagonist that is FDA approved for the treatment of inhibition of premature LH surges in women undergoing controlled ovarian stimulation. Common adverse reactions include Ovarian hyperstimulation syndrome, Nausea, Headache ..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Cetrotide® (cetrorelix acetate for injection) is indicated for the inhibition of premature LH surges in women undergoing controlled ovarian stimulation.
### Dosage
- Ovarian stimulation therapy with gonadotropins (FSH, hMG) is started on cycle Day 2 or 3. The dose of gonadotropins should be adjusted according to individual response. Cetrotide® (cetrorelix acetate for injection) 0.25 mg may be administered subcutaneously once daily during the early- to mid-follicular phase.
- Cetrotide® 0.25 mg is administered on either stimulation day 5 (morning or evening) or day 6 (morning) and continued daily until the day of hCG administration.
- When assessment by ultrasound shows a sufficient number of follicles of adequate size, hCG is administered to induce ovulation and final maturation of the oocytes. No hCG should be administered if the ovaries show an excessive response to the treatment with gonadotropins to reduce the chance of developing ovarian hyperstimulation syndrome (OHSS).
- Cetrotide® 0.25 mg can be administered by the patient herself after appropriate instructions by her doctor.
- Directions for using Cetrotide® 0.25 mg with the enclosed needles and pre-filled syringe:
- Wash hands thoroughly with soap and water.
- Flip off the plastic cover of the vial and wipe the aluminum ring and the rubber stopper with an alcohol swab.
- Twist the injection needle with the yellow mark (20 gauge) on the pre-filled syringe.
- Push the needle through the center of the rubber stopper of the vial and slowly inject the solvent into the vial.
- Leaving the syringe in the vial, gently swirl the vial until the solution is clear and without residues. Avoid forming bubbles.
- Draw the total contents of the vial into the syringe. If necessary, invert the vial and pull back the needle as far as needed to withdraw the entire contents of the vial.
- Replace the needle with the yellow mark by the injection needle with the grey mark (27 gauge).
- Invert the syringe and push the plunger until all air bubbles have been expelled.
- Choose an injection site in the lower abdominal area, preferably around, but staying at least one inch away from the navel. Choose a different injection site each day to minimize local irritation. Use the second alcohol swab to clean the skin at the injection site and allow alcohol to dry. Gently pinch up the skin surrounding the site of injection.
- Inject the prescribed dose as directed by your doctor, nurse or pharmacist.
- Use the syringe and needles only once. Dispose of the syringe and needles properly after use. If available, use a medical waste container for disposal.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cetrorelix in adult patients.
### Non–Guideline-Supported Use
- Uterine leiomyoma[1][2]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cetrorelix in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cetrorelix in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cetrorelix in pediatric patients.
# Contraindications
- Cetrotide® (cetrorelix acetate for injection) is contraindicated under the following conditions:
- Hypersensitivity to cetrorelix acetate, extrinsic peptide hormones or mannitol.
- Known hypersensitivity to GnRH or any other GnRH analogs.
- Known or suspected pregnancy, and lactation.
- Severe renal impairment
# Warnings
- Cetrotide® (cetrorelix acetate for injection) should be prescribed by physicians who are experienced in fertility treatment. Before starting treatment with Cetrotide®, pregnancy must be excluded
### Precautions
- Cases of hypersensitivity reactions, including anaphylactoid reactions with the first dose, have been reported during post-marketing surveillance. A severe anaphylactic reaction associated with cough, rash, and hypotension, was observed in one patient after seven months of treatment with Cetrotide® (10 mg/day) in a study for an indication unrelated to infertility.
- Special care should be taken in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with Cetrotide® is not advised in women with severe allergic conditions.
- Prior to therapy with Cetrotide® (cetrorelix acetate for injection), patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed. Cetrotide® should not be prescribed if a patient is pregnant.
- If Cetrotide® is prescribed to patients for self-administration, information for proper use is given in the Patient Leaflet.
- After the exclusion of preexisting conditions, enzyme elevations (ALT, AST, GGT, alkaline phosphatase) were found in 1-2% of patients receiving Cetrotide® during controlled ovarian stimulation. The elevations ranged up to three times the upper limit of normal. The clinical significance of these findings was not determined.
- During stimulation with human menopausal gonadotropin, Cetrotide® had no notable effects on hormone levels aside from inhibition of LH surges.
# Adverse Reactions
## Clinical Trials Experience
- The safety of Cetrotide® (cetrorelix acetate for injection) in 949 patients undergoing controlled ovarian stimulation in clinical studies was evaluated. Women were between 19 and 40 years of age (mean: 32). 94.0% of them were Caucasian. Cetrotide® was given in doses ranging from 0.1 mg to 5 mg as either a single or multiple dose.
- Table 3 shows systemic adverse events, reported in clinical studies without regard to causality, from the beginning of Cetrotide® treatment until confirmation of pregnancy by ultrasound at an incidence ≥ 1% in Cetrotide® treated subjects undergoing COS.
- Local site reactions (e.g. redness, erythema, bruising, itching, swelling, and pruritus) were reported. Usually, they were of a transient nature, mild intensity and short duration. During post-marketing surveillance, rare cases of hypersensitivity reactions including anaphylactoid reactions have been reported.
- Two stillbirths were reported in Phase 3 studies of Cetrotide®.
- Clinical follow-up studies of 316 newborns of women administered Cetrotide® were reviewed. One infant of a set of twin neonates was found to have anencephaly at birth and died after four days. The other twin was normal. Developmental findings from ongoing baby follow-up included a child with a ventricular septal defect and another child with bilateral congenital glaucoma.
- Four pregnancies that resulted in therapeutic abortion in Phase 2 and Phase 3 controlled ovarian stimulation studies had major anomalies (diaphragmatic hernia, trisomy 21, Klinefelter syndrome, polymalformation, and trisomy 18). In three of these four cases, intracytoplasmic sperm injection (ICSI) was the fertilization method employed; in the fourth case, in vitro fertilization (IVF) was the method employed.
- The minor congenital anomalies reported include: supernumerary nipple, bilateral strabismus, imperforate hymen, congenital nevi, hemangiomata, and QT syndrome.
- The causal relationship between the reported anomalies and Cetrotide® is unknown. Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, and progesterone) make causal attribution difficult to study.
## Postmarketing Experience
- During post-marketing surveillance, rare cases of hypersensitivity reactions including anaphylactoid reactions have been reported.
# Drug Interactions
- No formal drug interaction studies have been performed with Cetrotide®.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Cetrotide® is contraindicated in pregnant women.
- When administered to rats for the first seven days of pregnancy, cetrorelix acetate did not affect the development of the implanted conceptus at doses up to 38 μg/kg (approximately 1 times the recommended human therapeutic dose based on body surface area). However, a dose of 139 μg/kg (approximately 4 times the human dose) resulted in a resorption rate and a postimplantation loss of 100%. When administered from day 6 to near term to pregnant rats and rabbits, very early resorptions and total implantation losses were seen in rats at doses from 4.6 μg/kg (0.2 times the human dose) and in rabbits at doses from 6.8 μg/kg (0.4 times the human dose). In animals that maintained their pregnancy, there was no increase in the incidence of fetal abnormalities.
- The fetal resorption observed in animals is a logical consequence of the alteration in hormonal levels effected by the antigonadotrophic properties of Cetrotide®, which could result in fetal loss in humans as well. Therefore, this drug should not be used in pregnant women.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cetrorelix in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cetrorelix during labor and delivery.
### Nursing Mothers
- It is not known whether Cetrotide® is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Cetrotide® on lactation and/or the breast-fed child have not been determined, Cetrotide® should not be used by nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Cetrorelix with respect to pediatric patients.
### Geriatic Use
- Cetrotide® is not intended to be used in subjects aged 65 and over.
### Gender
There is no FDA guidance on the use of Cetrorelix with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cetrorelix with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cetrorelix in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cetrorelix in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cetrorelix in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cetrorelix in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- subcutaneous
### Monitoring
There is limited information regarding Monitoring of Cetrorelix in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cetrorelix in the drug label.
# Overdosage
- There have been no reports of overdosage with Cetrotide® 0.25 mg or 3 mg in humans. Single doses up to 120 mg Cetrotide® have been well tolerated in patients treated for other indications without signs of overdosage.
# Pharmacology
## Mechanism of Action
- GnRH induces the production and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the gonadotrophic cells of the anterior pituitary. Due to a positive estradiol (E2) feedback at midcycle, GnRH liberation is enhanced resulting in an LH-surge. This LH-surge induces the ovulation of the dominant follicle, resumption of oocyte meiosis and subsequently luteinization as indicated by rising progesterone levels.
- Cetrotide® competes with natural GnRH for binding to membrane receptors on pituitary cells and thus controls the release of LH and FSH in a dose-dependent manner. The onset of LH suppression is approximately one hour with the 3 mg dose and two hours with the 0.25 mg dose. This suppression is maintained by continuous treatment and there is a more pronounced effect on LH than on FSH. An initial release of endogenous gonadotropins has not been detected with Cetrotide®, which is consistent with an antagonist effect.
- The effects of Cetrotide® on LH and FSH are reversible after discontinuation of treatment. In women, Cetrotide® delays the LH-surge, and consequently ovulation, in a dose-dependent fashion. FSH levels are not affected at the doses used during controlled ovarian stimulation. Following a single 3 mg dose of Cetrotide®, duration of action of at least 4 days has been established. A dose of Cetrotide® 0.25 mg every 24 hours has been shown to maintain the effect.
## Structure
- Cetrotide® (cetrorelix acetate for injection) is a synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic activity. Cetrorelix acetate is an analog of native GnRH with substitutions of amino acids at positions 1, 2, 3, 6, and 10. The molecular formula is Acetyl-D-3-(2´-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3´-pyridyl)-alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide, and the molecular weight is 1431.06, calculated as the anhydrous free base. The structural formula is as follows:
- Cetrotide® (cetrorelix acetate for injection) 0.25 mg is a sterile lyophilized powder intended for subcutaneous injection after reconstitution with Sterile Water for Injection, USP (pH 5-8), that comes supplied in a 1.0 mL pre-filled syringe. Each vial of Cetrotide® 0.25 mg contains 0.26-0.27 mg cetrorelix acetate, equivalent to 0.25 mg cetrorelix, and 54.80 mg mannitol.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Cetrorelix in the drug label.
## Pharmacokinetics
- The pharmacokinetic parameters of single and multiple doses of Cetrotide® (cetrorelix acetate for injection) in adult healthy female subjects are summarized in Table 1.
- Cetrotide® is rapidly absorbed following subcutaneous injection, maximal plasma concentrations being achieved approximately one to two hours after administration. The mean absolute bioavailability of Cetrotide® following subcutaneous administration to healthy female subjects is 85%.
- The volume of distribution of Cetrotide® following a single intravenous dose of 3 mg is about 1 l/kg. In vitro protein binding to human plasma is 86%.
- Cetrotide® concentrations in follicular fluid and plasma were similar on the day of oocyte pick-up in patients undergoing controlled ovarian stimulation. Following subcutaneous administration of Cetrotide® 0.25 mg and 3 mg, plasma concentrations of cetrorelix were below or in the range of the lower limit of quantitation on the day of oocyte pick-up and embryo transfer.
- After subcutaneous administration of 10 mg Cetrotide® to females and males, Cetrotide® and small amounts of (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples over 24 hours.
- In in vitro studies, Cetrotide® was stable against phase I- and phase II-metabolism. Cetrotide® was transformed by peptidases, and the (1-4) peptide was the predominant metabolite.
- Following subcutaneous administration of 10 mg cetrorelix to males and females, only unchanged cetrorelix was detected in urine. In 24 hours, cetrorelix and small amounts of the (1-9), (1-7), (1-6), and (1-4) peptides were found in bile samples. 2-4% of the dose was eliminated in the urine as unchanged cetrorelix, while 5-10% was eliminated as cetrorelix and the four metabolites in bile. Therefore, only 7-14% of the total dose was recovered as unchanged cetrorelix and metabolites in urine and bile up to 24 hours. The remaining portion of the dose may not have been recovered since bile and urine were not collected for a longer period of time.
- Pharmacokinetic investigations have not been performed either in subjects with impaired renal or liver function, or in the elderly, or in children.
- Pharmacokinetic differences in different races have not been determined.
- There is no evidence of differences in pharmacokinetic parameters for Cetrotide® between healthy subjects and patients undergoing controlled ovarian stimulation.
- No formal drug-drug interaction studies have been performed with Cetrotide®
## Nonclinical Toxicology
- Long-term carcinogenicity studies in animals have not been performed with cetrorelix acetate. Cetrorelix acetate was not genotoxic in vitro (Ames test, HPRT test, chromosome aberration test) or in vivo (chromosome aberration test, mouse micronucleus test). Cetrorelix acetate induced polyploidy in CHL-Chinese hamster lung fibroblasts, but not in V79-Chinese hamster lung fibroblasts, cultured peripheral human lymphocytes or in an in vitro micronucleus test in the CHL-cell line. Treatment with 0.46 mg/kg cetrorelix acetate for 4 weeks resulted in complete infertility in female rats which was reversed 8 weeks after cessation of treatment.
# Clinical Studies
- Seven hundred thirty two (732) patients were treated with Cetrotide® (cetrorelix acetate for injection) in five (two Phase 2 dose-finding and three Phase 3) clinical trials. The clinical trial population consisted of Caucasians (95.5%) and Black, Asian, Arabian and others (4.5%). Women were between 19 and 40 years of age (mean: 32). The studies excluded subjects with polycystic ovary syndrome (PCOS), subjects with low or no ovarian reserve, and subjects with stage III-IV endometriosis.
- Two dose regimens were investigated in these clinical trials, either a single dose per treatment cycle or multiple dosing. In the Phase 2 studies, a single dose of 3 mg was established as the minimal effective dose for the inhibition of premature LH surges with a protection period of at least 4 days. When Cetrotide® is administered in a multidose regimen, 0.25 mg was established as the minimal effective dose. The extent and duration of LH-suppression is dose dependent.
- In the Phase 3 program, efficacy of the single 3 mg dose regimen of Cetrotide® and the multiple 0.25 mg dose regimen of Cetrotide® was established separately in two adequate and well controlled clinical studies utilizing active comparators. A third non-comparative clinical study evaluated only the multiple 0.25 mg dose regimen of Cetrotide®. The ovarian stimulation treatment with recombinant FSH or human menopausal gonadotropin (hMG) was initiated on day 2 or 3 of a normal menstrual cycle. The dose of gonadotropins was administered according to the individual patient's disposition and response.
- In the single dose regimen study, Cetrotide® 3 mg was administered on the day of controlled ovarian stimulation when adequate estradiol levels (400 pg/mL) were obtained, usually on day 7 (range day 5-12). If hCG was not given within 4 days of the 3 mg dose of Cetrotide®, then 0.25 mg of Cetrotide® was administered daily beginning 96 hours after the 3 mg injection until and including the day of hCG administration.
- In the two multiple dose regimen studies, Cetrotide® 0.25 mg was started on day 5 or 6 of COS. Both gonadotropins and Cetrotide® were continued daily (multiple dose regimen) until the injection of human chorionic gonadotropin (hCG).
- Oocyte pick-up (OPU) followed by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) as well as embryo transfer (ET) were subsequently performed. The results for Cetrotide® are summarized below in Table 2.
- In addition to IVF and ICSI, one pregnancy was obtained after intrauterine insemination. In the five Phase 2 and Phase 3 clinical trials, 184 pregnancies have been reported out of a total of 732 patients (including 21 pregnancies following the replacement of frozen-thawed embryos).
- In the 3 mg regimen, 9 patients received an additional dose of 0.25 mg of Cetrotide® and two other patients received two additional doses of 0.25 mg Cetrotide®. The median number of days of Cetrotide® multiple dose treatment was 5 (range 1-15) in both studies.
- No drug related allergic reactions were reported from these clinical studies.
# How Supplied
- Cetrotide® (cetrorelix acetate for injection) 0.25 mg is available in a carton of one packaged tray (NDC 44087-1225-1).
- Each packaged tray contains: one glass vial containing 0.26 - 0.27 mg cetrorelix acetate (corresponding to 0.25 mg cetrorelix), one pre-filled glass syringe with 1 mL of Sterile Water for Injection, USP (pH 5-8), one 20 gauge needle (yellow), one 27 gauge needle (grey), and two alcohol swabs.
## Storage
- Store Cetrotide® 0.25 mg refrigerated, 2-8°C (36-46°F). Store the packaged tray in the outer carton in order to protect from light.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL - CARTON
NDC 44087-1225-1
Cetrotide ® .25 mg
(cetrorelix acetate for injection)
Store refrigerated, 2-8°C (36-46°F).
One carton contains one packaged tray which contains:
1 vial with lyophilized powder for reconstitution
1 pre-filled syringe with diluent
1 20-gauge needle
1 27-gauge needle
2 alcohol swabs
Sterile - for subcutaneous use only
Rx only
### Ingredients and Appearance
# Patient Counseling Information
- Prior to therapy with Cetrotide® (cetrorelix acetate for injection), patients should be informed of the duration of treatment and monitoring procedures that will be required. The risk of possible adverse reactions should be discussed (see ADVERSE REACTIONS). Cetrotide® should not be prescribed if a patient is pregnant.
- If Cetrotide® is prescribed to patients for self-administration, information for proper use is given in the Patient Leaflet
### PATIENT PACKAGE INSERT
- Active ingredient: cetrorelix acetate
- Cetrotide® blocks the effects of a natural hormone, called gonadotropin-releasing hormone (GnRH). GnRH controls the secretion of another hormone, called luteinizing hormone (LH), which induces ovulation during the menstrual cycle. During hormone treatment for ovarian stimulation, premature ovulation may lead to eggs that are not suitable for fertilization. Cetrotide® blocks such undesirable premature ovulation.
- Cetrotide® is used to prevent premature ovulation during controlled ovarian stimulation.
- Do not use Cetrotide® if you
- have kidney disease
- are allergic to cetrorelix acetate, mannitol or exogenous peptide hormones (medicines similar to Cetrotide®) or
- are pregnant, or think that you might be pregnant, or if you are breast-feeding.
- Consult your doctor before taking Cetrotide® if you have had severe allergic reactions.
- Ovarian stimulation therapy is started on cycle Day 2 or 3. Cetrotide® 0.25 mg is injected under the skin once daily , as directed by your physician. When an ultrasound examination shows that you are ready, another drug (hCG) is injected to induce ovulation.
- You may self-inject Cetrotide® after special instruction from your doctor.
- To fully benefit from Cetrotide®, please read carefully and follow the instructions given below, unless your doctor advises you otherwise.
- Cetrotide® is for injection under the skin of the lower abdominal area, preferably around, but staying at least one inch away from the belly button. Choose a different injection site each day to minimize local irritation.
- Dissolve Cetrotide® powder only with the water contained in the pre-filled syringe. Do not use a Cetrotide® solution if it contains particles or if it is not clear.
- Before you inject Cetrotide® yourself, please read the following instructions carefully:
### SPECIAL ADVICE
- Contact your doctor in case of overdosage immediately to check whether an adjustment of the further ovarian stimulation procedure is required.
- Mild and short lasting reactions may occur at the injection site like reddening, itching, and swelling. Nausea and headache have also been reported.
- Call your doctor if you have any side effect not mentioned in this leaflet or if you are unsure about the effect of this medicine.
- Store Cetrotide® in a cool dry place protected from excess moisture and heat.
- Store Cetrotide® 0.25 mg in the refrigerator at 2-8°C (36-46°F). Keep the packaged tray in the outer carton in order to protect it from light.
- Do not use the Cetrotide® powder or the pre-filled syringe after the expiration date, which is printed on the labels and on the carton, and dispose of the vial and the syringe properly.
- The solution should be used immediately after preparation.
- If you suspect that you may have taken more than the prescribed dose of this medicine, contact your doctor immediately. This medicine was prescribed for your particular condition. Do not use it for another condition or give the drug to others.
- This leaflet provides a summary of the information about Cetrotide®. Medicines are sometimes prescribed for uses other than those listed in the Leaflet. If you have any questions or concerns, or want more information about Cetrotide®, contact your doctor or pharmacist.
# Precautions with Alcohol
- Alcohol-Cetrorelix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Cetrotide®[3]
# Look-Alike Drug Names
There is limited information regarding Cetrorelix Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cetrorelix | |
ce37b6fedd13ac27ed79eabd4fabb3a72321cb0b | wikidoc | Cevimeline | Cevimeline
# Disclaimer
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# Overview
Cevimeline is a cholinergic agonist that is FDA approved for the treatment of Sjögren’s syndrome. Common adverse reactions include nausea, dyspepsia, diarrhea, excessive sweating, rhinitis, headache and rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Cevimeline is indicated for the treatment of symptoms of dry mouth in patients with Sjögren’s Syndrome.
### Dosing Information
- The recommended dose of cevimeline hydrochloride is 30 mg taken three times a day. There is insufficient safety information to support doses greater than 30 mg tid. There is also insufficient evidence for additional efficacy of cevimeline hydrochloride at doses greater than 30 mg tid.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cevimeline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cevimeline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cevimeline in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cevimeline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cevimeline in pediatric patients.
# Contraindications
- Cevimeline is contraindicated in patients with uncontrolled asthma, known hypersensitivity to cevimeline, and when miosis is undesirable, e.g., in acute iritis and in narrow-angle (angle-closure) glaucoma.
# Warnings
- Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by EVOXAC®. EVOXAC® should be used with caution and under close medical supervision in patients with a history of cardiovascular disease evidenced by angina pectoris or myocardial infarction.
- Cevimeline can potentially increase airway resistance, bronchial smooth muscle tone, and bronchial secretions. Cevimeline should be administered with caution and with close medical supervision to patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease.
- Ophthalmic formulations of muscarinic agonists have been reported to cause visual blurring which may result in decreased visual acuity, especially at night and in patients with central lens changes, and to cause impairment of depth perception. Caution should be advised while driving at night or performing hazardous activities in reduced lighting.
### PRECAUTIONS
- Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic effects. These may include: headache, visual disturbance, lacrimation, sweating, respiratory distress, gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and tremors.
- Cevimeline should be administered with caution to patients with a history of nephrolithiasis or cholelithiasis. Contractions of the gallbladder or biliary smooth muscle could precipitate complications such as cholecystitis, cholangitis and biliary obstruction. An increase in the ureteral smooth muscle tone could theoretically precipitate renal colic or ureteral reflux in patients with nephrolithiasis.
# Adverse Reactions
## Clinical Trials Experience
- Cevimeline was administered to 1777 patients during clinical trials worldwide, including Sjögren’s patients and patients with other conditions. In placebo-controlled Sjögren’s studies in the U.S., 320 patients received cevimeline doses ranging from 15 mg tid to 60 mg tid, of whom 93% were women and 7% were men. Demographic distribution was 90% Caucasian, 5% Hispanic, 3% Black and 2% of other origin. In these studies, 14.6% of patients discontinued treatment with cevimeline due to adverse events.
- The following adverse events associated with muscarinic agonism were observed in the clinical trials of cevimeline in Sjögren’s syndrome patients:
- In addition, the following adverse events (≥3% incidence) were reported in the Sjögren’s clinical trials:
- The following events were reported in Sjögren’s patients at incidences of <3% and ≥1%: constipation, tremor, abnormal vision, hypertonia, peripheral edema, chest pain, myalgia, fever, anorexia, eye pain, earache, dry mouth, vertigo, salivary gland pain, pruritus, influenza-like symptoms, eye infection, post-operative pain, vaginitis, skin disorder, depression, hiccup, hyporeflexia, infection, fungal infection, sialoadenitis, otitis media, erythematous rash, pneumonia, edema, salivary gland enlargement, allergy, gastroesophageal reflux, eye abnormality, migraine, tooth disorder, epistaxis, flatulence, toothache, ulcerative stomatitis, anemia, hypoesthesia, cystitis, leg cramps, abscess, eructation, moniliasis, palpitation, increased amylase, xerophthalmia, allergic reaction.
- The following events were reported rarely in treated Sjögren’s patients (<1%): Causal relation is unknown:
- Aggravated allergy, precordial chest pain, abnormal crying, hematoma, leg pain, edema, periorbital edema, activated pain trauma, pallor, changed sensation temperature, weight decrease, weight increase, choking, mouth edema, syncope, malaise, face edema, substernal chest pain
- Abnormal ECG, heart disorder, heart murmur, aggravated hypertension, hypotension, arrhythmia, extrasystoles, t wave inversion, tachycardia, supraventricular tachycardia, angina pectoris, myocardial infarction, pericarditis, pulmonary embolism, peripheral ischemia, superficial phlebitis, purpura, deep thrombophlebitis, vascular disorder, vasculitis, hypertension
- Appendicitis, increased appetite, ulcerative colitis, diverticulitis, duodenitis, dysphagia, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal hemorrhage, gingivitis, glossitis, rectum hemorrhage, hemorrhoids, ileus, irritable bowel syndrome, melena, mucositis, esophageal stricture, esophagitis, oral hemorrhage, peptic ulcer, periodontal destruction, rectal disorder, stomatitis, tenesmus, tongue discoloration, tongue disorder, geographic tongue, tongue ulceration, dental caries
- Increased glucocorticoids, goiter, hypothyroidism
- Thrombocytopenic purpura, thrombocythemia, thrombocytopenia, hypochromic anemia, eosinophilia, granulocytopenia, leucopenia, leukocytosis, cervical lymphadenopathy, lymphadenopathy
- Cholelithiasis, increased gamma-glutamyl transferase, increased hepatic enzymes, abnormal hepatic function, viral hepatitis, increased serum glutamate oxaloacetic transaminase (SGOT) (also called AST-aspartate aminotransferase), increased serum glutamate pyruvate transaminase (SGPT) (also called ALT-alanine aminotransferase)
- Dehydration, diabetes mellitus, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, thirst
- Arthritis, aggravated arthritis, arthropathy, femoral head avascular necrosis, bone disorder, bursitis, costochondritis, plantar fasciitis, muscle weakness, osteomyelitis, osteoporosis, synovitis, tendinitis, tenosynovitis
- Basal cell carcinoma, squamous carcinoma
- Carpal tunnel syndrome, coma, abnormal coordination, dysesthesia, dyskinesia, dysphonia, aggravated multiple sclerosis, involuntary muscle contractions, neuralgia, neuropathy, paresthesia, speech disorder, agitation, confusion, depersonalization, aggravated depression, abnormal dreaming, emotional lability, manic reaction, paroniria, somnolence, abnormal thinking, hyperkinesia, hallucination
- Fall, food poisoning, heat stroke, joint dislocation, post-operative hemorrhage
- Cellulitis, herpes simplex, herpes zoster, bacterial infection, viral infection, genital moniliasis, sepsis
- Asthma, bronchospasm, chronic obstructive airway disease, dyspnea, hemoptysis, laryngitis, nasal ulcer, pleural effusion, pleurisy, pulmonary congestion, pulmonary fibrosis, respiratory disorder
- Aggravated rheumatoid arthritis, lupus erythematosus rash, lupus erythematosus syndrome
- Acne, alopecia, burn, dermatitis, contact dermatitis, lichenoid dermatitis, eczema, furunculosis, hyperkeratosis, lichen planus, nail discoloration, nail disorder, onychia, onychomycosis, paronychia, photosensitivity reaction, rosacea, scleroderma, seborrhea, skin discoloration, dry skin, skin exfoliation, skin hypertrophy, skin ulceration, urticaria, verruca, bullous eruption, cold clammy skin
- Deafness, decreased hearing, motion sickness, parosmia, taste perversion, blepharitis, cataract, corneal opacity, corneal ulceration, diplopia, glaucoma, anterior chamber eye hemorrhage, keratitis, keratoconjunctivitis, mydriasis, myopia, photopsia, retinal deposits, retinal disorder, scleritis, vitreous detachment, tinnitus
- Epididymitis, prostatic disorder, abnormal sexual function, amenorrhea, female breast neoplasm, malignant female breast neoplasm, female breast pain, positive cervical smear test, dysmenorrhea, endometrial disorder, intermenstrual bleeding, leukorrhea, menorrhagia, menstrual disorder, ovarian cyst, ovarian disorder, genital pruritus, uterine hemorrhage, vaginal hemorrhage, atrophic vaginitis, albuminuria, bladder discomfort, increased blood urea nitrogen, dysuria, hematuria, micturition disorder, nephrosis, nocturia, increased nonprotein nitrogen, pyelonephritis, renal calculus, abnormal renal function, renal pain, strangury, urethral disorder, abnormal urine, urinary incontinence, decreased urine flow, pyuria
- In one subject with lupus erythematosus receiving concomitant multiple drug therapy, a highly elevated ALT level was noted after the fourth week of cevimeline therapy. In two other subjects receiving cevimeline in the clinical trials, very high AST levels were noted. The significance of these findings is unknown.
- Additional adverse events (relationship unknown) which occurred in other clinical studies (patient population different from Sjögren’s patients) are as follows:
- cholinergic syndrome, blood pressure fluctuation, cardiomegaly, postural hypotension, aphasia, convulsions, abnormal gait, hyperesthesia, paralysis, abnormal sexual function, enlarged abdomen, change in bowel habits, gum hyperplasia, intestinal obstruction, bundle branch block, increased creatine phosphokinase, electrolyte abnormality, glycosuria, gout, hyperkalemia, hyperproteinemia, increased lactic dehydrogenase (LDH), increased alkaline phosphatase, failure to thrive, abnormal platelets, aggressive reaction, amnesia, apathy, delirium, delusion, dementia, illusion, impotence, neurosis, paranoid reaction, personality disorder, hyperhemoglobinemia, apnea, atelectasis, yawning, oliguria, urinary retention, distended vein, lymphocytosis
- The following adverse reaction has been identified during post-approval use of EVOXAC®. Because post-marketing adverse 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.
## Postmarketing Experience
- Cholecystitis
# Drug Interactions
- Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with cevimeline can be expected to have additive effects. Cevimeline might interfere with desirable antimuscarinic effects of drugs used concomitantly.
- Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevimeline. Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at a higher risk of adverse events. In an in vitro study, cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were not inhibited by exposure to cevimeline.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Cevimeline was associated with a reduction in the mean number of implantations when given to pregnant Sprague-Dawley rats from 14 days prior to mating through day seven of gestation at a dosage of 45 mg/kg/day (approximately 5 times the maximum recommended dose for a 60 kg human when compared on the basis of body surface area estimates). This effect may have been secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Cevimeline 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 Cevimeline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cevimeline during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is secreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from EVOXAC®, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Cevimeline with respect to pediatric patients.
### Geriatic Use
- Although clinical studies of cevimeline included subjects over the age of 65, the numbers were not sufficient to determine whether they respond differently from younger subjects. Special care should be exercised when cevimeline treatment is initiated in an elderly patient, considering the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in the elderly.
### Gender
There is no FDA guidance on the use of Cevimeline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cevimeline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cevimeline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cevimeline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cevimeline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cevimeline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cevimeline in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Cevimeline in the drug label.
# Overdosage
- Management of the signs and symptoms of acute overdosage should be handled in a manner consistent with that indicated for other muscarinic agonists: general supportive measures should be instituted. If medically indicated, atropine, an anti-cholinergic agent, may be of value as an antidote for emergency use in patients who have had an overdose of cevimeline. If medically indicated, epinephrine may also be of value in the presence of severe cardiovascular depression or bronchoconstriction. It is not known if cevimeline is dialyzable.
# Pharmacology
## Mechanism of Action
- - Cevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts.
## Structure
## Pharmacodynamics
- Cevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts.
## Pharmacokinetics
- After administration of a single 30 mg capsule, cevimeline was rapidly absorbed with a mean time to peak concentration of 1.5 to 2 hours. No accumulation of active drug or its metabolites was observed following multiple dose administration. When administered with food, there is a decrease in the rate of absorption, with a fasting TMAX of 1.53 hours and a TMAX of 2.86 hours after a meal; the peak concentration is reduced by 17.3%. Single oral doses across the clinical dose range are dose proportional.
- Cevimeline has a volume of distribution of approximately 6L/kg and is <20% bound to human plasma proteins. This suggests that cevimeline is extensively bound to tissues; however, the specific binding sites are unknown.
- Isozymes CYP2D6 and CYP3A3/4 are responsible for the metabolism of cevimeline. After 24 hours, 86.7% of the dose was recovered (16.0% unchanged, 44.5% as cis and trans-sulfoxide, 22.3% of the dose as glucuronic acid conjugate and 4% of the dose as N-oxide of cevimeline). Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate and eliminated. Cevimeline did not inhibit cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4.
- The mean half-life of cevimeline is 5+/-1 hours. After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine. After seven days, 97% of the dose was recovered in the urine and 0.5% was recovered in the feces.
- The effects of renal impairment, hepatic impairment, or ethnicity on the pharmacokinetics of cevimeline have not been investigated.
## Nonclinical Toxicology
- Lifetime carcinogenicity studies were conducted in CD-1 mice and F-344 rats. A statistically significant increase in the incidence of adenocarcinomas of the uterus was observed in female rats that received cevimeline at a dosage of 100 mg/kg/day (approximately 8 times the maximum human exposure based on comparison of AUC data). No other significant differences in tumor incidence were observed in either mice or rats.
- Cevimeline exhibited no evidence of mutagenicity or clastogenicity in a battery of assays that included an Ames test, an in vitro chromosomal aberration study in mammalian cells, a mouse lymphoma study in L5178Y cells, or a micronucleus assay conducted in vivo in ICR mice.
- Cevimeline did not adversely affect the reproductive performance or fertility of male Sprague-Dawley rats when administered for 63 days prior to mating and throughout the period of mating at dosages up to 45 mg/kg/day (approximately 5 times the maximum recommended dose for a 60 kg human following normalization of the data on the basis of body surface area estimates). Females that were treated with cevimeline at dosages up to 45 mg/kg/day from 14 days prior to mating through day seven of gestation exhibited a statistically significantly smaller number of implantations than did control animals.
# Clinical Studies
- Cevimeline has been shown to improve the symptoms of dry mouth in patients with Sjögren’s Syndrome.
- A 6-week, randomized, double blind, placebo-controlled study was conducted in 75 patients (10 men, 65 women) with a mean age of 53.6 years (range 33-75). The racial distribution was Caucasian 92%, Black 1% and other 7%. The effects of cevimeline at 30 mg tid (90 mg/day) and 60 mg tid (180 mg/day) were compared to those of placebo. Patients were evaluated by a measure called global improvement, which is defined as a response of “better” to the question, “Please rate the overall condition of your dry mouth now compared with how you felt before starting treatment in this study.” Patients also had the option of selecting “worse” or “no change” as answers. Seventy-six percent of the patients in the 30 mg tid group reported a global improvement in their dry mouth symptoms compared to 35% of the patients in the placebo group. This difference was statistically significant at p=0.0043. There was no evidence that patients in the 60 mg tid group had better global evaluation scores than the patients in the 30 mg tid group.
- A 12-week, randomized, double-blind, placebo-controlled study was conducted in 197 patients (10 men, 187 women) with a mean age of 54.5 years (range 23-74). The racial distribution was Caucasian 91.4%, Black 3% and other 5.6%. The effects of cevimeline at 15 mg tid (45 mg/day) and 30 mg tid (90 mg/day) were compared to those of placebo. Statistically significant global improvement in the symptoms of dry mouth (p=0.0004) was seen for the 30 mg tid group compared to placebo, but not for the 15 mg group compared to placebo. Salivary flow showed statistically significant increases at both doses of cevimeline during the study compared to placebo.
- A second 12-week, randomized, double-blind, placebo-controlled study was conducted in 212 patients (11 men, 201 women) with a mean age of 55.3 years (range 24-75). The racial distribution was Caucasian 88.7%, Black 1.9% and other 9.4%. The effects of cevimeline at 15 mg tid (45 mg/day) and 30 mg tid (90 mg/day) were compared to those of placebo. No statistically significant differences were noted in the patient global evaluations. However, there was a higher placebo response rate in this study compared to the aforementioned studies. The 30 mg tid group showed a statistically significant increase in salivary flow from pre-dose to post-dose compared to placebo (p=0.0017).
# How Supplied
EVOXAC® is available as white, hard gelatin capsules containing 30 mg of cevimeline hydrochloride. EVOXAC® capsules have a white opaque cap and a white opaque body. The capsules are imprinted with “EVOXAC” on the cap and “30 mg” on the body with a black bar above “30 mg”. It is supplied in child resistant bottles of:
100 capsules (NDC 63395-201-13
Rx Only
Distributed and Marketed by:
Daiichi Sankyo Pharma Development, a Division of Daiichi Sankyo, Inc.
Edison, NJ 08837
PRT40 11/2006 Printed in U.S.A.
## Storage
- Store at 25°C (77°F) excursion permitted to 15°-30°C (59°-86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that cevimeline may cause visual disturbances, especially at night, that could impair their ability to drive safely.
- If a patient sweats excessively while taking cevimeline, dehydration may develop. The patient should drink extra water and consult a health care provider.
# Precautions with Alcohol
- Alcohol-Cevimeline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- EVOXAC®
# Look-Alike Drug Names
There is limited information regarding Cevimeline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cevimeline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
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# Overview
Cevimeline is a cholinergic agonist that is FDA approved for the treatment of Sjögren’s syndrome. Common adverse reactions include nausea, dyspepsia, diarrhea, excessive sweating, rhinitis, headache and rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Cevimeline is indicated for the treatment of symptoms of dry mouth in patients with Sjögren’s Syndrome.
### Dosing Information
- The recommended dose of cevimeline hydrochloride is 30 mg taken three times a day. There is insufficient safety information to support doses greater than 30 mg tid. There is also insufficient evidence for additional efficacy of cevimeline hydrochloride at doses greater than 30 mg tid.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cevimeline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cevimeline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cevimeline in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cevimeline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cevimeline in pediatric patients.
# Contraindications
- Cevimeline is contraindicated in patients with uncontrolled asthma, known hypersensitivity to cevimeline, and when miosis is undesirable, e.g., in acute iritis and in narrow-angle (angle-closure) glaucoma.
# Warnings
- Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by EVOXAC®. EVOXAC® should be used with caution and under close medical supervision in patients with a history of cardiovascular disease evidenced by angina pectoris or myocardial infarction.
- Cevimeline can potentially increase airway resistance, bronchial smooth muscle tone, and bronchial secretions. Cevimeline should be administered with caution and with close medical supervision to patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease.
- Ophthalmic formulations of muscarinic agonists have been reported to cause visual blurring which may result in decreased visual acuity, especially at night and in patients with central lens changes, and to cause impairment of depth perception. Caution should be advised while driving at night or performing hazardous activities in reduced lighting.
### PRECAUTIONS
- Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic effects. These may include: headache, visual disturbance, lacrimation, sweating, respiratory distress, gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and tremors.
- Cevimeline should be administered with caution to patients with a history of nephrolithiasis or cholelithiasis. Contractions of the gallbladder or biliary smooth muscle could precipitate complications such as cholecystitis, cholangitis and biliary obstruction. An increase in the ureteral smooth muscle tone could theoretically precipitate renal colic or ureteral reflux in patients with nephrolithiasis.
# Adverse Reactions
## Clinical Trials Experience
- Cevimeline was administered to 1777 patients during clinical trials worldwide, including Sjögren’s patients and patients with other conditions. In placebo-controlled Sjögren’s studies in the U.S., 320 patients received cevimeline doses ranging from 15 mg tid to 60 mg tid, of whom 93% were women and 7% were men. Demographic distribution was 90% Caucasian, 5% Hispanic, 3% Black and 2% of other origin. In these studies, 14.6% of patients discontinued treatment with cevimeline due to adverse events.
- The following adverse events associated with muscarinic agonism were observed in the clinical trials of cevimeline in Sjögren’s syndrome patients:
- In addition, the following adverse events (≥3% incidence) were reported in the Sjögren’s clinical trials:
- The following events were reported in Sjögren’s patients at incidences of <3% and ≥1%: constipation, tremor, abnormal vision, hypertonia, peripheral edema, chest pain, myalgia, fever, anorexia, eye pain, earache, dry mouth, vertigo, salivary gland pain, pruritus, influenza-like symptoms, eye infection, post-operative pain, vaginitis, skin disorder, depression, hiccup, hyporeflexia, infection, fungal infection, sialoadenitis, otitis media, erythematous rash, pneumonia, edema, salivary gland enlargement, allergy, gastroesophageal reflux, eye abnormality, migraine, tooth disorder, epistaxis, flatulence, toothache, ulcerative stomatitis, anemia, hypoesthesia, cystitis, leg cramps, abscess, eructation, moniliasis, palpitation, increased amylase, xerophthalmia, allergic reaction.
- The following events were reported rarely in treated Sjögren’s patients (<1%): Causal relation is unknown:
- Aggravated allergy, precordial chest pain, abnormal crying, hematoma, leg pain, edema, periorbital edema, activated pain trauma, pallor, changed sensation temperature, weight decrease, weight increase, choking, mouth edema, syncope, malaise, face edema, substernal chest pain
- Abnormal ECG, heart disorder, heart murmur, aggravated hypertension, hypotension, arrhythmia, extrasystoles, t wave inversion, tachycardia, supraventricular tachycardia, angina pectoris, myocardial infarction, pericarditis, pulmonary embolism, peripheral ischemia, superficial phlebitis, purpura, deep thrombophlebitis, vascular disorder, vasculitis, hypertension
- Appendicitis, increased appetite, ulcerative colitis, diverticulitis, duodenitis, dysphagia, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal hemorrhage, gingivitis, glossitis, rectum hemorrhage, hemorrhoids, ileus, irritable bowel syndrome, melena, mucositis, esophageal stricture, esophagitis, oral hemorrhage, peptic ulcer, periodontal destruction, rectal disorder, stomatitis, tenesmus, tongue discoloration, tongue disorder, geographic tongue, tongue ulceration, dental caries
- Increased glucocorticoids, goiter, hypothyroidism
- Thrombocytopenic purpura, thrombocythemia, thrombocytopenia, hypochromic anemia, eosinophilia, granulocytopenia, leucopenia, leukocytosis, cervical lymphadenopathy, lymphadenopathy
- Cholelithiasis, increased gamma-glutamyl transferase, increased hepatic enzymes, abnormal hepatic function, viral hepatitis, increased serum glutamate oxaloacetic transaminase (SGOT) (also called AST-aspartate aminotransferase), increased serum glutamate pyruvate transaminase (SGPT) (also called ALT-alanine aminotransferase)
- Dehydration, diabetes mellitus, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, thirst
- Arthritis, aggravated arthritis, arthropathy, femoral head avascular necrosis, bone disorder, bursitis, costochondritis, plantar fasciitis, muscle weakness, osteomyelitis, osteoporosis, synovitis, tendinitis, tenosynovitis
- Basal cell carcinoma, squamous carcinoma
- Carpal tunnel syndrome, coma, abnormal coordination, dysesthesia, dyskinesia, dysphonia, aggravated multiple sclerosis, involuntary muscle contractions, neuralgia, neuropathy, paresthesia, speech disorder, agitation, confusion, depersonalization, aggravated depression, abnormal dreaming, emotional lability, manic reaction, paroniria, somnolence, abnormal thinking, hyperkinesia, hallucination
- Fall, food poisoning, heat stroke, joint dislocation, post-operative hemorrhage
- Cellulitis, herpes simplex, herpes zoster, bacterial infection, viral infection, genital moniliasis, sepsis
- Asthma, bronchospasm, chronic obstructive airway disease, dyspnea, hemoptysis, laryngitis, nasal ulcer, pleural effusion, pleurisy, pulmonary congestion, pulmonary fibrosis, respiratory disorder
- Aggravated rheumatoid arthritis, lupus erythematosus rash, lupus erythematosus syndrome
- Acne, alopecia, burn, dermatitis, contact dermatitis, lichenoid dermatitis, eczema, furunculosis, hyperkeratosis, lichen planus, nail discoloration, nail disorder, onychia, onychomycosis, paronychia, photosensitivity reaction, rosacea, scleroderma, seborrhea, skin discoloration, dry skin, skin exfoliation, skin hypertrophy, skin ulceration, urticaria, verruca, bullous eruption, cold clammy skin
- Deafness, decreased hearing, motion sickness, parosmia, taste perversion, blepharitis, cataract, corneal opacity, corneal ulceration, diplopia, glaucoma, anterior chamber eye hemorrhage, keratitis, keratoconjunctivitis, mydriasis, myopia, photopsia, retinal deposits, retinal disorder, scleritis, vitreous detachment, tinnitus
- Epididymitis, prostatic disorder, abnormal sexual function, amenorrhea, female breast neoplasm, malignant female breast neoplasm, female breast pain, positive cervical smear test, dysmenorrhea, endometrial disorder, intermenstrual bleeding, leukorrhea, menorrhagia, menstrual disorder, ovarian cyst, ovarian disorder, genital pruritus, uterine hemorrhage, vaginal hemorrhage, atrophic vaginitis, albuminuria, bladder discomfort, increased blood urea nitrogen, dysuria, hematuria, micturition disorder, nephrosis, nocturia, increased nonprotein nitrogen, pyelonephritis, renal calculus, abnormal renal function, renal pain, strangury, urethral disorder, abnormal urine, urinary incontinence, decreased urine flow, pyuria
- In one subject with lupus erythematosus receiving concomitant multiple drug therapy, a highly elevated ALT level was noted after the fourth week of cevimeline therapy. In two other subjects receiving cevimeline in the clinical trials, very high AST levels were noted. The significance of these findings is unknown.
- Additional adverse events (relationship unknown) which occurred in other clinical studies (patient population different from Sjögren’s patients) are as follows:
- cholinergic syndrome, blood pressure fluctuation, cardiomegaly, postural hypotension, aphasia, convulsions, abnormal gait, hyperesthesia, paralysis, abnormal sexual function, enlarged abdomen, change in bowel habits, gum hyperplasia, intestinal obstruction, bundle branch block, increased creatine phosphokinase, electrolyte abnormality, glycosuria, gout, hyperkalemia, hyperproteinemia, increased lactic dehydrogenase (LDH), increased alkaline phosphatase, failure to thrive, abnormal platelets, aggressive reaction, amnesia, apathy, delirium, delusion, dementia, illusion, impotence, neurosis, paranoid reaction, personality disorder, hyperhemoglobinemia, apnea, atelectasis, yawning, oliguria, urinary retention, distended vein, lymphocytosis
- The following adverse reaction has been identified during post-approval use of EVOXAC®. Because post-marketing adverse 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.
## Postmarketing Experience
- Cholecystitis
# Drug Interactions
- Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with cevimeline can be expected to have additive effects. Cevimeline might interfere with desirable antimuscarinic effects of drugs used concomitantly.
- Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevimeline. Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at a higher risk of adverse events. In an in vitro study, cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were not inhibited by exposure to cevimeline.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Cevimeline was associated with a reduction in the mean number of implantations when given to pregnant Sprague-Dawley rats from 14 days prior to mating through day seven of gestation at a dosage of 45 mg/kg/day (approximately 5 times the maximum recommended dose for a 60 kg human when compared on the basis of body surface area estimates). This effect may have been secondary to maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Cevimeline 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 Cevimeline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cevimeline during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is secreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from EVOXAC®, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of Cevimeline with respect to pediatric patients.
### Geriatic Use
- Although clinical studies of cevimeline included subjects over the age of 65, the numbers were not sufficient to determine whether they respond differently from younger subjects. Special care should be exercised when cevimeline treatment is initiated in an elderly patient, considering the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in the elderly.
### Gender
There is no FDA guidance on the use of Cevimeline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cevimeline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cevimeline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cevimeline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cevimeline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cevimeline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cevimeline in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Cevimeline in the drug label.
# Overdosage
- Management of the signs and symptoms of acute overdosage should be handled in a manner consistent with that indicated for other muscarinic agonists: general supportive measures should be instituted. If medically indicated, atropine, an anti-cholinergic agent, may be of value as an antidote for emergency use in patients who have had an overdose of cevimeline. If medically indicated, epinephrine may also be of value in the presence of severe cardiovascular depression or bronchoconstriction. It is not known if cevimeline is dialyzable.
# Pharmacology
## Mechanism of Action
- * Cevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts.
## Structure
## Pharmacodynamics
- Cevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts.
## Pharmacokinetics
- After administration of a single 30 mg capsule, cevimeline was rapidly absorbed with a mean time to peak concentration of 1.5 to 2 hours. No accumulation of active drug or its metabolites was observed following multiple dose administration. When administered with food, there is a decrease in the rate of absorption, with a fasting TMAX of 1.53 hours and a TMAX of 2.86 hours after a meal; the peak concentration is reduced by 17.3%. Single oral doses across the clinical dose range are dose proportional.
- Cevimeline has a volume of distribution of approximately 6L/kg and is <20% bound to human plasma proteins. This suggests that cevimeline is extensively bound to tissues; however, the specific binding sites are unknown.
- Isozymes CYP2D6 and CYP3A3/4 are responsible for the metabolism of cevimeline. After 24 hours, 86.7% of the dose was recovered (16.0% unchanged, 44.5% as cis and trans-sulfoxide, 22.3% of the dose as glucuronic acid conjugate and 4% of the dose as N-oxide of cevimeline). Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate and eliminated. Cevimeline did not inhibit cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4.
- The mean half-life of cevimeline is 5+/-1 hours. After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine. After seven days, 97% of the dose was recovered in the urine and 0.5% was recovered in the feces.
- The effects of renal impairment, hepatic impairment, or ethnicity on the pharmacokinetics of cevimeline have not been investigated.
## Nonclinical Toxicology
- Lifetime carcinogenicity studies were conducted in CD-1 mice and F-344 rats. A statistically significant increase in the incidence of adenocarcinomas of the uterus was observed in female rats that received cevimeline at a dosage of 100 mg/kg/day (approximately 8 times the maximum human exposure based on comparison of AUC data). No other significant differences in tumor incidence were observed in either mice or rats.
- Cevimeline exhibited no evidence of mutagenicity or clastogenicity in a battery of assays that included an Ames test, an in vitro chromosomal aberration study in mammalian cells, a mouse lymphoma study in L5178Y cells, or a micronucleus assay conducted in vivo in ICR mice.
- Cevimeline did not adversely affect the reproductive performance or fertility of male Sprague-Dawley rats when administered for 63 days prior to mating and throughout the period of mating at dosages up to 45 mg/kg/day (approximately 5 times the maximum recommended dose for a 60 kg human following normalization of the data on the basis of body surface area estimates). Females that were treated with cevimeline at dosages up to 45 mg/kg/day from 14 days prior to mating through day seven of gestation exhibited a statistically significantly smaller number of implantations than did control animals.
# Clinical Studies
- Cevimeline has been shown to improve the symptoms of dry mouth in patients with Sjögren’s Syndrome.
- A 6-week, randomized, double blind, placebo-controlled study was conducted in 75 patients (10 men, 65 women) with a mean age of 53.6 years (range 33-75). The racial distribution was Caucasian 92%, Black 1% and other 7%. The effects of cevimeline at 30 mg tid (90 mg/day) and 60 mg tid (180 mg/day) were compared to those of placebo. Patients were evaluated by a measure called global improvement, which is defined as a response of “better” to the question, “Please rate the overall condition of your dry mouth now compared with how you felt before starting treatment in this study.” Patients also had the option of selecting “worse” or “no change” as answers. Seventy-six percent of the patients in the 30 mg tid group reported a global improvement in their dry mouth symptoms compared to 35% of the patients in the placebo group. This difference was statistically significant at p=0.0043. There was no evidence that patients in the 60 mg tid group had better global evaluation scores than the patients in the 30 mg tid group.
- A 12-week, randomized, double-blind, placebo-controlled study was conducted in 197 patients (10 men, 187 women) with a mean age of 54.5 years (range 23-74). The racial distribution was Caucasian 91.4%, Black 3% and other 5.6%. The effects of cevimeline at 15 mg tid (45 mg/day) and 30 mg tid (90 mg/day) were compared to those of placebo. Statistically significant global improvement in the symptoms of dry mouth (p=0.0004) was seen for the 30 mg tid group compared to placebo, but not for the 15 mg group compared to placebo. Salivary flow showed statistically significant increases at both doses of cevimeline during the study compared to placebo.
- A second 12-week, randomized, double-blind, placebo-controlled study was conducted in 212 patients (11 men, 201 women) with a mean age of 55.3 years (range 24-75). The racial distribution was Caucasian 88.7%, Black 1.9% and other 9.4%. The effects of cevimeline at 15 mg tid (45 mg/day) and 30 mg tid (90 mg/day) were compared to those of placebo. No statistically significant differences were noted in the patient global evaluations. However, there was a higher placebo response rate in this study compared to the aforementioned studies. The 30 mg tid group showed a statistically significant increase in salivary flow from pre-dose to post-dose compared to placebo (p=0.0017).
# How Supplied
EVOXAC® is available as white, hard gelatin capsules containing 30 mg of cevimeline hydrochloride. EVOXAC® capsules have a white opaque cap and a white opaque body. The capsules are imprinted with “EVOXAC” on the cap and “30 mg” on the body with a black bar above “30 mg”. It is supplied in child resistant bottles of:
100 capsules (NDC 63395-201-13
Rx Only
Distributed and Marketed by:
Daiichi Sankyo Pharma Development, a Division of Daiichi Sankyo, Inc.
Edison, NJ 08837
PRT40 11/2006 Printed in U.S.A.
## Storage
- Store at 25°C (77°F) excursion permitted to 15°-30°C (59°-86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed that cevimeline may cause visual disturbances, especially at night, that could impair their ability to drive safely.
- If a patient sweats excessively while taking cevimeline, dehydration may develop. The patient should drink extra water and consult a health care provider.
# Precautions with Alcohol
- Alcohol-Cevimeline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- EVOXAC®
# Look-Alike Drug Names
There is limited information regarding Cevimeline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cevimeline | |
5fa63ef41c31dae58fa18df93d7b01667d2c4e1f | wikidoc | Chalicosis | Chalicosis
Synonyms and keywords: Flint disease
# Overview
Chalicosis (Greek, χάλιξ, gravel), also called Flint disease, is a disorder of the lungs or bronchioles (chiefly among stonecutters), due to the inhalation of fine particles of stones; it is a form of pneumoconiosis.
# Historical Perspective
- The term chalicosis was first introduced by Merkel in 1870, for pneumoconiosis cases caused due to fine gravel or stone.
- Chalicosis is seen mostly in stonecutters.
# Pathophysiology
The ciliated epithelium in the lungs, along with mucus secretions and phagocytes protect the airways from dust. When there is exposure to excessive dust, the epithelium is unable to arrest all the pigment, resulting in it's leakage into subpleaural and interbronchial tissues; and interspaces of alveoli. This results in an inflammatory response and release of tumor necrosis factors, interleukin-1, leukotriene B4 and other cytokines resulting in activation of fibroblasts to proliferate and produce collagen around the dust particle; which causes fibrosis and nodular lesions in the lungs.
## Associated Conditions
- Hepatosplenic involvement is not uncommon with chalicosis.
# Causes
- Inhalation of fine particles of stones.
# Differentiating type page name here from other Diseases
- Should be differentiated from other diseases causing pneumoconiosis and those with similar presentation including: cough, dyspnea, pulmonary nodules and fibrosis on chest x-ray
- Silicosis
- asbestosis
- tuberculosis
- aspergillosis
- pulmonary malignancy.
# Risk Factors
- Occupations with excessive exposure to stone dust like excavations in mines, mining of nonferrous metal ores, tunnels, quarries, underground galleries, dry cutting, grinding, sieving and manipulation of minerals and rock, foundry work, milling work, sandblasting and grinding, pottery industry.
# Natural History
Chalicosis is a slowly progressive disease where it can take upto 10 years for the manifestations to occur.
# Diagnosis
- Detailed occupational history should be obtained, including time of exposure to stone dust and measurement of respirable dust.
- Chest X-ray findings are similar to those of pneumoconiosis may include small rounded opacities, small irregular opacities, profusion of opacities, large opacities, zonal distribution of opacities (upper, middle, and/or lower), and pleural thickening (diffuse or circumscribed).
- Pulmonary function test: Decreased TLC, FVC, and DLCO , Normal FEV1 / FVC ratio
## Symptoms
Dyspnea, dyspnea on exertion, chronic, non-productive cough may be present.
## Physical Examination
### Lungs:
- Crackles/rales and inspiratory wheezes maybe present
### Other:
- Cyanosis
- Clubbing
## Laboratory Findings
### Chest X Ray
Chest X-ray findings are similar to those of pneumoconiosis may include small rounded opacities, small irregular opacities, profusion of opacities, large opacities, zonal distribution of opacities (upper, middle, and/or lower), and pleural thickening (diffuse or circumscribed).
# Treatment
## Pharmacotherapy
- Treatment of chalicosis consists of managing associated respiratory symptoms and comorbidities and complications (e.g. COPD or tuberculosis). There is no targeted therapy for chalicosis
- Management goals include avoidance of exposure to stone dust, optimization of respiratory function, and preventive care.
### Acute Pharmacotherapies
- Systemic steroids may be used for acute management of symptoms.
### Chronic Pharmacotherapies
- Systemic steroids are not recommended for chronic management.
- Supplemental oxygen is administered to prevent complications of chronic hypoxemia
- Bronchodilators if airflow limitation is present on spirometry.
- Smoking cessation | Chalicosis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Flint disease
# Overview
Chalicosis (Greek, χάλιξ, gravel), also called Flint disease, is a disorder of the lungs or bronchioles (chiefly among stonecutters), due to the inhalation of fine particles of stones; it is a form of pneumoconiosis.
# Historical Perspective
- The term chalicosis was first introduced by Merkel in 1870, for pneumoconiosis cases caused due to fine gravel or stone.
- Chalicosis is seen mostly in stonecutters.
# Pathophysiology
The ciliated epithelium in the lungs, along with mucus secretions and phagocytes protect the airways from dust. When there is exposure to excessive dust, the epithelium is unable to arrest all the pigment, resulting in it's leakage into subpleaural and interbronchial tissues; and interspaces of alveoli. This results in an inflammatory response and release of tumor necrosis factors, interleukin-1, leukotriene B4 and other cytokines resulting in activation of fibroblasts to proliferate and produce collagen around the dust particle; which causes fibrosis and nodular lesions in the lungs.
## Associated Conditions
- Hepatosplenic involvement is not uncommon with chalicosis.
# Causes
- Inhalation of fine particles of stones.
# Differentiating type page name here from other Diseases
- Should be differentiated from other diseases causing pneumoconiosis and those with similar presentation including: cough, dyspnea, pulmonary nodules and fibrosis on chest x-ray
- Silicosis
- asbestosis
- tuberculosis
- aspergillosis
- pulmonary malignancy.
# Risk Factors
- Occupations with excessive exposure to stone dust like excavations in mines, mining of nonferrous metal ores, tunnels, quarries, underground galleries, dry cutting, grinding, sieving and manipulation of minerals and rock, foundry work, milling work, sandblasting and grinding, pottery industry.
# Natural History
Chalicosis is a slowly progressive disease where it can take upto 10 years for the manifestations to occur.
# Diagnosis
- Detailed occupational history should be obtained, including time of exposure to stone dust and measurement of respirable dust.
- Chest X-ray findings are similar to those of pneumoconiosis may include small rounded opacities, small irregular opacities, profusion of opacities, large opacities, zonal distribution of opacities (upper, middle, and/or lower), and pleural thickening (diffuse or circumscribed).
- Pulmonary function test: Decreased TLC, FVC, and DLCO , Normal FEV1 / FVC ratio
## Symptoms
Dyspnea, dyspnea on exertion, chronic, non-productive cough may be present.
## Physical Examination
### Lungs:
- Crackles/rales and inspiratory wheezes maybe present
### Other:
- Cyanosis
- Clubbing
## Laboratory Findings
### Chest X Ray
Chest X-ray findings are similar to those of pneumoconiosis may include small rounded opacities, small irregular opacities, profusion of opacities, large opacities, zonal distribution of opacities (upper, middle, and/or lower), and pleural thickening (diffuse or circumscribed).
# Treatment
## Pharmacotherapy
- Treatment of chalicosis consists of managing associated respiratory symptoms and comorbidities and complications (e.g. COPD or tuberculosis). There is no targeted therapy for chalicosis
- Management goals include avoidance of exposure to stone dust, optimization of respiratory function, and preventive care.
### Acute Pharmacotherapies
- Systemic steroids may be used for acute management of symptoms.
### Chronic Pharmacotherapies
- Systemic steroids are not recommended for chronic management.
- Supplemental oxygen is administered to prevent complications of chronic hypoxemia
- Bronchodilators if airflow limitation is present on spirometry.
- Smoking cessation | https://www.wikidoc.org/index.php/Chalicosis | |
7a93a3a29c036d7f4cd3cd07e82652987e220720 | wikidoc | Charmstone | Charmstone
A charmstone is a mineral specimen which certain prehistoric, historic or contemporary peoples invest with healing, mystical or paranormal powers. This belief has been part of several indigenous cultures for centuries, e.g., cintamani. The mineral specimen may either be naturally occurring or honed from a natural stone; in some cases, the specimen may be entirely manufactured as in the case of certain Mayan pottery finds. For example, the Miwok and Pomo tribes of Northern California have left thousands of charmstones in the bed of Tolay Lake in Sonoma County. Charmstones are evidenced by the Shalagram and lingam in the Hindu tradition and by maban in the indigenous Australian tradition. Jigme Lingpa in the Vajrayana tradition wrote a treatise on charmestone usage which Namkhai Norbu mentions. Charmstones were used in prehistoric Native American cermonies for broader spiritual purposes including securing of productive harvests. Today it is becoming popular among certain countercultures within Western society such as the new age movement, but is regarded as baseless by scientists and medical professionals.
# Healing
Some crystal healers claim that each living organism has a "vibrational energy system," which includes chakras, electromagnetic fields around the body known as auras, subtle bodies and meridians. By using the appropriate crystals one can allegedly "tune" an energy system or rebalance energies, thus improving well-being due to the vibrations produced by the crystals, according to color, chemical composition, atomic structure and overall physical form. Using the vibrations of the crystals a trained practitioner can allegedly move, absorb, focus, direct and diffuse energy within the body, using the structure of the crystal for the body to emulate. Crystal healing also allegedly gives the body a chance to relax, which may aid in the body’s natural abilities of the immune system.
The earliest records of crystal healing come from ancient Egypt. The Ebers papyrus states the medicinal uses of many different gems. Healing with crystals is also recorded in India's Ayurvedic records and in traditional Chinese medicine from around five thousand years ago. Several shamanistic cultures practice crystal healing, including the Inuit of Canada, which was adopted by New Age healers.
Various fictional works have used crystals as a focal point for magical spells; an idea probably founded on scrying-gems such as John Dee's shew stone. This, and similar, was used by magicians, fortune-tellers, etc. for one of two purposes; to co-ordinate the visionary power or to misdirect the attention of the customer.
# Criticism
Scientists, medical professionals, and skeptics consider crystal healing to be pseudoscientific, since there is no scientific evidence that healing can be achieved by 'crystal power'. The placebo effect, cognitive bias and memory biases are strong possible explanations for any examples of healing that occurs in the presence of a crystal. Even some crystal healing practitioners have cautioned that crystal healing should be used as a supplement to and not a replacement of conventional medicine.
It can also be classified as a pseudo-science under a number of Stephen Carey's criteria. Carey explains that the "respectability" of science and scientific concepts comes from the experiments and the manner in which they are performed. He goes on to assert that the difference between pseudo-science and science includes the "self-correction" of science, where incorrect conjectures have been reversed by further investigation, and the publication and reversal of reviewed journals. Thus far there are very few to no reviewed journals or published experiments regarding the use of crystal healing, further strengthening the argument for it as a pseudo-science. Moreover, scientific findings are "open to revision" where seldom do the declarations of pseudo-sciences change, as illustrated with the old theory of the planets and sun revolving around the earth, whereas the claims of crystal healing are based on historical beliefs. | Charmstone
A charmstone is a mineral specimen which certain prehistoric[citation needed], historic or contemporary peoples invest with healing, mystical or paranormal powers. This belief has been part of several indigenous cultures for centuries, e.g., cintamani. The mineral specimen may either be naturally occurring or honed from a natural stone; in some cases, the specimen may be entirely manufactured as in the case of certain Mayan pottery finds. For example, the Miwok and Pomo tribes of Northern California have left thousands of charmstones in the bed of Tolay Lake in Sonoma County.[1] Charmstones are evidenced by the Shalagram and lingam in the Hindu tradition and by maban in the indigenous Australian tradition. Jigme Lingpa in the Vajrayana tradition wrote a treatise on charmestone usage which Namkhai Norbu mentions. Charmstones were used in prehistoric Native American cermonies for broader spiritual purposes including securing of productive harvests.[2] Today it is becoming popular among certain countercultures within Western society such as the new age movement, but is regarded as baseless by scientists and medical professionals.[3]
# Healing
Some crystal healers claim that each living organism has a "vibrational energy system," which includes chakras, electromagnetic fields around the body known as auras, subtle bodies and meridians.[citation needed] By using the appropriate crystals one can allegedly "tune" an energy system or rebalance energies, thus improving well-being due to the vibrations produced by the crystals, according to color, chemical composition, atomic structure and overall physical form.[citation needed] Using the vibrations of the crystals a trained practitioner can allegedly move, absorb, focus, direct and diffuse energy within the body, using the structure of the crystal for the body to emulate.[citation needed] Crystal healing also allegedly gives the body a chance to relax, which may aid in the body’s natural abilities of the immune system.[citation needed]
The earliest records of crystal healing come from ancient Egypt.[citation needed] The Ebers papyrus states the medicinal uses of many different gems. Healing with crystals is also recorded in India's Ayurvedic records and in traditional Chinese medicine from around five thousand years ago.[citation needed] Several shamanistic cultures practice crystal healing, including the Inuit of Canada, which was adopted by New Age healers.[citation needed]
Various fictional works have used crystals as a focal point for magical spells; an idea probably founded on scrying-gems such as John Dee's shew stone. This, and similar, was used by magicians, fortune-tellers, etc. for one of two purposes; to co-ordinate the visionary power or to misdirect the attention of the customer.
# Criticism
Scientists, medical professionals, and skeptics consider crystal healing to be pseudoscientific, since there is no scientific evidence that healing can be achieved by 'crystal power'. The placebo effect, cognitive bias and memory biases are strong possible explanations for any examples of healing that occurs in the presence of a crystal.[4] Even some crystal healing practitioners have cautioned that crystal healing should be used as a supplement to and not a replacement of conventional medicine.[citation needed]
It can also be classified as a pseudo-science under a number of Stephen Carey's criteria. Carey explains that the "respectability" of science and scientific concepts comes from the experiments and the manner in which they are performed.[5] He goes on to assert that the difference between pseudo-science and science includes the "self-correction" of science, where incorrect conjectures have been reversed by further investigation, and the publication and reversal of reviewed journals. Thus far there are very few to no reviewed journals or published experiments regarding the use of crystal healing, further strengthening the argument for it as a pseudo-science. Moreover, scientific findings are "open to revision" where seldom do the declarations of pseudo-sciences change, as illustrated with the old theory of the planets and sun revolving around the earth, whereas the claims of crystal healing are based on historical beliefs.[5] | https://www.wikidoc.org/index.php/Charmstone | |
d5344f27fc375f84c816006c11402e8510dd68d8 | wikidoc | Chemotroph | Chemotroph
Chemotrophs are organisms that obtain energy by the oxidation of electron donating molecules in their environments. These molecules can be organic (organotrophs) or inorganic (lithotrophs). The chemotroph designation is in contrast to phototrophs which utilize solar energy. Chemotrophs can be either autotrophic or heterotrophic.
- Chemoautotrophs (or chemotrophic autotroph), in addition to deriving energy from chemical reactions, synthesize all necessary organic compounds from carbon dioxide. Chemoautotrophs generally only use inorganic energy sources. Most are bacteria or archaea that live in hostile environments such as deep sea vents and are the primary producers in such ecosystems. Evolutionary scientists believe that the first organisms to inhabit Earth were chemoautotrophs that produced oxygen as a by-product and later evolved into both aerobic, animal-like organisms and photosynthetic, plant-like organisms. Chemoautotrophs generally fall into several groups: methanogens, halophiles, sulfur reducers, nitrifiers, anammoxbacteria and thermoacidophiles.
- Chemoheterotrophs (or chemotrophic heterotrophs) must ingest organic building blocks that they are incapable of creating on their own. Most chemoheterotrophs derive energy from organic molecules like glucose.
The names of these primary nutritional groups are built from Greek roots. "Chemo" means "chemical" and "troph" means "nourishment". "Auto" means "self" and "hetero" means "other". | Chemotroph
Chemotrophs are organisms that obtain energy by the oxidation of electron donating molecules in their environments. These molecules can be organic (organotrophs) or inorganic (lithotrophs). The chemotroph designation is in contrast to phototrophs which utilize solar energy. Chemotrophs can be either autotrophic or heterotrophic.
- Chemoautotrophs (or chemotrophic autotroph), in addition to deriving energy from chemical reactions, synthesize all necessary organic compounds from carbon dioxide. Chemoautotrophs generally only use inorganic energy sources. Most are bacteria or archaea that live in hostile environments such as deep sea vents and are the primary producers in such ecosystems. Evolutionary scientists believe that the first organisms to inhabit Earth were chemoautotrophs that produced oxygen as a by-product and later evolved into both aerobic, animal-like organisms and photosynthetic, plant-like organisms. Chemoautotrophs generally fall into several groups: methanogens, halophiles, sulfur reducers, nitrifiers, anammoxbacteria and thermoacidophiles.
- Chemoheterotrophs (or chemotrophic heterotrophs) must ingest organic building blocks that they are incapable of creating on their own. Most chemoheterotrophs derive energy from organic molecules like glucose.
The names of these primary nutritional groups are built from Greek roots. "Chemo" means "chemical" and "troph" means "nourishment". "Auto" means "self" and "hetero" means "other". | https://www.wikidoc.org/index.php/Chemoheterotroph | |
c7c091e49b44c465671ca1b5c9a478395c9f4de2 | wikidoc | Chemotaxis | Chemotaxis
# Overview
Chemotaxis, a kind of taxis, is the phenomenon in which bodily cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food (for example, glucose) by swimming towards the highest concentration of food molecules, or to flee from poisons (for example, phenol). In multicellular organisms, chemotaxis is critical to development as well as normal function. In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverted during cancer metastasis.
Chemotaxis is called positive if movement is in the direction of a higher concentration of the chemical in question, and negative if the direction is opposite.
# History of chemotaxis research
Although migration of cells was detected from the early days of the development of microscopy (Leeuwenhoek), erudite description of chemotaxis was first made by T.W. Engelmann (1881) and W.F. Pfeffer (1884) in bacteria and H.S. Jennings (1906) in ciliates. The Nobel Prize Laureate E. Metchnikoff also contributed to the study of the field with investigations of the process as an initial step of phagocytosis. The significance of chemotaxis in biology and clinical pathology was widely accepted in the 1930s. The most fundamental definitions belonging to the phenomenon were also drafted by this time. The most important aspects in quality control of chemotaxis assays were described by H. Harris in the 1950s. In the 1960s and 1970s, the revolution of modern cell biology and biochemistry provided a series of novel techniques which became available to investigate the migratory responder cells and subcellular fractions responsible for chemotactic activity. The pioneering works of J. Adler represented a significant turning point in understanding the whole process of intracellular signal transduction of bacteria.
On November 3, 2006, Dr. Dennis Bray of University of Cambridge was awarded the Microsoft European Science Award for his work on chemotaxis on E. coli.
# Phylogeny and chemotactic signalling
Chemotaxis is one of the most basic cell physiological responses. Development of receptor systems for the detection of harmful and favorable substances in the environment was most essential to unicellular organisms from the very early stages of phylogeny. Comprehensive analysis of chemotactic activity of the eukaryotic protozoon Tetrahymena pyriformis and consensus sequences of appearance of amino acids in the primordial soup suggest that there was a good correlation between the chemotactic character of these relative simple organic molecules and their development on the Earth. In this way the earliest molecules are suggested to be highly chemoattractant (e.g. Gly, Glu, Pro), while latter ones are thought to be strongly chemorepellent (e.g. Tyr, Trp, Phe) amino acids.
# Bacterial chemotaxis
Some bacteria, such as E. coli, have several flagella per cell (4–10 typically). These can rotate in two ways :
- Counter-clockwise rotation aligns the flagella into a single rotating bundle, causing the bacterium to swim in a straight line.
- Clockwise rotation breaks the flagella bundle apart such that each flagellum points in a different direction, causing the bacterium to tumble in place.
The directions of rotation are given for an observer outside the cell looking down the flagella toward the cell.
## Behavior
The overall movement of a bacterium is the result of alternating tumble and swim phases. If one watches a bacterium swimming in a uniform environment, its movement will look like a random walk with relatively straight swims interrupted by random tumbles that reorient the bacterium. Bacteria such as E. coli are unable to choose the direction in which they swim, and are unable to swim in a straight line for more than a few seconds due to rotational diffusion. In other words, bacteria "forget" the direction in which they are going. Given these limitations, it is remarkable that bacteria can direct their motion to find favorable locations with high concentrations of attractants (usually food) and avoid repellents (usually poisons).
In the presence of a chemical gradient bacteria will chemotax, or direct their overall motion based on the gradient. If the bacterium senses that it is moving in the correct direction (toward attractant/away from repellent), it will keep swimming in a straight line for a longer time before tumbling. If it is moving in the wrong direction, it will tumble sooner and try a new direction at random. In other words, bacteria like E. coli use temporal sensing to decide whether life is getting better or worse. In this way, it finds the location with the highest concentration of attractant (usually the source) quite well. Even under very high concentrations, it can still distinguish very small differences in concentration. Fleeing from a repellent works with the same efficiency.
It seems remarkable that this purposeful random walk is a result of simply choosing between two methods of random movement; namely tumbling and straight swimming. In fact, chemotactic responses such as forgetting direction and choosing movements resemble the decision-making abilities of higher lifeforms with brains that process sensory data.
The helical nature of the individual flagellar filament is critical for this movement to occur. As such, the protein that makes up the flagellar filament, flagellin, is quite similar among all flagellated bacteria. Vertebrates seem to have taken advantage of this fact by possessing an immune receptor (TLR5) designed to recognize this conserved protein.
As in many instances in biology, there are bacteria that do not follow this rule. Many bacteria, such as Vibrio, are monoflagellated and have a single flagellum at one pole of the cell. Their method of chemotaxis is different. Others possess a single flagellum that is kept inside the cell wall. These bacteria move by spinning the whole cell, which is shaped like a corkscrew.
## Signal transduction
Chemical gradients are sensed through multiple transmembrane receptors, called methyl accepting chemotaxis proteins (MCPs), which vary in the molecules that they detect. These receptors may bind attractants or repellents directly or indirectly through interaction with proteins of periplasmatic space. The signals from these receptors are transmitted across the plasma membrane into the cytosol, where Che proteins are activated. The Che proteins alter the tumbling frequency, and alter the receptors.
### Flagellum regulation
The proteins CheW and CheA bind to the receptor. The activation of the receptor by an external stimulus causes autophosphorylation in the histidine kinase, CheA, at a single highly conserved histidine residue. CheA in turn transfers phosphoryl groups to conserved aspartate residues in the response regulators CheB and CheY . This mechanism of signal transduction is called a 'Two Component System' and is a common form of signal transduction in bacteria. CheY induces tumbling by interacting with the flagellar switch protein FliM, inducing a change from counter-clockwise to clockwise rotation of the flagellum. Change in the rotation state of a single flagellum can disrupt the entire flagella bundle and cause a tumble.
### Receptor regulation
CheB, when activated by CheA, acts as a methylesterase, removing methyl groups from glutamate residues on the cytosolic side of the receptor. It works antagonistically with CheR, a methyltransferase, which adds methyl residues to the same glutamate residues. The more methyl residues are attached to the receptor, the more sensitive the receptor. As the signal from the receptor induces demethylation of the receptor in a feedback loop, the system is continuously adjusted to environmental chemical levels, remaining sensitive for small changes even under extreme chemical concentrations. This regulation allows the bacterium to 'remember' chemical concentrations from the recent past and compare them to those it is currently experiencing, thus 'know' whether it is traveling up or down a gradient. However, the methylation system alone cannot account for the wide range of sensitivity that bacteria have to chemical gradients. Additional regulatory mechanisms such as receptor clustering and receptor-receptor interactions also modulate the signalling pathway.
# Eukaryotic chemotaxis
The mechanism by which eukaryotic cells chemotax is quite different from that in bacteria; however, sensing of chemical gradients is still a crucial step in the process. Due to their size, prokaryotes cannot detect effective concentration gradients, therefore these cells scan and evaluate their environment by a constant swimming (consecutive steps of straight swims and tumbles). In contrast to prokaryotes, the size of eukaryotic cells allows for the possibility of detecting gradients, which results in a dynamic and polarized distribution of receptors. Induction of these receptors by chemoattractants or chemorepellents results in migration towards or away from the chemotactic substance.
Levels of receptors, intracellular signalling pathways and the effector mechanisms all represent diverse, eukaryotic type components. In eukaryotic unicellular cells, ameboid movement and cilium or the eukaryotic flagellum are the main effectors (e.g. Amoeba or Tetrahymena).
Some eukaryotic cells of higher vertebrate origin, such as immune cells also move to where they need to be. Besides immune competent cells (granulocyte, monocyte, lymphocyte) a large group of cells - considered previously to be fixed into tissues - are also motile in special physiological (e.g. mast cell, fibroblast, endothelial cells)or pathological conditions (e.g. metastases). Chemotaxis has high significance in the early phases of embryogenesis as development of germ layers is guided by gradients of signal molecules.
## Motility
Unlike motility in bacterial chemotaxis, the mechanism by which eukaryotic cells physically move is unclear. There appear to be mechanisms by which an external chemotactic gradient is sensed and turned into an intracellular PIP3 gradient, which results in a gradient in the activation of signaling pathway culminating in the polymerisation of actin filaments. The growing distal end of actin filaments develops connections with the internal surface of the plasma membrane via different sets of peptides and results in the formation of pseudopods.
Cilium of eukaryotic cells can also result in chemotaxis, while in this case it is mainly a Ca2+ dependent induction of the microtubular system of the basal body and the 9x2+2 microtubules stroke of cilia. The orchestered beating of hundreds of cilia is synchronized by a submembranous system built between basal bodies.
The details of the signaling pathways are still not totally clear.
### Chemotaxis related migratory responses
Although chemotaxis is the most frequently studied form of migration there are several other forms of locomotion on the cellular level.
- Chemokinesis is also induced by molecules of the liquid phase of the surrounding environment; however, the response elicited is a not vectorial, random taxis. Neither amplitude nor frequency of motion has characteristic, directional components as this behaviour provides more scanning of the environment than migration between two distinct points.
- In haptotaxis the gradient of the chemoattractant is expressed or bound on a surface, in contrast to the classical way of chemotaxis when the gradient develops in a soluble space. The main biologically active haptotactic surface is the extracellular matrix (ECM); the presence of bound ligands is responsible for induction of transendothelial migration and angiogenesis.
- Necrotaxis embodies a special type of chemotaxis when the chemoattractant molecules are released from necrotic or apoptotic cells. Depending on the chemical character of released substances necrotaxis can accumulate or repel cells, which underlines the pathophysiological significance of this phenomenon.
## Receptors
For the most part, eukaryotic cells sense the presence of chemotactic stimuli though the use of 7-transmembrane (or serpentine) heterotrimeric G-protein coupled receptors. This class of receptors is huge, representing a significant portion of the genome. Some members of this gene superfamily are used in eyesight (rhodopsins) as well as in olfaction (smelling).
The main classes of professional chemotaxis receptors are triggered by formyl peptides - formyl peptide receptors (FPR), chemokines - chemokine receptors (CCR or CXCR) and leukotrienes - leukotriene receptors (BLT); however, induction of a wide set of membrane receptors (e.g. amino acids, insulin, vasoactive peptides) also elicit migration of the cell.
### Chemotactic selection
While some chemotaxis receptors are expressed in the surface membrane with long-term characteristics as they are determined genetically, others have short-term dynamics as they are assembled ad hoc in the presence of the ligand. The diverse features of the chemotaxis receptors and ligands allows for the possibility of selecting chemotactic responder cells with a simple chemotaxis assay. By chemotactic selection we can determine whether a still uncharacterized molecule acts via the long- or the short-term receptor pathway.
The term chemotactic selection is also used to designate a technique which separates eukaryotic or prokaryotic cells according to their chemotactic responsiveness to selector ligands.
## Chemotactic ligands
The number of molecules capable of eliciting chemotactic responses is relatively high, and we can distinguish primary and secondary chemotactic molecules. The main groups of the primary ligands are as follows:
- Formyl peptides are di-, tri-, tetrapeptides of bacterial origin (see formyl group on the N terminus of the peptide). They are released from bacteria in vivo or after decomposition of the cell. A typical member of this group is the N-formylmethionyl-leucyl-phenylalanine (fMLF or fMLP in references). The bacterial origin fMLF as a key component of inflammation has characteristic chemoattractant effects in neutrophil granulocytes and monocytes.
- Complement 3a (C3a) and complement 5a (C5a) are intermediate products of complement cascade. Their synthesis is joined to the three alternative pathways (classical, lectin dependent and alternative) of complement activation by a convertase enzyme. The main target cells of these derivaties are neutrophil garnulocytes and monocytes as well.
- Chemokines belong to a special class of cytokines. Their groups (C, CC, CXC, CX3C chemokines) represent not only structurally related molecules with a special arrangement of disulfide bridges, but their target cell specificity is also diverse: CC chemokines are acting on monocytes (e.g. RANTES), CXC chemokines are neutrophil granulocyte specific (e.g. IL-8).
Investigations of the three-dimensional structures of chemokines proved that a characteristic composition of beta-sheets and an alpha helix provides expression of sequences required for interaction with the chemokine receptors. Formation of dimers and their increased biological acitvity was demonstrated by crystallography of several chemokines e.g. IL-8.
- Leukotrienes belong to the group eicosanoids. They are significant lipid mediators of the arachidonic acid cascade converted by 5-lipoxigenase. Their predominant member is leukotriene B4 (LTB4) which elicits adhesion, chemotaxis and aggregation of leukocytes. The characteristic chemoattractant effect of LTB4 is induced via G-protein linked seven-transmembrane spanning leukotriene receptors which are highly expressed in inflammation and allergy.
### Chemotactic range fitting (CRF)
Chemotactic responses elicited by the ligand-receptor interactions are distinguished generally upon the optimal effective concentration(s) of the ligand. Nevertheless, correlation of the amplitude elicited and ratio of the responder cells compared to the total number are also characteristic features of the chemotactic signaling. Investigations of ligand families (e.g. amino acids or oligo peptides) proved that there is a fitting of ranges (amplitudes; number of responder cells) and chemotactic activities: chemoattractant moiety is accompanied by wide ranges, while chemorepellent character by narrow ranges.
# Clinical significance
A changed migratory potential of cells has relatively high importance in the development of several clinical symptoms and syndromes.
Altered chemotactic activity of extracellular (e.g. Escherichia coli) or intracellular (e.g. Listeria monocytogenes) pathogens itself represents a significant clinical target. Modification of endogenous chemotactic ability of these microorganisms by pharmaceutical agents can decrease or inhibit the ratio of infections or spreading of infectious diseases.
Apart from infections, there are some other diseases where impaired chemotaxis is the primary ethiological factor, as in Chediak-Higashi syndrome where giant intracellular vesicles inhibit normal migration of cells.
# Measurement of chemotaxis
A wide range of techniques is available to evaluate chemotactic activity of cells or the chemoattractant and chemorepellent character of ligands.
The basic requirements of the measurement are as follows:
- concentration gradients can develop relatively fast and persist for a long time in the system
- chemotactic and chemokinetic activities are distinguished
- migration of cells is free towards and away on the axis of the concentration gradient
- detected responses are the results of active migration of cells
Despite the fact that an ideal chemotaxis assay is still not available, there are several protocols and pieces of equipment which offer good correspondence with the conditions described above. The most commonly used are:
- Agar plate assays
E.g. PP-chamber
- Two-chamber techniques
E.g. Boyden-chamber
- Zigmond chamber
- Dunn chambers
- Multi-well chambers
- Capillary techniques
- Others
E.g. T-maze technique
- Opalescence technique
- Orientation assays
(A more detailed chapter you can find under Chemotaxis assay)
For a cell to move, it requires a number of cellular components (such as cellular motors various enzymes, etc.), and for a cell to be able to move, it has to be able to change shape.
Cell movement, broadly speaking can be of two types…
Hapoptatic (which means movement in response to physical and mechanical stimuli).
Chemotactic (which is movement in response to a chemical gradient). | Chemotaxis
# Overview
Chemotaxis, a kind of taxis, is the phenomenon in which bodily cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food (for example, glucose) by swimming towards the highest concentration of food molecules, or to flee from poisons (for example, phenol). In multicellular organisms, chemotaxis is critical to development as well as normal function. In addition, it has been recognized that mechanisms that allow chemotaxis in animals can be subverted during cancer metastasis.
Chemotaxis is called positive if movement is in the direction of a higher concentration of the chemical in question, and negative if the direction is opposite.
# History of chemotaxis research
Although migration of cells was detected from the early days of the development of microscopy (Leeuwenhoek), erudite description of chemotaxis was first made by T.W. Engelmann (1881) and W.F. Pfeffer (1884) in bacteria and H.S. Jennings (1906) in ciliates. The Nobel Prize Laureate E. Metchnikoff also contributed to the study of the field with investigations of the process as an initial step of phagocytosis. The significance of chemotaxis in biology and clinical pathology was widely accepted in the 1930s. The most fundamental definitions belonging to the phenomenon were also drafted by this time. The most important aspects in quality control of chemotaxis assays were described by H. Harris in the 1950s. In the 1960s and 1970s, the revolution of modern cell biology and biochemistry provided a series of novel techniques which became available to investigate the migratory responder cells and subcellular fractions responsible for chemotactic activity. The pioneering works of J. Adler represented a significant turning point in understanding the whole process of intracellular signal transduction of bacteria.[1]
On November 3, 2006, Dr. Dennis Bray of University of Cambridge was awarded the Microsoft European Science Award for his work on chemotaxis on E. coli.[2][3]
# Phylogeny and chemotactic signalling
Chemotaxis is one of the most basic cell physiological responses. Development of receptor systems for the detection of harmful and favorable substances in the environment was most essential to unicellular organisms from the very early stages of phylogeny. Comprehensive analysis of chemotactic activity of the eukaryotic protozoon Tetrahymena pyriformis and consensus sequences of appearance of amino acids in the primordial soup suggest that there was a good correlation between the chemotactic character of these relative simple organic molecules and their development on the Earth. In this way the earliest molecules are suggested to be highly chemoattractant (e.g. Gly, Glu, Pro), while latter ones are thought to be strongly chemorepellent (e.g. Tyr, Trp, Phe) amino acids.[4]
# Bacterial chemotaxis
Some bacteria, such as E. coli, have several flagella per cell (4–10 typically). These can rotate in two ways :
- Counter-clockwise rotation aligns the flagella into a single rotating bundle, causing the bacterium to swim in a straight line.
- Clockwise rotation breaks the flagella bundle apart such that each flagellum points in a different direction, causing the bacterium to tumble in place.
The directions of rotation are given for an observer outside the cell looking down the flagella toward the cell.
## Behavior
The overall movement of a bacterium is the result of alternating tumble and swim phases. If one watches a bacterium swimming in a uniform environment, its movement will look like a random walk with relatively straight swims interrupted by random tumbles that reorient the bacterium. Bacteria such as E. coli are unable to choose the direction in which they swim, and are unable to swim in a straight line for more than a few seconds due to rotational diffusion. In other words, bacteria "forget" the direction in which they are going. Given these limitations, it is remarkable that bacteria can direct their motion to find favorable locations with high concentrations of attractants (usually food) and avoid repellents (usually poisons).
In the presence of a chemical gradient bacteria will chemotax, or direct their overall motion based on the gradient. If the bacterium senses that it is moving in the correct direction (toward attractant/away from repellent), it will keep swimming in a straight line for a longer time before tumbling. If it is moving in the wrong direction, it will tumble sooner and try a new direction at random. In other words, bacteria like E. coli use temporal sensing to decide whether life is getting better or worse. In this way, it finds the location with the highest concentration of attractant (usually the source) quite well. Even under very high concentrations, it can still distinguish very small differences in concentration. Fleeing from a repellent works with the same efficiency.
It seems remarkable that this purposeful random walk is a result of simply choosing between two methods of random movement; namely tumbling and straight swimming. In fact, chemotactic responses such as forgetting direction and choosing movements resemble the decision-making abilities of higher lifeforms with brains that process sensory data.
The helical nature of the individual flagellar filament is critical for this movement to occur. As such, the protein that makes up the flagellar filament, flagellin, is quite similar among all flagellated bacteria. Vertebrates seem to have taken advantage of this fact by possessing an immune receptor (TLR5) designed to recognize this conserved protein.
As in many instances in biology, there are bacteria that do not follow this rule. Many bacteria, such as Vibrio, are monoflagellated and have a single flagellum at one pole of the cell. Their method of chemotaxis is different. Others possess a single flagellum that is kept inside the cell wall. These bacteria move by spinning the whole cell, which is shaped like a corkscrew.[5]
## Signal transduction
Chemical gradients are sensed through multiple transmembrane receptors, called methyl accepting chemotaxis proteins (MCPs), which vary in the molecules that they detect. These receptors may bind attractants or repellents directly or indirectly through interaction with proteins of periplasmatic space. The signals from these receptors are transmitted across the plasma membrane into the cytosol, where Che proteins are activated. The Che proteins alter the tumbling frequency, and alter the receptors.
### Flagellum regulation
The proteins CheW and CheA bind to the receptor. The activation of the receptor by an external stimulus causes autophosphorylation in the histidine kinase, CheA, at a single highly conserved histidine residue. CheA in turn transfers phosphoryl groups to conserved aspartate residues in the response regulators CheB and CheY [ note: CheA is a histidine kinase and it does not actively transfer the phosphoryl group. The response regulator CheB takes the phosphoryl group from CheA]. This mechanism of signal transduction is called a 'Two Component System' and is a common form of signal transduction in bacteria. CheY induces tumbling by interacting with the flagellar switch protein FliM, inducing a change from counter-clockwise to clockwise rotation of the flagellum. Change in the rotation state of a single flagellum can disrupt the entire flagella bundle and cause a tumble.
### Receptor regulation
CheB, when activated by CheA, acts as a methylesterase, removing methyl groups from glutamate residues on the cytosolic side of the receptor. It works antagonistically with CheR, a methyltransferase, which adds methyl residues to the same glutamate residues. The more methyl residues are attached to the receptor, the more sensitive the receptor. As the signal from the receptor induces demethylation of the receptor in a feedback loop, the system is continuously adjusted to environmental chemical levels, remaining sensitive for small changes even under extreme chemical concentrations. This regulation allows the bacterium to 'remember' chemical concentrations from the recent past and compare them to those it is currently experiencing, thus 'know' whether it is traveling up or down a gradient. However, the methylation system alone cannot account for the wide range of sensitivity that bacteria have to chemical gradients. Additional regulatory mechanisms such as receptor clustering and receptor-receptor interactions also modulate the signalling pathway.
# Eukaryotic chemotaxis
The mechanism by which eukaryotic cells chemotax is quite different from that in bacteria; however, sensing of chemical gradients is still a crucial step in the process. Due to their size, prokaryotes cannot detect effective concentration gradients, therefore these cells scan and evaluate their environment by a constant swimming (consecutive steps of straight swims and tumbles). In contrast to prokaryotes, the size of eukaryotic cells allows for the possibility of detecting gradients, which results in a dynamic and polarized distribution of receptors. Induction of these receptors by chemoattractants or chemorepellents results in migration towards or away from the chemotactic substance.
Levels of receptors, intracellular signalling pathways and the effector mechanisms all represent diverse, eukaryotic type components. In eukaryotic unicellular cells, ameboid movement and cilium or the eukaryotic flagellum are the main effectors (e.g. Amoeba or Tetrahymena).
Some eukaryotic cells of higher vertebrate origin, such as immune cells also move to where they need to be. Besides immune competent cells (granulocyte, monocyte, lymphocyte) a large group of cells - considered previously to be fixed into tissues - are also motile in special physiological (e.g. mast cell, fibroblast, endothelial cells)or pathological conditions (e.g. metastases). Chemotaxis has high significance in the early phases of embryogenesis as development of germ layers is guided by gradients of signal molecules.
## Motility
Unlike motility in bacterial chemotaxis, the mechanism by which eukaryotic cells physically move is unclear. There appear to be mechanisms by which an external chemotactic gradient is sensed and turned into an intracellular PIP3 gradient, which results in a gradient in the activation of signaling pathway culminating in the polymerisation of actin filaments. The growing distal end of actin filaments develops connections with the internal surface of the plasma membrane via different sets of peptides and results in the formation of pseudopods.
Cilium of eukaryotic cells can also result in chemotaxis, while in this case it is mainly a Ca2+ dependent induction of the microtubular system of the basal body and the 9x2+2 microtubules stroke of cilia. The orchestered beating of hundreds of cilia is synchronized by a submembranous system built between basal bodies.
The details of the signaling pathways are still not totally clear.
### Chemotaxis related migratory responses
Although chemotaxis is the most frequently studied form of migration there are several other forms of locomotion on the cellular level.
- Chemokinesis is also induced by molecules of the liquid phase of the surrounding environment; however, the response elicited is a not vectorial, random taxis. Neither amplitude nor frequency of motion has characteristic, directional components as this behaviour provides more scanning of the environment than migration between two distinct points.
- In haptotaxis the gradient of the chemoattractant is expressed or bound on a surface, in contrast to the classical way of chemotaxis when the gradient develops in a soluble space. The main biologically active haptotactic surface is the extracellular matrix (ECM); the presence of bound ligands is responsible for induction of transendothelial migration and angiogenesis.
- Necrotaxis embodies a special type of chemotaxis when the chemoattractant molecules are released from necrotic or apoptotic cells. Depending on the chemical character of released substances necrotaxis can accumulate or repel cells, which underlines the pathophysiological significance of this phenomenon.
## Receptors
For the most part, eukaryotic cells sense the presence of chemotactic stimuli though the use of 7-transmembrane (or serpentine) heterotrimeric G-protein coupled receptors. This class of receptors is huge, representing a significant portion of the genome. Some members of this gene superfamily are used in eyesight (rhodopsins) as well as in olfaction (smelling).
The main classes of professional chemotaxis receptors are triggered by formyl peptides - formyl peptide receptors (FPR), chemokines - chemokine receptors (CCR or CXCR) and leukotrienes - leukotriene receptors (BLT); however, induction of a wide set of membrane receptors (e.g. amino acids, insulin, vasoactive peptides) also elicit migration of the cell.
### Chemotactic selection
While some chemotaxis receptors are expressed in the surface membrane with long-term characteristics as they are determined genetically, others have short-term dynamics as they are assembled ad hoc in the presence of the ligand. The diverse features of the chemotaxis receptors and ligands allows for the possibility of selecting chemotactic responder cells with a simple chemotaxis assay. By chemotactic selection we can determine whether a still uncharacterized molecule acts via the long- or the short-term receptor pathway.
The term chemotactic selection is also used to designate a technique which separates eukaryotic or prokaryotic cells according to their chemotactic responsiveness to selector ligands.[6]
## Chemotactic ligands
The number of molecules capable of eliciting chemotactic responses is relatively high, and we can distinguish primary and secondary chemotactic molecules. The main groups of the primary ligands are as follows:
- Formyl peptides are di-, tri-, tetrapeptides of bacterial origin (see formyl group on the N terminus of the peptide). They are released from bacteria in vivo or after decomposition of the cell. A typical member of this group is the N-formylmethionyl-leucyl-phenylalanine (fMLF or fMLP in references). The bacterial origin fMLF as a key component of inflammation has characteristic chemoattractant effects in neutrophil granulocytes and monocytes.
- Complement 3a (C3a) and complement 5a (C5a) are intermediate products of complement cascade. Their synthesis is joined to the three alternative pathways (classical, lectin dependent and alternative) of complement activation by a convertase enzyme. The main target cells of these derivaties are neutrophil garnulocytes and monocytes as well.
- Chemokines belong to a special class of cytokines. Their groups (C, CC, CXC, CX3C chemokines) represent not only structurally related molecules with a special arrangement of disulfide bridges, but their target cell specificity is also diverse: CC chemokines are acting on monocytes (e.g. RANTES), CXC chemokines are neutrophil granulocyte specific (e.g. IL-8).
Investigations of the three-dimensional structures of chemokines proved that a characteristic composition of beta-sheets and an alpha helix provides expression of sequences required for interaction with the chemokine receptors. Formation of dimers and their increased biological acitvity was demonstrated by crystallography of several chemokines e.g. IL-8.
- Leukotrienes belong to the group eicosanoids. They are significant lipid mediators of the arachidonic acid cascade converted by 5-lipoxigenase. Their predominant member is leukotriene B4 (LTB4) which elicits adhesion, chemotaxis and aggregation of leukocytes. The characteristic chemoattractant effect of LTB4 is induced via G-protein linked seven-transmembrane spanning leukotriene receptors which are highly expressed in inflammation and allergy.
### Chemotactic range fitting (CRF)
Chemotactic responses elicited by the ligand-receptor interactions are distinguished generally upon the optimal effective concentration(s) of the ligand. Nevertheless, correlation of the amplitude elicited and ratio of the responder cells compared to the total number are also characteristic features of the chemotactic signaling. Investigations of ligand families (e.g. amino acids or oligo peptides) proved that there is a fitting of ranges (amplitudes; number of responder cells) and chemotactic activities: chemoattractant moiety is accompanied by wide ranges, while chemorepellent character by narrow ranges.
# Clinical significance
A changed migratory potential of cells has relatively high importance in the development of several clinical symptoms and syndromes.
Altered chemotactic activity of extracellular (e.g. Escherichia coli) or intracellular (e.g. Listeria monocytogenes) pathogens itself represents a significant clinical target. Modification of endogenous chemotactic ability of these microorganisms by pharmaceutical agents can decrease or inhibit the ratio of infections or spreading of infectious diseases.
Apart from infections, there are some other diseases where impaired chemotaxis is the primary ethiological factor, as in Chediak-Higashi syndrome where giant intracellular vesicles inhibit normal migration of cells.
# Measurement of chemotaxis
A wide range of techniques is available to evaluate chemotactic activity of cells or the chemoattractant and chemorepellent character of ligands.
The basic requirements of the measurement are as follows:
- concentration gradients can develop relatively fast and persist for a long time in the system
- chemotactic and chemokinetic activities are distinguished
- migration of cells is free towards and away on the axis of the concentration gradient
- detected responses are the results of active migration of cells
Despite the fact that an ideal chemotaxis assay is still not available, there are several protocols and pieces of equipment which offer good correspondence with the conditions described above. The most commonly used are:
- Agar plate assays
E.g. PP-chamber
- Two-chamber techniques
E.g. Boyden-chamber
- Zigmond chamber
- Dunn chambers
- Multi-well chambers
- Capillary techniques
- Others
E.g. T-maze technique
- Opalescence technique
- Orientation assays
(A more detailed chapter you can find under Chemotaxis assay)
For a cell to move, it requires a number of cellular components (such as cellular motors various enzymes, etc.), and for a cell to be able to move, it has to be able to change shape.
Cell movement, broadly speaking can be of two types…
Hapoptatic (which means movement in response to physical and mechanical stimuli).
Chemotactic (which is movement in response to a chemical gradient). | https://www.wikidoc.org/index.php/Chemotactic | |
e2652d8c1c2ac539b855c5a6a57952d2812d3b99 | wikidoc | Chest tube | Chest tube
For the WikiPatient page for this topic, click here
# Overview
A chest tube or chest drain is a flexible plastic tube that is inserted through the side of the chest into the pleural space. It is used to remove air (pneumothorax) or fluid (pleural effusion, blood, chyle), or pus (empyema) from the intrathoracic space. The procedure is called tube thoracostomy in the United Kingdom. It is also known as a Bülau drain.
# Technique
The free end of the tube is usually attached to an underwater seal, below the level of the chest. This allows the air or fluid to escape from the pleural space, and prevents anything returning to the chest. Alternatively, the tube can be attached to a flutter valve. This allows patients with pneumothorax to remain more mobile.
The British Thoracic Society recommends the tube is inserted in an area described as the "safe zone", a region bordered by: the lateral border of pectoralis major, a horizontal line inferior to the axilla, the anterior border of latissimus dorsi and a horizontal line superior to the nipple.
Chest tubes are usually inserted under local anesthesia. The skin over the area of insertion is first cleansed with antiseptic solution, such as iodine, before sterile drapes are placed around the area. The local anesthetic is injected into the skin and down to the muscle, and after the area is numb a small incision is made in the skin and a passage made through the skin and muscle into the chest. The tube is placed through this passage. If necessary, patients may be given additional analgesics for the procedure. Once the tube is in place it is sutured to the skin to prevent it falling out and a dressing applied to the area. The tube stays in for as long as there is air or fluid to be removed, or risk of air gathering.
Once the drain is in place, a chest radiograph will be taken to check the location of the drain.
Chest tubes can also be placed using a trocar, which is a pointed metallic bar used to guide the tube through the chest wall. This method is less popular due to an increased risk of iatrogenic lung injury.
Placement using the Seldinger technique, in which a blunt guidewire is passed through a needle (over which the chest tube is then inserted) has been described.
# Indications
- Pneumothorax: accumulation of air in the pleural space
- Pleural effusion: accumulation of fluid in the pleural space
Chylothorax: a collection of lymphatic fluid in the pleural space
Empyema: a pyogenic infection of the pleural space
Hemothorax: accumulation of blood in the pleural space
Hydrothorax: accumulation of serous fluid in the pleural space
- Chylothorax: a collection of lymphatic fluid in the pleural space
- Empyema: a pyogenic infection of the pleural space
- Hemothorax: accumulation of blood in the pleural space
- Hydrothorax: accumulation of serous fluid in the pleural space
# Contraindications
Contraindications to chest tube placement include refractory coagulopathy, lack of cooperation by the patient, and diaphragmatic hernia.
# Complications
Major complications are hemorrhage, infection, and reexpansion pulmonary edema. Injury to the liver, spleen or diaphragm is possible if the tube is placed inferior to the pleural cavity. Injuries to the thoracic aorta and heart have also been described.
Minor complications include a subcutaneous hematoma or seroma, anxiety, shortness of breath (dyspnea), and cough (after removing large volume of fluid).
# Additional Resources
- Intensive Care Medicine by Irwin and Rippe
- The ICU Book by Marino
- Procedures and Techniques in Intensive Care Medicine by Irwin and Rippe
de:Thoraxdrainage | Chest tube
For the WikiPatient page for this topic, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A chest tube or chest drain is a flexible plastic tube that is inserted through the side of the chest into the pleural space. It is used to remove air (pneumothorax) or fluid (pleural effusion, blood, chyle), or pus (empyema) from the intrathoracic space. The procedure is called tube thoracostomy in the United Kingdom. It is also known as a Bülau drain.
# Technique
The free end of the tube is usually attached to an underwater seal, below the level of the chest. This allows the air or fluid to escape from the pleural space, and prevents anything returning to the chest. Alternatively, the tube can be attached to a flutter valve. This allows patients with pneumothorax to remain more mobile.
The British Thoracic Society recommends the tube is inserted in an area described as the "safe zone", a region bordered by: the lateral border of pectoralis major, a horizontal line inferior to the axilla, the anterior border of latissimus dorsi and a horizontal line superior to the nipple.
Chest tubes are usually inserted under local anesthesia. The skin over the area of insertion is first cleansed with antiseptic solution, such as iodine, before sterile drapes are placed around the area. The local anesthetic is injected into the skin and down to the muscle, and after the area is numb a small incision is made in the skin and a passage made through the skin and muscle into the chest. The tube is placed through this passage. If necessary, patients may be given additional analgesics for the procedure. Once the tube is in place it is sutured to the skin to prevent it falling out and a dressing applied to the area. The tube stays in for as long as there is air or fluid to be removed, or risk of air gathering.
Once the drain is in place, a chest radiograph will be taken to check the location of the drain.
Chest tubes can also be placed using a trocar, which is a pointed metallic bar used to guide the tube through the chest wall. This method is less popular due to an increased risk of iatrogenic lung injury.
Placement using the Seldinger technique, in which a blunt guidewire is passed through a needle (over which the chest tube is then inserted) has been described.
# Indications
- Pneumothorax: accumulation of air in the pleural space
- Pleural effusion: accumulation of fluid in the pleural space
Chylothorax: a collection of lymphatic fluid in the pleural space
Empyema: a pyogenic infection of the pleural space
Hemothorax: accumulation of blood in the pleural space
Hydrothorax: accumulation of serous fluid in the pleural space
- Chylothorax: a collection of lymphatic fluid in the pleural space
- Empyema: a pyogenic infection of the pleural space
- Hemothorax: accumulation of blood in the pleural space
- Hydrothorax: accumulation of serous fluid in the pleural space
# Contraindications
Contraindications to chest tube placement include refractory coagulopathy, lack of cooperation by the patient, and diaphragmatic hernia.
# Complications
Major complications are hemorrhage, infection, and reexpansion pulmonary edema. Injury to the liver, spleen or diaphragm is possible if the tube is placed inferior to the pleural cavity. Injuries to the thoracic aorta and heart have also been described.
Minor complications include a subcutaneous hematoma or seroma, anxiety, shortness of breath (dyspnea), and cough (after removing large volume of fluid).
# Additional Resources
- Intensive Care Medicine by Irwin and Rippe
- The ICU Book by Marino
- Procedures and Techniques in Intensive Care Medicine by Irwin and Rippe
Template:Emergency medicine
de:Thoraxdrainage
Template:WS | https://www.wikidoc.org/index.php/Chest_drain | |
408f72590978edcee42bb7a94a6c1c625a513edf | wikidoc | Chest hair | Chest hair
The term chest hair is generally used to describe hair that grows on the chest of human males, in the region between the neck and the abdomen. Chest hair, which is a secondary sex characteristic, develops during and after puberty. It is therefore part of the androgenic hair.
# Development and growth
Although vellus hair is already present in the area in childhood, the term chest hair is generally restricted to the terminal hair that develops as an effect of rising levels of androgens (primarily testosterone and its derivatives) due to puberty. Different from the head hair it is therefore a secondary sexual characteristic. In contrast to women the body of men tends to be covered far more with terminal hair, particularly on the chest, the abdomen and the face.
The development of chest hair begins normally during late puberty. It can also start later, between the age of 20 and 30, so that many men in their twenties have not yet reached their full chest hair development. The growth continues subsequently. In older adult years androgens cause thickening of the hair.
# Patterns and characteristics
The individual occurrence and characteristics of chest hair depend on the genetic disposition, the hormonal status and the age of the person. The genes primarily determine the amount, patterns and thickness of chest hair. Some men are very hairy, while others have no chest hair at all. Each pattern of hair growth is normal. The areas where terminal hair may grow are the periareolar areas (nipples), the centre and sides of the chest and the clavicle (collarbone).
The direction of growth of hair can make for interesting patterns, akin to depictions of mathematical vector fields. Typical males will exhibit
a node on the upper sternum, the hair above which points up and the hair below which points down. Some individuals (of say the pattern in diagram 3) have spirals on their upper pectoral regions (several inches from the nipple towards the neck) which run clockwise on the left breast and counter-clockwise on the right.
Considering an individual occurrence of chest hair as abnormal does not implicitly depend on medical indications but primarily on cultural and social attitudes. An excessive growth of terminal hair on the body of men and women is called hypertrichosis. This medical term has to be distinguished from hirsutism that just affects women. These women can develop terminal hair on the chest following the male pattern as a symptom of an endocrine disease.
There have been occasional studies documenting patterns of chest hair in men and occurrence of these patterns. A study of 1100 men aged 17 to 71 defined and documented ten patterns of chest hair in Caucasoid men. In this study 6 percent of the men were found to have no chest hair. The largest group, 56 percent, displayed pattern four as shown in the accompanying figure. The remaining 38 percent of the men displayed a lesser quantity of chest hair. Seven percent displayed pattern one, 13 percent displayed pattern two and 18 percent displayed various other patterns.
The same study documented the chest hair patterns of 60 African-American men aged 20-40. For these men 22 percent were found to have no chest hair. The largest group, 37 percent displayed pattern four and the remaining 41 percent had a lesser quantity of chest hair. Eight percent displayed pattern one, 12 percent pattern two and 11 percent displayed various other patterns.
# Cultural and social attitudes
The attitudes towards chest hair vary between different cultures and times. In some cultures, it is a symbol for virility and masculinity; other societies display a hairless body as a sign of youthfulness. Some people find men with a lot of chest hair, pattern four, very sexually arousing. In ancient Greece and ancient Rome male statues did not show any chest hair. Even on paintings and sculptures from Middle Ages to modern times men were often portrayed without any hair on their anterior torso.
While in the early and middle twentieth century the attitude towards hair on the chest was largely indifferent, there was a late twentieth century trend within Western societies to remove chest hair. Some young men in their teens and twenties, especially in the United States and those involved in beach culture, remove their chest hair. It is quite common for actors, who will appear shirtless in a movie or television show, to shave their chests. The removal of body hair (depilation and epilation) by men was labelled by the personal hygiene industry as manscaping. This public trend, distributed by the media, began in the United States and spread to other Western societies. Many companies catered to men looking for ways to remove their chest hair, such as Nair for Men and Nads for Men. While most men depicted in fashion advertising still have no chest hair, a few exceptions can now be seen. Bucking the larger trend, a positive acceptance of body hair could be found amongst adherents of naturism as well as the bear community, the latter a gay subculture whose members tend to exhibit typical masculine gender traits. Removing or maintaining chest hair ultimately depends on one's individual preference, which can be influenced by what is considered most attractive. | Chest hair
The term chest hair is generally used to describe hair that grows on the chest of human males, in the region between the neck and the abdomen. Chest hair, which is a secondary sex characteristic, develops during and after puberty. It is therefore part of the androgenic hair.
## Development and growth
Although vellus hair is already present in the area in childhood, the term chest hair is generally restricted to the terminal hair that develops as an effect of rising levels of androgens (primarily testosterone and its derivatives) due to puberty. Different from the head hair it is therefore a secondary sexual characteristic. In contrast to women the body of men tends to be covered far more with terminal hair, particularly on the chest, the abdomen and the face.
The development of chest hair begins normally during late puberty. It can also start later, between the age of 20 and 30, so that many men in their twenties have not yet reached their full chest hair development. The growth continues subsequently. In older adult years androgens cause thickening of the hair.
## Patterns and characteristics
The individual occurrence and characteristics of chest hair depend on the genetic disposition, the hormonal status and the age of the person. The genes primarily determine the amount, patterns and thickness of chest hair. Some men are very hairy, while others have no chest hair at all. Each pattern of hair growth is normal. The areas where terminal hair may grow are the periareolar areas (nipples), the centre and sides of the chest and the clavicle (collarbone).
The direction of growth of hair can make for interesting patterns, akin to depictions of mathematical vector fields. Typical males will exhibit
a node on the upper sternum, the hair above which points up and the hair below which points down. Some individuals (of say the pattern in diagram 3) have spirals on their upper pectoral regions (several inches from the nipple towards the neck) which run clockwise on the left breast and counter-clockwise on the right.
Considering an individual occurrence of chest hair as abnormal does not implicitly depend on medical indications but primarily on cultural and social attitudes. An excessive growth of terminal hair on the body of men and women is called hypertrichosis. This medical term has to be distinguished from hirsutism that just affects women. These women can develop terminal hair on the chest following the male pattern as a symptom of an endocrine disease.
There have been occasional studies documenting patterns of chest hair in men and occurrence of these patterns. A study of 1100 men aged 17 to 71 defined and documented ten patterns of chest hair in Caucasoid men. In this study 6 percent of the men were found to have no chest hair. The largest group, 56 percent, displayed pattern four as shown in the accompanying figure. The remaining 38 percent of the men displayed a lesser quantity of chest hair. Seven percent displayed pattern one, 13 percent displayed pattern two and 18 percent displayed various other patterns.
The same study documented the chest hair patterns of 60 African-American men aged 20-40. For these men 22 percent were found to have no chest hair. The largest group, 37 percent displayed pattern four and the remaining 41 percent had a lesser quantity of chest hair. Eight percent displayed pattern one, 12 percent pattern two and 11 percent displayed various other patterns.[1] [2]
## Cultural and social attitudes
The attitudes towards chest hair vary between different cultures and times. In some cultures, it is a symbol for virility and masculinity; other societies display a hairless body as a sign of youthfulness. Some people find men with a lot of chest hair, pattern four, very sexually arousing. In ancient Greece and ancient Rome male statues did not show any chest hair. Even on paintings and sculptures from Middle Ages to modern times men were often portrayed without any hair on their anterior torso.
While in the early and middle twentieth century the attitude towards hair on the chest was largely indifferent, there was a late twentieth century trend within Western societies to remove chest hair. Some young men in their teens and twenties, especially in the United States and those involved in beach culture, remove their chest hair. It is quite common for actors, who will appear shirtless in a movie or television show, to shave their chests. The removal of body hair (depilation and epilation) by men was labelled by the personal hygiene industry as manscaping. This public trend, distributed by the media, began in the United States and spread to other Western societies. Many companies catered to men looking for ways to remove their chest hair, such as Nair for Men and Nads for Men. While most men depicted in fashion advertising still have no chest hair, a few exceptions can now be seen. Bucking the larger trend, a positive acceptance of body hair could be found amongst adherents of naturism as well as the bear community, the latter a gay subculture whose members tend to exhibit typical masculine gender traits. Removing or maintaining chest hair ultimately depends on one's individual preference, which can be influenced by what is considered most attractive. | https://www.wikidoc.org/index.php/Chest_hair | |
2a26d15af408c1f9ae1b26f18eb64875cd0c3b9b | wikidoc | Childbirth | Childbirth
# Overview
Childbirth (also called labour, birth, partus or parturition) is the culmination of a human pregnancy or gestation period with the delivery of one or more newborn infants from a woman's uterus. The process of human childbirth is categorized in 3 stages of labour. In the first stage, the uterus begins rhythmic contractions which steadily increase in strength and frequency, gradually widening and thinning the cervix. During the second stage, the infant passes from the uterus, through the cervix and birth canal. In the third stage, the placenta pulls from the uterine wall and is expelled through the birth canal.
# The Natural Birth
## First Stage: Contractions
Normal childbirth begins with the onset of contractions of the uterus. The frequency and duration of these contractions varies with the individual. The onset of labour may be sudden or gradual, and is defined as regular uterine activity in the presence of cervical dilatation.
During a contraction, long muscles of the uterus contract, starting at the top of the uterus and working their way down to the bottom. At the end of the contraction, the muscles relax to a state shorter than at the beginning of the contraction. This draws the cervix up over the baby's head. Each contraction dilates the cervix until it becomes completely dilated, often referred to as 10+ centimeters (cm) or 4+ inches (in) in diameter by midwives or doctors.
A gradual onset with slow cervical change towards 3 cm (just over 1 inch) dilation is referred to as the "latent phase". A woman is said to be in "active labour" when contractions have become regular in frequency (3 to 4 in 10 minutes) and about 60 seconds in duration. The cervix must shorten (efface) before it can dilate; for women giving birth for the first time, this can take a substantial period of time and can be a tiring and difficult time. However, once the cervix is effaced dilatation can occur and the downward journey of the baby can commence. The now powerful contractions are accompanied by cervical effacement and dilation greater than 3 cm (1¼ in) . The labour may begin with a rupture of the amniotic sac, the paired amnion and chorion ("breaking of the water"). The contractions will strengthen and accelerate in frequency. In the "transition phase" from 8 cm–10 cm (3 or 4 in) of dilation, the contractions often come every two minutes and typically last 70–90 seconds. Transition is often regarded as the most challenging and intense for the woman. It is also the shortest phase.
During this stage, the woman giving birth typically goes through several emotional phases. At first, she may be excited and nervous. Then, as the contractions become stronger, demanding more energy from the woman, she may become more serious and focused. However, as the cervix finishes its dilation, some women experience confusion or bouts of self-doubt or giving up. It is important during this time for the birth partners to stay positive and supportive of the woman; to actively encourage if this is what she wishes and to provide nutrition and hydration in order to keep her energy reserves up.
The duration of labour varies widely, but averages some 13 hours for women giving birth to their first child ("primiparae") and 8 hours for women who have already given birth ("multiparae").
If there is a significant medical risk to continuing the pregnancy, induction may be necessary. As this carries some risk, it is only done if the fetus or the woman are in danger from prolonged pregnancy. Forty-two weeks' gestation without spontaneous labour is often said to be an indication for induction although evidence does not show improved outcomes when labour is induced for post-term pregnancies. Inducing labour increases the risk of cesarean section uterine rupture in women that have had a previous cesarean section.
## Second Stage: Delivery
In the second stage of labour, the baby is pushed through the womb through the vagina by both the uterine contractions and by the additional maternal efforts of "bearing down," which many women describe as similar in sensation to straining to expel a large bowel movement. The imminence of this stage can be evaluated by the Malinas score. In a vertex (normal head first delivery) when the top of the head is visible at the vagina or in other words the birth canal, this is called crowning (the perineum or the region between the vagina and anus could tear or needs to be cut in a procedure called episiotomy); at this point the woman may feel a burning or stinging sensation, but this soon passes (some people refer the crowning stage as 'The ring of fire').
This stage begins when the cervix is fully dilated. This can be determined by the woman's onset of her desire to 'push' or it can be determined by performing a vaginal exam.
Mechanism of Labor-(Head First) Flexion, Internal Rotation, Extension, External Rotation, Expulsion.
Flexion- When the descending head meets resistance if flexes so that the chin is brought closer to the chest. Internal Rotation- It begins at the ischial spine and is not completed until it reaches lower pelvis. Extension- When fetal head reaches perineum it is deflected anteriorly by perineum. External Rotation-After head is born it rotates 45 degrees to realign with its shoulders and back. Expulsion- After birth of shoulders, the shoulders are lifted up and trunk of body is born by flexing in laterally.
The baby is most commonly born head-first. In some cases the baby is "breech" meaning either the feet or buttocks are descending first. Babies in the breech position can be helped to be born vaginally by a midwife, although caesarean births are becoming more common for breech presentation.
There are several types of breech presentations, but the most common is where the baby's buttocks are born first and the legs are folded onto the baby's body with the knees bent and feet near the buttocks (full or breech). Others include frank breech, much like full breech but the baby's legs are extended toward its ears, and footling or incomplete breech, in which one or both legs are extended and the foot or feet are the presenting part. Another rare presentation is a transverse lie. This is where the baby is sideways in the womb and a hand or elbow has entered the birth canal first. While babies who present transverse will often move to a different position, this is not always the case and a cesarean birth then becomes necessary.
The length of the second stage varies and may be affected by whether a woman has given birth before, the position she is in and mobility. The length of the second stage should be guided by the condition of the fetus and health of the woman. Problems may be encountered at this stage due to reasons such as maternal exhaustion, the front of the baby's head facing forwards instead of backwards (posterior baby), or extremely rarely, because the baby's head does not fit properly into the woman's pelvis (Cephalo-Pelvic Disproportion (CPD)). True CPD is typically seen in women with rickets and bone deforming illnesses or injuries, as well as arbitrary time limits placed on second stage by caregivers or medical facilities.
Immediately after birth, the child undergoes extensive physiological modifications as it acclimates to independent breathing. Several cardiovascular structures start regressing soon after birth, such as the ductus arteriosus and the foramen ovale. In some cultures, the father cuts the umbilical cord and the infant is given a lukewarm bath to remove blood and some of the vernix on its skin before being handed back to its parents.
The medical condition of the child is assessed with the Apgar score, based on five parameters: heart rate, respiration, muscle tone, skin color, and response to stimuli. Apgar scores are typically assessed at both 1 and 5 minutes after birth.
## Third Stage: Placenta
In this stage, the uterus expels the placenta (afterbirth). Breastfeeding the baby will help to cause this. The woman normally loses less than 500 mL (2 cups, or 1 pint) of blood. The placenta should never be pulled from the woman by an untrained person; this could cause it to tear and not be expelled whole. It is essential that the placenta be examined to ensure that it was expelled whole. Remaining parts can cause postpartum bleeding or infection.
The alternative to natural delivery of the placenta is what is called Active Management: this involves administration of a prophylactic oxytocic before delivery of the placenta, and usually early cord clamping and cutting, and controlled cord traction of the umbilical cord.
A Cochrane database study suggests strongly that blood loss and the risk of postpartum bleeding will be reduced in women offered active management of the third stage of labour. However, there was an increased risk of unpleasant side effects to the baby or mother (such as nausea or vomiting) and hypertension. The authors suggest that this is due to the use of ergometrine as a component of the oxytocic. No advantages or disadvantages were apparent for the baby.
Details of CCT are available. This procedure must not be attempted except by appropriately trained providers.
## After the Birth
Medical professionals typically recommend breastfeeding of the first milk, colostrum, to reduce postpartum bleeding/hemorrhage in the mother, and to pass immunities and other benefits to the baby.
Parents usually bestow the infant its given name soon after birth.
Often people visit and bring a gift for the baby.
Many cultures feature initiation rites for newborns, such as naming ceremonies, baptism, and others.
Mothers are often allowed a period where they are relieved of their normal duties to recover from childbirth. The length of this period varies. In China it is 30 days and is referred to as "doing the month" or "sitting month" (see Postpartum period). In other countries taking time off from work to care for a newborn is called "maternity leave" and varies from a few days to several months.
# Variations
When the amniotic sac has not ruptured during labour or pushing, the infant can be born with the membranes intact. This is referred to as "being born in the caul." The caul is harmless and its membranes are easily broken and wiped away. In medieval times, and in some cultures still today, a caul was seen as a sign of good fortune for the baby, even giving the child psychic gifts such as clairvoyance, and in some cultures was seen as protection against drowning. The caul was often impressed onto paper and stored away as an heirloom for the child. With the advent of modern interventive obstetrics, premature artificial rupture of the membranes has become common, so babies are rarely born in the caul.
# Pain
The amounts of pain experienced by women during childbirth varies. For some women, the pain is intense and agonizing; for other women there is little to no pain. Many factors affect pain perception; fear, number of previous births, fetal presentation, cultural ideas of childbirth, birthing position, support given during labor, beta-endorphin levels, and a woman's natural pain threshold. Uterine contractions are always intense during childbirth. Some women report these sensations as painful, though the degree of pain varies from individual to individual.
## Non-medical Pain Control
Some women believe that reliance on analgesic medication is unnatural, or believe that it may harm the child. They still can alleviate labour pain using psychological preparation, education, massage, hypnosis, or water therapy in a tub or shower. Some women like to have someone to support them during labour and birth, such as the woman's mother, a sister, the father of the baby, a close friend, a partner or a trained professional doula. Some women deliver in a squatting or crawling position in order to more effectively push during the second stage and so that gravity can aid the descent of the baby through the birth canal.
The human body also has its own method of pain control for labour and childbirth in the form of beta-endorphins. As a naturally occurring opiate, beta-endorphin has properties similar to pethidine, morphine, and heroin, and has been shown to work on the same receptors of the brain. Like oxytocin, beta-endorphin is secreted from the pituitary gland, and high levels are present during sex, pregnancy, birth, and breastfeeding. This hormone can induce feelings of pleasure and euphoria during childbirth.
Water birth is an option chosen by some women for pain relief during labour and childbirth, and some studies have shown waterbirth in an uncomplicated pregnancy to reduce the need for analgesia, without evidence of increased risk to mother or newborn. The American Academy of Pediatrics still considers underwater birthing "an experimental procedure that should not be performed except within the context of an appropriately designed after informed parental consent."
Many hospitals and birthing centres now offer women the option of waterbirth, either via custom-made 'birthing pools' or large bath tubs, and have policies to safeguard their use.
Meditation and mind medicine techniques for the use of pain control during labor and delivery. These techniques are used in conjunction with progressive muscle relaxation and many other forms of relaxation for the mind and body to aid in pain control for women during childbirth. These techniques are a form of natural pain control. One such technique is the use of hypnosis in childbirth. This technique is a form of meditation that empowers and liberates the woman by uplifting her body and its natural process to welcoming her new child into the world.
## Medical Pain Control
In some countries of Europe, doctors commonly prescribe inhaled nitrous oxide gas for pain control; in the UK, midwives may use this gas without a doctor's prescription. Pethidine (with or without promethazine) may be used early in labour, as well as other opioids, but if given too close to birth there is a risk of respiratory depression in the infant.
Popular medical pain control in hospitals include the regional anesthetics epidural blocks, and spinal anaesthesia. Doctors and many parents favor the epidural block because medication does not enter the woman's circulatory system, thus it does not cross the placenta and enter the bloodstream of the fetus. Some studies find that although epidural use can lengthen the labour and increase the need for operative intervention, it has no adverse effect on perinatal outcome, and is a safe and effective method of pain control.
Different measures for pain control have varying degrees of success and side effects to the woman and her baby. The risks of medical pain control should be balanced against the fact that childbirth can be extremely painful, and anesthetics are an effective and generally safe way to control pain.
# Complications and Risks of Birth
Problems that occur during childbirth are called complications. They can affect the woman, the baby, or both. Sometimes they cause injury or even death. Doctors and midwives are trained to deal with these problems if they should occur.
Infant deaths (neonatal deaths from birth to 28 days, or perinatal deaths if including fetal deaths at 28 weeks gestation and later) are around 1% in modernized countries. The risk of maternal death during childbirth in developed nations is comparatively low; only about 1 in 1800 women die in childbirth (only 1 in 3700 in North America). In the Third World, it is a much riskier proposition: neonatal deaths rates in Sub-Saharan Africa and South Asia are more than 3.7%, and on average 1 in 48 women die during childbirth. The "natural" mortality rate of childbirth—where nothing is done to avert maternal death—has been estimated as being between 1,000 and 1,500 deaths per 100,000 births. (See main article: neonatal death, maternal death)
The most important factors affecting mortality in childbirth are adequate nutrition and access to quality medical care ("access" is affected both by the cost of available care, and distance from health services). "Medical care" in this context does not refer specifically to treatment in hospitals, but simply routine prenatal care and the presence, at the birth, of an attendant with midwifery skills. A 1983-1989 study by the Texas Department of Health revealed that the infant death rate was 0.57% for doctor-attended births, and 0.19% for births attended by non-nurse midwives. (The comparison may be misleading because higher-risk births are less likely to be attended solely by a midwife.) Conversely, some studies demonstrate a higher perinatal mortality rate with assisted home births. Around 80% of pregnancies are low-risk. Factors that may make a birth high risk include prematurity, high blood pressure, gestational diabetes and a previous cesarean section.
One of the most dangerous risks to the fetus is that of premature birth, and its associated low neonatal weight. The more premature (or underweight) a baby is, the greater the risks for neonatal death and for pulmonary, respiratory, neurological or other sequelae. About 12% of all infants born in the United States are born prematurely. In the past 25 years, medical technology has greatly improved the chances of survival of premature infants in industrialized nations. In the 1950s and 1960s, approximately half of all low birth weight babies in the US died. Today, more than 90% survive. The first hours of life for "premies" are critical, especially the very first hour of life. Rapid access to a Neonatal Intensive Care Unit is of paramount importance.
Some of the possible complications are:
- Heavy bleeding during or after childbirth, which is the most common cause of mortality in new mothers, in both developed and undeveloped nations. Heavy blood loss leads to hypovolemic shock, insufficient perfusion of vital organs and death if not rapidly treated by stemming the blood loss (medically with ergometrine and pitocin or surgically) and blood transfusion. Hypopituitarism after obstetric hypovolemic shock is termed Sheehan's syndrome.
- Non-progression of labour (longterm contractions without adequate cervical dilation) is generally treated with intravenous synthetic oxytocin preparations. If this is ineffective, Caesarean section may be necessary. Changes in maternal position is effective in many cases.
- Fetal distress is the development of signs of distress by the child. These may include rising or decreasing heartbeat (monitored on cardiotocography/CTG), shedding of meconium in the amniotic fluid, and other signs.
- Non-progression of expulsion (the head or presenting parts are not delivered despite adequate contractions): this can require interventions such as vacuum extraction, forceps extraction or Caesarean section.
- In the past, a large proportion of women died from infection puerperal fever, but since the introduction of basic hygiene during parturition by Ignaz Semmelweis, this number has fallen precipitously.
- Lacerations can be painful. An episiotomy was once thought necessary to avoid tears involving the anal sphincter, but its routine use—once normal—has now been shown to increase the risk of deep lacerations especially involving and extending through the anal sphincter.
- Pelvic girdle pain. Hormones and enzymes work together to produce ligamentous relaxation and widening of the symphysis pubis during the last trimester of pregnancy. The physiologic changes of pregnancy are superimposed by the trauma of birth. During delivery, the ligaments stretch and small amounts of tearing in the fibro cartilage occurs, this tearing can be in any direction, progressively loosening the symphysis, producing cartilage nodules, cysts and reactive bone formation. For some women an event during the delivery can cause some degree of injury to the symphysis pubis or sacroiliac joint. This could be the result of:
- A large baby.
- A mid to high forceps delivery.
- Previous pelvic trauma.
- Hypermobility.
- Pelvic girdle pain during the pregnancy.
Pain is usually felt low down over the symphysis pubis; which may be extremely tender to the touch. Swelling and/or inflammation will be present. She will experience difficulty lifting leg, pain pulling legs apart, standing on one leg, transferring weight through pelvis and legs, and restriction of hip movement. Pain may also be felt in the groin, hips, sacroiliac joints and lower abdomen and can radiate down the inner thighs. The woman and may be aware of an audible 'tearing' sound coming form the pelvis during the delivery as the fibrocartilage tears apart. For women who have pain and instability they can experience mild to major disabilities.
Instrumental delivery (Forceps and Ventouse)
- The woman will have her legs apart supported in stirrups.
- If an anaesthetic is not already in place it will be given.
- For a forceps delivery an episiotomy will be done (a cut in the perineum or the region between the vagina and anus), for ventouse extraction an episiotomy is not always done.
- After the head is delivered the rest of the delivery is done in the manual method.
- After episiotomy or tears the woman is stitched up.
- In some cases a 'Trial of Forceps' will be tried out, this will be done in the operating theatre, meaning they will try a forceps delivery and will switch to a caesarean section if it fails.
# Twins and Multiple Births
Twins can be delivered vaginally. In some cases twin delivery is done in a larger delivery room or in theatre, just in case complications occur e.g.
- Both twins born vaginally - one comes normally but the other is breech and/or helped by a forceps/ventouse delivery
- One twin born vaginally and the other by caesarean section.
- If the twins are joined at any part of the body - called conjoined twins, delivery is mostly by caesarean section.
Triplets or more are always delivered by caesarean section.
# Professions Associated with Childbirth
Midwives are experts in normal birth. Midwives believe that childbirth is a normal process that is best accomplished with as little interference as possible. Midwives are trained to assist at births, either through direct-entry or nurse-midwifery programs. Lay midwives typically train in apprenticeship programs with experienced midwives.
Obstetricians are experts in dealing with abnormal births and pathological labour conditions, though they sometimes attend normal births as a precautionary measure. Obstetricians in most countries are trained as surgeons, so they can undertake surgical procedures relating to childbirth. Such procedures include caesarean sections, episiotomies, or emergency hysterectomies. Obstetricians' tendency to intervene surgically to overcome complications has led to criticism that they perform surgery too readily. In the United States, obstetric malpractice settlements are typically very large, so obstetricians argue that they are forced to intervene aggressively to limit their liability.
Maternal-fetal medicine specialists are experts in managing and treating high-risk pregnancy and delivery.
Obstetric nurses assist midwives, doctors, women, and babies prior to, during, and after the birth process. Some midwives are also obstetric nurses. Obstetric nurses hold various certifications and typically undergo additional obstetric training in addition to standard nursing training
Doulas are trained assistants who support mothers during pregnancy, labour, birth, and postpartum. They are not medical attendants; rather, they provide emotional support and non-medical pain relief for women during labour.
# Social Aspects
In most cultures, childbirth is considered to be the beginning of a person's life, and their age is defined relative to it.
Some families view the placenta as a special part of birth, since it has been the child's life support for so many months. Some parents like to see and touch this organ. In some cultures, parents plant a tree along with the placenta on the child's first birthday. The placenta may be eaten by the newborn's family, ceremonially or otherwise.
# Psychological Aspects
Childbirth can be a stressful event. As with any stressful event, strong emotions can be brought to the surface.
Some women report symptoms compatible with post-traumatic stress disorder (PTSD) after birth. Between 70 and 80% of mothers in the United States report some feelings of sadness or "baby blues" after childbirth. Postpartum depression may develop in some women; about 10% of mothers in the United States are diagnosed with this condition. Abnormal and persistent fear of childbirth is known as tokophobia.
Preventative group therapy has proven effective as a prophylactic treatment for postpartum depression.
There are some who argue that childbirth is stressful for the infant. Stresses associated with breech birth, such as asphyxiation, may affect the infant's brain.
# Partner and Other Support
There is increasing evidence to show that the participation of the woman's partner in the birth leads to better birth and also post-birth outcomes, providing the partner does not exhibit excessive anxiety. Research also shows that when a labouring woman was supported by a female helper such as a family member or doula during labour, she had less need for chemical pain relief, the likelihood of caesarean section was reduced, use of forceps and other instrumental deliveries were reduced and there was a reduction in the length of labour and the baby had a higher Apgar score (Dellman 2004, Vernon 2006).
It is the traditional history of home labour that makes The Netherlands an attractive site for studies related to birth. One third of all baby deliveries there are still happening at home in contrast with other western industrialized countries. Apparently, Dutch fathers have been in the scene of labor for a long time as can be observed in paintings from the 17th and 18th centuries.
During this study, it was found that fathers can have different roles during birth and that little is said about the conflicts between partners or partners and professionals. Among other findings were also: the interpretation of the presence of fathers during birth as a modern version of the anthropological couvade ritual to ease the woman's pain; the majority of fathers did not perceive any limitation to participate in their childbirth and upper generations did not play an important rule in the transmission of knowledge about birth to those fathers but the wives, feminine acquaintances and midwives.
The research was based, mainly, on in-depth interviews, where fathers described what was happening from their partner’s first signals of birth labour until the placenta delivery.
# Postnatal Care
# Well Known Authors on Childbirth
- Janet Balaskas
- Jeannine Parvati Baker
- Robert A. Bradley
- Ina May Gaskin
- Sheila Kitzinger
- Frederick Leboyer
- Francesca Naish & Janette Roberts
- Michel Odent
- William Sears
- Laura Shanley
- Miriam Stoppard
- David Vernon
- Erna Wright
- Robbie Davis-Floyd
- Penny Simkin
# Related Chapters
- Pre- and perinatal psychology
- Postnatal
- Lamaze
- Natalism
- Homebirth
- Unassisted childbirth
- Waterbirth
- hypnosis in childbirth
- Pre-labor | Childbirth
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Childbirth (also called labour, birth, partus or parturition) is the culmination of a human pregnancy or gestation period with the delivery of one or more newborn infants from a woman's uterus. The process of human childbirth is categorized in 3 stages of labour. In the first stage, the uterus begins rhythmic contractions which steadily increase in strength and frequency, gradually widening and thinning the cervix. During the second stage, the infant passes from the uterus, through the cervix and birth canal. In the third stage, the placenta pulls from the uterine wall and is expelled through the birth canal.[1]
# The Natural Birth
## First Stage: Contractions
Normal childbirth begins with the onset of contractions of the uterus. The frequency and duration of these contractions varies with the individual. The onset of labour may be sudden or gradual, and is defined as regular uterine activity in the presence of cervical dilatation.
During a contraction, long muscles of the uterus contract, starting at the top of the uterus and working their way down to the bottom. At the end of the contraction, the muscles relax to a state shorter than at the beginning of the contraction. This draws the cervix up over the baby's head. Each contraction dilates the cervix until it becomes completely dilated, often referred to as 10+ centimeters (cm) or 4+ inches (in) in diameter by midwives or doctors.
A gradual onset with slow cervical change towards 3 cm (just over 1 inch) dilation is referred to as the "latent phase". A woman is said to be in "active labour" when contractions have become regular in frequency (3 to 4 in 10 minutes) and about 60 seconds in duration. The cervix must shorten (efface) before it can dilate; for women giving birth for the first time, this can take a substantial period of time and can be a tiring and difficult time. However, once the cervix is effaced dilatation can occur and the downward journey of the baby can commence. The now powerful contractions are accompanied by cervical effacement and dilation greater than 3 cm (1¼ in) . The labour may begin with a rupture of the amniotic sac, the paired amnion and chorion ("breaking of the water"). The contractions will strengthen and accelerate in frequency. In the "transition phase" from 8 cm–10 cm (3 or 4 in) of dilation, the contractions often come every two minutes and typically last 70–90 seconds. Transition is often regarded as the most challenging and intense for the woman. It is also the shortest phase.
During this stage, the woman giving birth typically goes through several emotional phases. At first, she may be excited and nervous. Then, as the contractions become stronger, demanding more energy from the woman, she may become more serious and focused. However, as the cervix finishes its dilation, some women experience confusion or bouts of self-doubt or giving up. It is important during this time for the birth partners to stay positive and supportive of the woman; to actively encourage if this is what she wishes and to provide nutrition and hydration in order to keep her energy reserves up.
The duration of labour varies widely, but averages some 13 hours for women giving birth to their first child ("primiparae") and 8 hours for women who have already given birth ("multiparae").
If there is a significant medical risk to continuing the pregnancy, induction may be necessary. As this carries some risk, it is only done if the fetus or the woman are in danger from prolonged pregnancy. Forty-two weeks' gestation without spontaneous labour is often said to be an indication for induction although evidence does not show improved outcomes when labour is induced for post-term pregnancies. Inducing labour increases the risk of cesarean section uterine rupture in women that have had a previous cesarean section.
## Second Stage: Delivery
In the second stage of labour, the baby is pushed through the womb through the vagina by both the uterine contractions and by the additional maternal efforts of "bearing down," which many women describe as similar in sensation to straining to expel a large bowel movement. The imminence of this stage can be evaluated by the Malinas score. In a vertex (normal head first delivery) when the top of the head is visible at the vagina or in other words the birth canal, this is called crowning (the perineum or the region between the vagina and anus could tear or needs to be cut in a procedure called episiotomy); at this point the woman may feel a burning or stinging sensation, but this soon passes (some people refer the crowning stage as 'The ring of fire').
This stage begins when the cervix is fully dilated. This can be determined by the woman's onset of her desire to 'push' or it can be determined by performing a vaginal exam.
Mechanism of Labor-(Head First) Flexion, Internal Rotation, Extension, External Rotation, Expulsion.
Flexion- When the descending head meets resistance if flexes so that the chin is brought closer to the chest. Internal Rotation- It begins at the ischial spine and is not completed until it reaches lower pelvis. Extension- When fetal head reaches perineum it is deflected anteriorly by perineum. External Rotation-After head is born it rotates 45 degrees to realign with its shoulders and back. Expulsion- After birth of shoulders, the shoulders are lifted up and trunk of body is born by flexing in laterally.
The baby is most commonly born head-first. In some cases the baby is "breech" meaning either the feet or buttocks are descending first. Babies in the breech position can be helped to be born vaginally by a midwife, although caesarean births are becoming more common for breech presentation.
There are several types of breech presentations, but the most common is where the baby's buttocks are born first and the legs are folded onto the baby's body with the knees bent and feet near the buttocks (full or breech). Others include frank breech, much like full breech but the baby's legs are extended toward its ears, and footling or incomplete breech, in which one or both legs are extended and the foot or feet are the presenting part. Another rare presentation is a transverse lie. This is where the baby is sideways in the womb and a hand or elbow has entered the birth canal first. While babies who present transverse will often move to a different position, this is not always the case and a cesarean birth then becomes necessary.
The length of the second stage varies and may be affected by whether a woman has given birth before, the position she is in and mobility. The length of the second stage should be guided by the condition of the fetus and health of the woman. Problems may be encountered at this stage due to reasons such as maternal exhaustion, the front of the baby's head facing forwards instead of backwards (posterior baby), or extremely rarely, because the baby's head does not fit properly into the woman's pelvis (Cephalo-Pelvic Disproportion (CPD)). True CPD is typically seen in women with rickets and bone deforming illnesses or injuries, as well as arbitrary time limits placed on second stage by caregivers or medical facilities.
Immediately after birth, the child undergoes extensive physiological modifications as it acclimates to independent breathing. Several cardiovascular structures start regressing soon after birth, such as the ductus arteriosus and the foramen ovale. In some cultures, the father cuts the umbilical cord and the infant is given a lukewarm bath to remove blood and some of the vernix on its skin before being handed back to its parents.
The medical condition of the child is assessed with the Apgar score, based on five parameters: heart rate, respiration, muscle tone, skin color, and response to stimuli. Apgar scores are typically assessed at both 1 and 5 minutes after birth.
## Third Stage: Placenta
In this stage, the uterus expels the placenta (afterbirth). Breastfeeding the baby will help to cause this. The woman normally loses less than 500 mL (2 cups, or 1 pint) of blood. The placenta should never be pulled from the woman by an untrained person; this could cause it to tear and not be expelled whole. It is essential that the placenta be examined to ensure that it was expelled whole. Remaining parts can cause postpartum bleeding or infection.
The alternative to natural delivery of the placenta is what is called Active Management: this involves administration of a prophylactic oxytocic before delivery of the placenta, and usually early cord clamping and cutting, and controlled cord traction of the umbilical cord.
A Cochrane database study[2] suggests strongly that blood loss and the risk of postpartum bleeding will be reduced in women offered active management of the third stage of labour. However, there was an increased risk of unpleasant side effects to the baby or mother (such as nausea or vomiting) and hypertension. The authors suggest that this is due to the use of ergometrine as a component of the oxytocic. No advantages or disadvantages were apparent for the baby.
Details of CCT are available. This procedure must not be attempted except by appropriately trained providers.
## After the Birth
Medical professionals typically recommend breastfeeding of the first milk, colostrum, to reduce postpartum bleeding/hemorrhage in the mother, and to pass immunities and other benefits to the baby.
Parents usually bestow the infant its given name soon after birth.
Often people visit and bring a gift for the baby.
Many cultures feature initiation rites for newborns, such as naming ceremonies, baptism, and others.
Mothers are often allowed a period where they are relieved of their normal duties to recover from childbirth. The length of this period varies. In China it is 30 days and is referred to as "doing the month" or "sitting month" (see Postpartum period). In other countries taking time off from work to care for a newborn is called "maternity leave" and varies from a few days to several months.
# Variations
When the amniotic sac has not ruptured during labour or pushing, the infant can be born with the membranes intact. This is referred to as "being born in the caul." The caul is harmless and its membranes are easily broken and wiped away. In medieval times, and in some cultures still today, a caul was seen as a sign of good fortune for the baby, even giving the child psychic gifts such as clairvoyance, and in some cultures was seen as protection against drowning. The caul was often impressed onto paper and stored away as an heirloom for the child. With the advent of modern interventive obstetrics, premature artificial rupture of the membranes has become common, so babies are rarely born in the caul.
# Pain
The amounts of pain experienced by women during childbirth varies. For some women, the pain is intense and agonizing; for other women there is little to no pain. Many factors affect pain perception; fear, number of previous births, fetal presentation, cultural ideas of childbirth, birthing position, support given during labor, beta-endorphin levels, and a woman's natural pain threshold. Uterine contractions are always intense during childbirth. Some women report these sensations as painful, though the degree of pain varies from individual to individual.
## Non-medical Pain Control
Some women believe that reliance on analgesic medication is unnatural, or believe that it may harm the child. They still can alleviate labour pain using psychological preparation, education, massage, hypnosis, or water therapy in a tub or shower. Some women like to have someone to support them during labour and birth, such as the woman's mother, a sister, the father of the baby, a close friend, a partner or a trained professional doula. Some women deliver in a squatting or crawling position in order to more effectively push during the second stage and so that gravity can aid the descent of the baby through the birth canal.
The human body also has its own method of pain control for labour and childbirth in the form of beta-endorphins. As a naturally occurring opiate, beta-endorphin has properties similar to pethidine, morphine, and heroin, and has been shown to work on the same receptors of the brain.[3] Like oxytocin, beta-endorphin is secreted from the pituitary gland, and high levels are present during sex, pregnancy, birth, and breastfeeding. This hormone can induce feelings of pleasure and euphoria during childbirth.[4]
Water birth is an option chosen by some women for pain relief during labour and childbirth, and some studies have shown waterbirth in an uncomplicated pregnancy to reduce the need for analgesia, without evidence of increased risk to mother or newborn.[5] The American Academy of Pediatrics still considers underwater birthing "an experimental procedure that should not be performed except within the context of an appropriately designed [randomized controlled trial] after informed parental consent."[6]
Many hospitals and birthing centres now offer women the option of waterbirth, either via custom-made 'birthing pools' or large bath tubs, and have policies to safeguard their use.
Meditation and mind medicine techniques for the use of pain control during labor and delivery. These techniques are used in conjunction with progressive muscle relaxation and many other forms of relaxation for the mind and body to aid in pain control for women during childbirth. These techniques are a form of natural pain control. One such technique is the use of hypnosis in childbirth. This technique is a form of meditation that empowers and liberates the woman by uplifting her body and its natural process to welcoming her new child into the world.
## Medical Pain Control
In some countries of Europe, doctors commonly prescribe inhaled nitrous oxide gas for pain control; in the UK, midwives may use this gas without a doctor's prescription. Pethidine (with or without promethazine) may be used early in labour, as well as other opioids, but if given too close to birth there is a risk of respiratory depression in the infant.
Popular medical pain control in hospitals include the regional anesthetics epidural blocks, and spinal anaesthesia. Doctors and many parents favor the epidural block because medication does not enter the woman's circulatory system, thus it does not cross the placenta and enter the bloodstream of the fetus. Some studies find that although epidural use can lengthen the labour and increase the need for operative intervention, it has no adverse effect on perinatal outcome, and is a safe and effective method of pain control.[7]
Different measures for pain control have varying degrees of success and side effects to the woman and her baby. The risks of medical pain control should be balanced against the fact that childbirth can be extremely painful, and anesthetics are an effective and generally safe way to control pain.
# Complications and Risks of Birth
Problems that occur during childbirth are called complications. They can affect the woman, the baby, or both. Sometimes they cause injury or even death. Doctors and midwives are trained to deal with these problems if they should occur.
Infant deaths (neonatal deaths from birth to 28 days, or perinatal deaths if including fetal deaths at 28 weeks gestation and later) are around 1% in modernized countries. The risk of maternal death during childbirth in developed nations is comparatively low; only about 1 in 1800 women die in childbirth (only 1 in 3700 in North America). In the Third World, it is a much riskier proposition: neonatal deaths rates in Sub-Saharan Africa and South Asia are more than 3.7%,[8] and on average 1 in 48 women die during childbirth.[9] The "natural" mortality rate of childbirth—where nothing is done to avert maternal death—has been estimated as being between 1,000 and 1,500 deaths per 100,000 births.[10] (See main article: neonatal death, maternal death)
The most important factors affecting mortality in childbirth are adequate nutrition and access to quality medical care ("access" is affected both by the cost of available care, and distance from health services). "Medical care" in this context does not refer specifically to treatment in hospitals, but simply routine prenatal care and the presence, at the birth, of an attendant with midwifery skills. A 1983-1989 study by the Texas Department of Health revealed that the infant death rate was 0.57% for doctor-attended births, and 0.19% for births attended by non-nurse midwives. (The comparison may be misleading because higher-risk births are less likely to be attended solely by a midwife.) Conversely, some studies demonstrate a higher perinatal mortality rate with assisted home births.[11] Around 80% of pregnancies are low-risk. Factors that may make a birth high risk include prematurity, high blood pressure, gestational diabetes and a previous cesarean section.
One of the most dangerous risks to the fetus is that of premature birth, and its associated low neonatal weight. The more premature (or underweight) a baby is, the greater the risks for neonatal death and for pulmonary, respiratory, neurological or other sequelae. About 12% of all infants born in the United States are born prematurely. In the past 25 years, medical technology has greatly improved the chances of survival of premature infants in industrialized nations. In the 1950s and 1960s, approximately half of all low birth weight babies in the US died. Today, more than 90% survive. The first hours of life for "premies" are critical, especially the very first hour of life. Rapid access to a Neonatal Intensive Care Unit is of paramount importance.
Some of the possible complications are:
- Heavy bleeding during or after childbirth, which is the most common cause of mortality in new mothers, in both developed and undeveloped nations.[8] Heavy blood loss leads to hypovolemic shock, insufficient perfusion of vital organs and death if not rapidly treated by stemming the blood loss (medically with ergometrine and pitocin or surgically) and blood transfusion. Hypopituitarism after obstetric hypovolemic shock is termed Sheehan's syndrome.
- Non-progression of labour (longterm contractions without adequate cervical dilation) is generally treated with intravenous synthetic oxytocin preparations. If this is ineffective, Caesarean section may be necessary. Changes in maternal position is effective in many cases.
- Fetal distress is the development of signs of distress by the child. These may include rising or decreasing heartbeat (monitored on cardiotocography/CTG), shedding of meconium in the amniotic fluid, and other signs.
- Non-progression of expulsion (the head or presenting parts are not delivered despite adequate contractions): this can require interventions such as vacuum extraction, forceps extraction or Caesarean section.
- In the past, a large proportion of women died from infection puerperal fever, but since the introduction of basic hygiene during parturition by Ignaz Semmelweis, this number has fallen precipitously.
- Lacerations can be painful. An episiotomy was once thought necessary to avoid tears involving the anal sphincter, but its routine use—once normal—has now been shown to increase the risk of deep lacerations especially involving and extending through the anal sphincter.
- Pelvic girdle pain. Hormones and enzymes work together to produce ligamentous relaxation and widening of the symphysis pubis during the last trimester of pregnancy. The physiologic changes of pregnancy are superimposed by the trauma of birth. During delivery, the ligaments stretch and small amounts of tearing in the fibro cartilage occurs, this tearing can be in any direction, progressively loosening the symphysis, producing cartilage nodules, cysts and reactive bone formation. For some women an event during the delivery can cause some degree of injury to the symphysis pubis or sacroiliac joint. This could be the result of:
- A large baby.
- A mid to high forceps delivery.
- Previous pelvic trauma.
- Hypermobility.
- Pelvic girdle pain during the pregnancy.
Pain is usually felt low down over the symphysis pubis; which may be extremely tender to the touch. Swelling and/or inflammation will be present. She will experience difficulty lifting leg, pain pulling legs apart, standing on one leg, transferring weight through pelvis and legs, and restriction of hip movement. Pain may also be felt in the groin, hips, sacroiliac joints and lower abdomen and can radiate down the inner thighs. The woman and may be aware of an audible 'tearing' sound coming form the pelvis during the delivery as the fibrocartilage tears apart. For women who have pain and instability they can experience mild to major disabilities.
Instrumental delivery (Forceps and Ventouse)
- The woman will have her legs apart supported in stirrups.
- If an anaesthetic is not already in place it will be given.
- For a forceps delivery an episiotomy will be done (a cut in the perineum or the region between the vagina and anus), for ventouse extraction an episiotomy is not always done.
- After the head is delivered the rest of the delivery is done in the manual method.
- After episiotomy or tears the woman is stitched up.
- In some cases a 'Trial of Forceps' will be tried out, this will be done in the operating theatre, meaning they will try a forceps delivery and will switch to a caesarean section if it fails.
# Twins and Multiple Births
Twins can be delivered vaginally. In some cases twin delivery is done in a larger delivery room or in theatre, just in case complications occur e.g.
- Both twins born vaginally - one comes normally but the other is breech and/or helped by a forceps/ventouse delivery
- One twin born vaginally and the other by caesarean section.
- If the twins are joined at any part of the body - called conjoined twins, delivery is mostly by caesarean section.
Triplets or more are always delivered by caesarean section.
# Professions Associated with Childbirth
Midwives are experts in normal birth. Midwives believe that childbirth is a normal process that is best accomplished with as little interference as possible. Midwives are trained to assist at births, either through direct-entry or nurse-midwifery programs. Lay midwives typically train in apprenticeship programs with experienced midwives.
Obstetricians are experts in dealing with abnormal births and pathological labour conditions, though they sometimes attend normal births as a precautionary measure. Obstetricians in most countries are trained as surgeons, so they can undertake surgical procedures relating to childbirth. Such procedures include caesarean sections, episiotomies, or emergency hysterectomies. Obstetricians' tendency to intervene surgically to overcome complications has led to criticism that they perform surgery too readily. In the United States, obstetric malpractice settlements are typically very large, so obstetricians argue that they are forced to intervene aggressively to limit their liability.
Maternal-fetal medicine specialists are experts in managing and treating high-risk pregnancy and delivery.
Obstetric nurses assist midwives, doctors, women, and babies prior to, during, and after the birth process. Some midwives are also obstetric nurses. Obstetric nurses hold various certifications and typically undergo additional obstetric training in addition to standard nursing training
Doulas are trained assistants who support mothers during pregnancy, labour, birth, and postpartum. They are not medical attendants; rather, they provide emotional support and non-medical pain relief for women during labour.
# Social Aspects
In most cultures, childbirth is considered to be the beginning of a person's life, and their age is defined relative to it.
Some families view the placenta as a special part of birth, since it has been the child's life support for so many months. Some parents like to see and touch this organ. In some cultures, parents plant a tree along with the placenta on the child's first birthday. The placenta may be eaten by the newborn's family, ceremonially or otherwise.
# Psychological Aspects
Childbirth can be a stressful event. As with any stressful event, strong emotions can be brought to the surface.
Some women report symptoms compatible with post-traumatic stress disorder (PTSD) after birth. Between 70 and 80% of mothers in the United States report some feelings of sadness or "baby blues" after childbirth. Postpartum depression may develop in some women; about 10% of mothers in the United States are diagnosed with this condition. Abnormal and persistent fear of childbirth is known as tokophobia.
Preventative group therapy has proven effective as a prophylactic treatment for postpartum depression.[12]
There are some who argue that childbirth is stressful for the infant. Stresses associated with breech birth, such as asphyxiation, may affect the infant's brain.
# Partner and Other Support
There is increasing evidence to show that the participation of the woman's partner in the birth leads to better birth and also post-birth outcomes, providing the partner does not exhibit excessive anxiety.[13] Research also shows that when a labouring woman was supported by a female helper such as a family member or doula during labour, she had less need for chemical pain relief, the likelihood of caesarean section was reduced, use of forceps and other instrumental deliveries were reduced and there was a reduction in the length of labour and the baby had a higher Apgar score (Dellman 2004, Vernon 2006).
It is the traditional history of home labour that makes The Netherlands an attractive site for studies related to birth. One third of all baby deliveries there are still happening at home in contrast with other western industrialized countries. Apparently, Dutch fathers have been in the scene of labor for a long time as can be observed in paintings from the 17th and 18th centuries.
During this study, it was found that fathers can have different roles during birth and that little is said about the conflicts between partners or partners and professionals. Among other findings were also: the interpretation of the presence of fathers during birth as a modern version of the anthropological couvade ritual to ease the woman's pain; the majority of fathers did not perceive any limitation to participate in their childbirth and upper generations did not play an important rule in the transmission of knowledge about birth to those fathers but the wives, feminine acquaintances and midwives.
The research was based, mainly, on in-depth interviews, where fathers described what was happening from their partner’s first signals of birth labour until the placenta delivery.
# Postnatal Care
# Well Known Authors on Childbirth
- Janet Balaskas
- Jeannine Parvati Baker
- Robert A. Bradley
- Ina May Gaskin
- Sheila Kitzinger
- Frederick Leboyer
- Francesca Naish & Janette Roberts
- Michel Odent
- William Sears
- Laura Shanley
- Miriam Stoppard
- David Vernon
- Erna Wright
- Robbie Davis-Floyd
- Penny Simkin
# Related Chapters
- Pre- and perinatal psychology
- Postnatal
- Lamaze
- Natalism
- Homebirth
- Unassisted childbirth
- Waterbirth
- hypnosis in childbirth
- Pre-labor
# External Links
- Discovery Health's Ultimate Guide to Pregnancy Tools, video, information for a healthy pregnancy. | https://www.wikidoc.org/index.php/Child_birth | |
b72926a19a62beb7bba86fdd948135bd2b33e38c | wikidoc | Stuttering | Stuttering
Synonyms and keywords: Childhood-onset fluency disorder
# Overview
Stuttering, also known as stammering in the United Kingdom, is a speech disorder in which the flow of speech is disrupted by involuntary repetitions and prolongations of sounds, syllables, words or phrases, and involuntary silent pauses or blocks in which the stutterer is unable to produce sounds. 'Verbal non-fluency' is the accepted (as an umbrella term) for such speech impediments. The term stuttering is most commonly associated with involuntary sound repetition, but it also encompasses the abnormal hesitation or pausing before speech, referred to by stutterers as blocks, and the prolongation of certain sounds, usually vowels and semi-vowels. The term "stuttering", as popularly used, covers a wide spectrum of severity: it may encompass individuals with barely perceptible impediments, for whom the disorder is largely cosmetic, as well as others with extremely severe symptoms, for whom the problem can effectively prevent most oral communication. The impact of stuttering on a person's functioning and emotional state can be severe. Much of this goes unnoticed by the listener, and may include fears of having to enunciate specific vowels or consonants, fears of being caught stuttering in social situations, self-imposed isolation, anxiety, stress, shame, or a feeling of "loss of control" during speech.
Stuttering is generally not a problem with the physical production of speech sounds or putting thoughts into words. Despite popular perceptions to the contrary, stuttering does not affect and has no bearing on intelligence. Apart from their speech impediment, people who stutter may well be 'normal' in the clinical sense of the term. Anxiety, low self-esteem, nervousness, and stress therefore do not cause stuttering per se, although they are very often the result of living with a highly stigmatized disability and, in turn, exacerbate the problem.
The disorder is also variable, which means that in certain situations, such as talking on the telephone, the stuttering might be more severe or less, depending on the anxiety level connected with that activity. Although the exact etiology of stuttering is unknown, both genetics and neurophysiology are thought to contribute. Although there are many treatments and speech therapy techniques available that may help increase fluency in some stutterers, there is essentially no "cure" for the disorder at present.
# Classification
Developmental stuttering is stuttering that originates when a child is learning to speak and develops as the child matures into adulthood. Other speech disorders with symptoms resembling stuttering are cluttering, Parkinson's speech, essential tremor, spasmodic dysphonia, selective mutism and social anxiety.
# Characteristics
## Primary behaviors
Primary stuttering behaviors are the overt, observable signs of speech fluency breakdown, including repeating sounds, syllables, words or phrases, silent blocks and prolongation of sounds. These differ in from the normal disfluencies found in all speakers in that stuttering disfluencies may last longer, occur more frequently, and are produced with more effort and strain. Stuttering disfluencies also vary in quality: normal disfluencies tend to be a repetition of words, phrases or parts of phrases, while stuttering is characterized by prolongations, blocks and part-word repetitions.
- Repetition occurs when a unit of speech, such as a sound, syllable, word, or phrase is repeated and are typical in children who are beginning to stutter. For example, "to-to-to-tomorrow".
- Prolongations are the unnatural lengthening of continuant sounds, for example,"mmmmmmmmmilk". Prolongations are also common in children beginning to stutter.
- Blocks are inappropriate cessation of sound and air, often associated with freezing of the movement of the tongue, lips and/or vocal folds. Blocks often develop later, and can be associated with muscle tension and effort.
## Secondary behaviors
Secondary stuttering behaviors are unrelated to speech production and are learned behaviors which become linked to the primary behaviors.
Secondary behaviors include escape behaviors, in which a stutterer attempts to terminate a moment of stuttering. Examples might be physical movements such as sudden loss of eye contact, eye-blinking, head jerks, hand tapping, interjected "starter" sounds and words, such as "um," "ah," "you know". In many cases, these devices work at first, and are therefore reinforced, becoming a habit that is subsequently difficult to break.
Secondary behaviors also refer to the use of avoidance strategies such avoiding specific words, people or situations that the person finds difficult. Some stutterers successfully use extensive avoidance of situations and words to maintain fluency and may have little or no evidence of primary stuttering behaviors. Such covert stutterers may have high levels of anxiety, and extreme fear of even the most mild disfluency.
## Variability
The severity of a stutter is often not constant even for severe stutterers. Stutterers commonly report dramatically increased fluency when talking in unison with another speaker, copying another's speech, whispering, singing, and acting or when talking to pets, young children, or themselves. Other situations, such as public speaking and speaking on the telephone are often greatly feared by stutterers, and increased stuttering is reported.
## Feelings and attitudes
Stuttering may have a significant negative cognitive and affective impact on the stutterer. In a famous analogy, Joseph Sheehan, a prominent researcher in the field, compared stuttering to an iceberg], with the overt aspects of stuttering above the waterline, and the larger mass of negative emotions invisible below the surface. Feelings of embarrassment, shame, frustration, fear, anger, and guilt are frequent in stutterers, and may actually increase tension and effort, leading to increased stuttering. With time, continued exposure to difficult speaking experiences may crystallize into a negative self-concept and self-image. A stutterer may project his or her attitudes onto others, believing that they think he is nervous or stupid. Such negative feelings and attitudes may need to be a major focus of a treatment program.
# Sub-types
## Developmental
Stuttering is typically a developmental disorder beginning in early childhood and continuing into adulthood in at least 20% of affected children. The mean onset of stuttering is 30 months. Although there is variability, early stuttering behaviours usually consist of word or syllable repetitions, and secondary behaviours such as tension, avoidance or escape behaviours are absent. Most young children are unaware of the interruptions in their speech. With early stutterers, disfluency may be episodic, and periods of stuttering are followed by periods of relative fluency.
Though the rate of early recovery is very high, with time a young stutterer may transition from easy, relaxed repetition to more tense and effortful stuttering, including blocks and prolongations. Some propose that parental reaction may affect the development of chronic stutter. Recommendations to slow down, take a breath, say it again, etc may increase the child’s anxiety and fear, leading to more difficulties with speaking and, in the “cycle of stuttering” to ever yet more fear, anxiety and expectation of stuttering. With time secondary stuttering including escape behaviours such eye blinking, lip movements, etc. may be used, as well as fear and avoidance of sounds, words, people, or speaking situations. Eventually, many become fully aware of their disorder and begin to identify themselves as "stutterers." With this may come deeper frustration, embarrassment and shame. Other, rarer, patterns of stuttering development have been described, including sudden onset with the child being unable to speak, despite attempts to do so. The child usually blocks silently of the first sound of a sentence, and shows high levels of awareness and frustration. Another variety also begins suddenly with frequent word and phrase repetition, and do not develop secondary stuttering behaviours.
## Acquired
In rare cases, stuttering may be acquired in adulthood as the result of a neurological event such as a head injury, tumour, stroke or drug abuse/misuse. The stuttering has different characteristics from its developmental equivalent: it tends to be limited to part-word or sound repetitions, and is associated with a relative lack of anxiety and secondary stuttering behaviors. Techniques such as altered auditory feedback (see below) which may promote fluency in stutterers with the developmental condition, are not effective with the acquired type.
Psychogenic stuttering may also arise after a traumatic experience such as a bereavement, the breakup of a relationship or as the psychological reaction to physical trauma. Its symptoms tend to be homogeneous: the stuttering is of sudden onset and associated with a significant event, it is constant and uninfluenced by different speaking situations, and there is little awareness or concern shown by the speaker.
# Causes of Developmental Stuttering
No single, exclusive cause of developmental stuttering is known. A variety of hypotheses and theories suggest multiple factors contributing to stuttering.
Among these is the strong evidence that stuttering has a genetic basis. Children who have first-degree relatives who stutter are three times as likely to develop a stutter. However, twin and adoption studies suggest that genetic factors interact with environmental factors for stuttering to occur, and forty to seventy percent of stutterers have no family history of the disorder.
There is evidence that stuttering is more common in children who also have concomitant speech, language, learning or motor difficulties.
In some stutterers, congenital factors may play a role. These may include physical trauma at or around birth, including cerebral palsy, retardation, or stressful situations, such as the birth of a sibling, moving, or a sudden growth in linguistic ability.
There is clear empirical evidence for structural and functional differences in the brains of stutterers. Research is complicated somewhat by the possibility that such differences could be the consequences of stuttering rather than a cause, but recent research on older children confirm structural differences thereby giving strength to the argument that at least some of the differences are not a consequence of stuttering.
Auditory processing deficits have also been proposed as a cause of stuttering. Stuttering is less prevalent in deaf and hard of hearing individuals, and stuttering may be improved when auditory feedback is altered, such as masking, delayed auditory feedback (DAF), or frequency altered feedback. There is some evidence that the functional organization of the auditory cortex may be different in stutterers.
There is evidence of differences in linguistic processing between stutterers and non-stutterers. Brain scans of adult stutterers have found increased activation of the right hemisphere, which is associated with emotions, than in the left hemisphere, which is associated with speech. In addition reduced activation in the left auditory cortex has been observed.
The capacities and demands model has been proposed to account for the heterogeneity of the disorder. In this approach, speech performance varies depending on the capacity that the individual has for producing fluent speech, and the demands placed upon the person by the speaking situation. Capacity for fluent speech, which may affected by a predisposition to the disorder, auditory processing or motor speech deficits, and cognitive or affective issues. Demands may be increased by internal factors such as lack of confidence or self esteem or inadequate language skills or external factors such as peer pressure, time pressure, stressful speaking situations, insistence on perfect speech etc. In stuttering, the severity of the disorder is seen as likely to increase when demands placed on the person's speech and language system is exceeded by their capacity to deal with these pressures.
# Differential Diagnosis
- Adult-onset dysfluencies
- Medication side effects
- Normal speech dysfluencies
- Sensory deficits
- Tourette’s disorder
# Epidemiology
The lifetime prevalence, or the proportion of individuals expected to stutter at one time in their lives, is about 5%, and overall males are affected two to five times more often than females. Most stuttering begins in early childhood and according studies suggest 2.5% of children under the age of 5 stutter. The sex ratio appears to widen as children grow: among preschoolers, boys who stutter outnumber girls who stutter about two to one, or less. but widens to three to one at first grade and five to one at fifth grade, due to higher recovery rates in girls. Due to high (approximately 65–75%) rates of early recovery, the overall prevalence of stuttering is generally considered to be approximately 1%.
Stuttering occurs in all cultures and races, and at similar rates. A US-based study indicated that there were no racial or ethnic differences in the incidence of stuttering in preschool children. Summarizing prevalence studies, E. Cooper and C. Cooper conclude: “On the basis of the data currently available, it appears the prevalence of fluency disorders varies among the cultures of the world, with some indications that the prevalence of fluency disorders labeled as stuttering is higher among black populations than white or Asian populations” (Cooper & Cooper, 1993:197)
# Risk Factors
- First-degree biological relatives with stuttering
# Diagnosis
## Diagnostic criteria
### DSM-V Diagnostic Criteria for Stuttering
# Treatment
## Fluency shaping therapy
Fluency shaping therapy, also known as "speak more fluently", "prolonged speech" or "connected speech", trains stutterers to speak fluently by controlling their breathing, phonation, and articulation (lips, jaw, and tongue). It is based on operant conditioning techniques.
Stutterers are trained to reduce their speaking rate by stretching vowels and consonants, and using other fluency techniques such as continuous airflow and soft speech contacts. The result is very slow, monotonic, but fluent speech used only in the speech clinic. After the stutterer masters these fluency skills, the speaking rate and intonation are increased gradually. This more normal-sounding, fluent speech is then transferred to daily life outside the speech clinic, though lack of speech naturalness at the end of treatment remains a frequent criticism. Fluency shaping approaches are often taught in intensive group therapy programs, which may take two to three weeks to complete, but more recently the Camperdown program, using a much shorter schedule, has been shown to be effective.
## Stuttering modification therapy
The goal of stuttering modification therapy is not to eliminate stuttering but to modify it so that stuttering is easier and less effortful. The rationale is that since fear and anxiety causes increased stuttering, using easier stuttering and with less fear and avoidance, stuttering will decrease. The most widely known approach was published by Charles Van Riper in 1973 and is also known as block modification therapy.
As proposed by Van Riper, stuttering modification therapy has four overlapping stages:
- In the first stage, called identification, the stutterer and clinician identify the core behaviors, secondary behaviors, and feelings and attitudes that characterize the stuttering.
- In the second stage, called desensitization, the stutterer works to reduce fear and anxiety by freezing stuttering behaviors, confronting difficult sounds, words and situations, and intentionally stuttering ("voluntary stuttering").
- In the third stage, called modification, the stutterer learns "easy stuttering." This is done by "cancellations" (stopping in a dysfluency, pausing a few moments, and saying the word again); "pull-outs," or pulling out of a dysfluency into fluent speech; and "preparatory sets," or looking ahead for words one may stutter on, and using "easy stuttering" on those words.
- In the fourth stage, called stabilization, the stutterer prepares practice assignments, makes preparatory sets and pull-outs automatic, and changes their self-concept from being a person who stutters to being a person who speaks fluently most of the time but who occasionally stutters mildly.
## Electronic fluency devices
Altered auditory feedback, so that stutterers hear their voice differently, have been used for over 50 years in the treatment of stuttering. Altered auditory feedback effect can be produced by speaking in chorus with another person, by providing blocking out the stutterer's voice while talking (masking), by delaying the stutterer's voice slightly (delayed auditory feedback) and/or by altering the frequency of the feedback (frequency altered feedback). Studies of these techniques have had mixed results, with some stutterers showing substantial reductions in stuttering, while others improved only slightly or not at all. In a 2006 review of the efficacy of stuttering treatments, none of the studies on altered auditory feedback met the criteria for experimental quality, such as the presence of control groups.
## Anti-stuttering medications
The effectiveness of pharmacological agents, such as anti-convulsants, anti-depressants, antipsychotic and antihypertensive medications, and dopamine antagonists in the treatment of stuttering has been evaluated in studies involving both adults and children.
A comprehensive review of pharmacological treatments of stuttering in 2006 concluded that few of the drug trials were methodologically sound. Of those that were, only one, not unflawed study, showed a reduction in the frequency stuttering to less than 5% of words spoken. In addition, potentially serious side effects of pharmacological treatments were noted.
## Support Groups and the Self-Help Movement
With existing behavioral, prosthetic, and pharmaceutical treatments providing limited relief from the overt symptoms of stuttering, support groups and the self-help movement continues to gain popularity and support by professionals and people who stutter. One of the basic tenets behind the self-help movement is that since a cure does not exist, quality of living can be improved by improved acceptance of self and stuttering.
# Prognosis
Among preschoolers, the prognosis for recovery is good. Based on research, about 65% of preschoolers who stutter recover spontaneously in the first two years of stuttering, and about 74% recover by their early teens. In particular, girls seem to recover well. For others, early intervention is effective in helping the child achieve normal fluency.
Once stuttering has become established, and the child has developed secondary behaviors, the prognosis is more guarded, and only 18% of children who stutter after five years recover spontaneously. However, with treatment young children may be left with little evidence of stuttering.
With adult stutterers, there is no known cure, though they may make partial recovery with intervention. Stutterers often learn to stutter less severely and be less affected emotionally, though others may make no progress with therapy.
# Related Chapters
- Developmental dysfluency
- Dyslexia
- Speech processing
- Basal ganglia | Stuttering
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
Synonyms and keywords: Childhood-onset fluency disorder
# Overview
Stuttering, also known as stammering in the United Kingdom, is a speech disorder in which the flow of speech is disrupted by involuntary repetitions and prolongations of sounds, syllables, words or phrases, and involuntary silent pauses or blocks in which the stutterer is unable to produce sounds. 'Verbal non-fluency' is the accepted (as an umbrella term) for such speech impediments. The term stuttering is most commonly associated with involuntary sound repetition, but it also encompasses the abnormal hesitation or pausing before speech, referred to by stutterers as blocks, and the prolongation of certain sounds, usually vowels and semi-vowels. The term "stuttering", as popularly used, covers a wide spectrum of severity: it may encompass individuals with barely perceptible impediments, for whom the disorder is largely cosmetic, as well as others with extremely severe symptoms, for whom the problem can effectively prevent most oral communication. The impact of stuttering on a person's functioning and emotional state can be severe. Much of this goes unnoticed by the listener, and may include fears of having to enunciate specific vowels or consonants, fears of being caught stuttering in social situations, self-imposed isolation, anxiety, stress, shame, or a feeling of "loss of control" during speech.
Stuttering is generally not a problem with the physical production of speech sounds or putting thoughts into words. Despite popular perceptions to the contrary[1], stuttering does not affect and has no bearing on intelligence. Apart from their speech impediment, people who stutter may well be 'normal' in the clinical sense of the term. Anxiety, low self-esteem, nervousness, and stress therefore do not cause stuttering per se, although they are very often the result of living with a highly stigmatized disability and, in turn, exacerbate the problem.
The disorder is also variable, which means that in certain situations, such as talking on the telephone, the stuttering might be more severe or less, depending on the anxiety level connected with that activity. Although the exact etiology of stuttering is unknown, both genetics and neurophysiology are thought to contribute. Although there are many treatments and speech therapy techniques available that may help increase fluency in some stutterers, there is essentially no "cure" for the disorder at present.
# Classification
Developmental stuttering is stuttering that originates when a child is learning to speak and develops as the child matures into adulthood. Other speech disorders with symptoms resembling stuttering are cluttering, Parkinson's speech, essential tremor, spasmodic dysphonia, selective mutism and social anxiety.
# Characteristics
## Primary behaviors
Primary stuttering behaviors are the overt, observable signs of speech fluency breakdown, including repeating sounds, syllables, words or phrases, silent blocks and prolongation of sounds. These differ in from the normal disfluencies found in all speakers in that stuttering disfluencies may last longer, occur more frequently, and are produced with more effort and strain.[2] Stuttering disfluencies also vary in quality: normal disfluencies tend to be a repetition of words, phrases or parts of phrases, while stuttering is characterized by prolongations, blocks and part-word repetitions.[3]
- Repetition occurs when a unit of speech, such as a sound, syllable, word, or phrase is repeated and are typical in children who are beginning to stutter. For example, "to-to-to-tomorrow".
- Prolongations are the unnatural lengthening of continuant sounds, for example,"mmmmmmmmmilk". Prolongations are also common in children beginning to stutter.
- Blocks are inappropriate cessation of sound and air, often associated with freezing of the movement of the tongue, lips and/or vocal folds. Blocks often develop later, and can be associated with muscle tension and effort.[4]
## Secondary behaviors
Secondary stuttering behaviors are unrelated to speech production and are learned behaviors which become linked to the primary behaviors.
Secondary behaviors include escape behaviors, in which a stutterer attempts to terminate a moment of stuttering. Examples might be physical movements such as sudden loss of eye contact, eye-blinking, head jerks, hand tapping, interjected "starter" sounds and words, such as "um," "ah," "you know".[5][6] In many cases, these devices work at first, and are therefore reinforced, becoming a habit that is subsequently difficult to break.[6]
Secondary behaviors also refer to the use of avoidance strategies such avoiding specific words, people or situations that the person finds difficult. Some stutterers successfully use extensive avoidance of situations and words to maintain fluency and may have little or no evidence of primary stuttering behaviors. Such covert stutterers may have high levels of anxiety, and extreme fear of even the most mild disfluency.[5]
## Variability
The severity of a stutter is often not constant even for severe stutterers. Stutterers commonly report dramatically increased fluency when talking in unison with another speaker, copying another's speech, whispering, singing, and acting or when talking to pets, young children, or themselves.[7] Other situations, such as public speaking and speaking on the telephone are often greatly feared by stutterers, and increased stuttering is reported.[8]
## Feelings and attitudes
Stuttering may have a significant negative cognitive and affective impact on the stutterer. In a famous analogy, Joseph Sheehan, a prominent researcher in the field, compared stuttering to an iceberg], with the overt aspects of stuttering above the waterline, and the larger mass of negative emotions invisible below the surface.[9] Feelings of embarrassment, shame, frustration, fear, anger, and guilt are frequent in stutterers,[10] and may actually increase tension and effort, leading to increased stuttering.[11] With time, continued exposure to difficult speaking experiences may crystallize into a negative self-concept and self-image. A stutterer may project his or her attitudes onto others, believing that they think he is nervous or stupid. Such negative feelings and attitudes may need to be a major focus of a treatment program.[11]
# Sub-types
## Developmental
Stuttering is typically a developmental disorder beginning in early childhood and continuing into adulthood in at least 20% of affected children.[12][13] The mean onset of stuttering is 30 months.[14] Although there is variability, early stuttering behaviours usually consist of word or syllable repetitions, and secondary behaviours such as tension, avoidance or escape behaviours are absent.[15] Most young children are unaware of the interruptions in their speech.[15] With early stutterers, disfluency may be episodic, and periods of stuttering are followed by periods of relative fluency.[16]
Though the rate of early recovery is very high,[12] with time a young stutterer may transition from easy, relaxed repetition to more tense and effortful stuttering, including blocks and prolongations.[15] Some propose that parental reaction may affect the development of chronic stutter. Recommendations to slow down, take a breath, say it again, etc may increase the child’s anxiety and fear, leading to more difficulties with speaking and, in the “cycle of stuttering” to ever yet more fear, anxiety and expectation of stuttering.[17] With time secondary stuttering including escape behaviours such eye blinking, lip movements, etc. may be used, as well as fear and avoidance of sounds, words, people, or speaking situations. Eventually, many become fully aware of their disorder and begin to identify themselves as "stutterers." With this may come deeper frustration, embarrassment and shame.[18] Other, rarer, patterns of stuttering development have been described, including sudden onset with the child being unable to speak, despite attempts to do so.[19] The child usually blocks silently of the first sound of a sentence, and shows high levels of awareness and frustration. Another variety also begins suddenly with frequent word and phrase repetition, and do not develop secondary stuttering behaviours.[20]
## Acquired
In rare cases, stuttering may be acquired in adulthood as the result of a neurological event such as a head injury, tumour, stroke or drug abuse/misuse. The stuttering has different characteristics from its developmental equivalent: it tends to be limited to part-word or sound repetitions, and is associated with a relative lack of anxiety and secondary stuttering behaviors. Techniques such as altered auditory feedback (see below) which may promote fluency in stutterers with the developmental condition, are not effective with the acquired type.[13][12][21]
Psychogenic stuttering may also arise after a traumatic experience such as a bereavement, the breakup of a relationship or as the psychological reaction to physical trauma. Its symptoms tend to be homogeneous: the stuttering is of sudden onset and associated with a significant event, it is constant and uninfluenced by different speaking situations, and there is little awareness or concern shown by the speaker.[22]
# Causes of Developmental Stuttering
No single, exclusive cause of developmental stuttering is known. A variety of hypotheses and theories suggest multiple factors contributing to stuttering.[12]
Among these is the strong evidence that stuttering has a genetic basis.[23] Children who have first-degree relatives who stutter are three times as likely to develop a stutter.[24] However, twin and adoption studies suggest that genetic factors interact with environmental factors for stuttering to occur,[25] and forty to seventy percent of stutterers have no family history of the disorder.[26]
There is evidence that stuttering is more common in children who also have concomitant speech, language, learning or motor difficulties.[27]
In some stutterers, congenital factors may play a role. These may include physical trauma at or around birth, including cerebral palsy, retardation, or stressful situations, such as the birth of a sibling, moving, or a sudden growth in linguistic ability.[25][23]
There is clear empirical evidence for structural and functional differences in the brains of stutterers. Research is complicated somewhat by the possibility that such differences could be the consequences of stuttering rather than a cause, but recent research on older children confirm structural differences thereby giving strength to the argument that at least some of the differences are not a consequence of stuttering.[28][29]
Auditory processing deficits have also been proposed as a cause of stuttering. Stuttering is less prevalent in deaf and hard of hearing individuals,[30] and stuttering may be improved when auditory feedback is altered, such as masking, delayed auditory feedback (DAF), or frequency altered feedback.[31][12] There is some evidence that the functional organization of the auditory cortex may be different in stutterers.[12]
There is evidence of differences in linguistic processing between stutterers and non-stutterers.[32] Brain scans of adult stutterers have found increased activation of the right hemisphere, which is associated with emotions, than in the left hemisphere, which is associated with speech. In addition reduced activation in the left auditory cortex has been observed.[12][25]
The capacities and demands model has been proposed to account for the heterogeneity of the disorder. In this approach, speech performance varies depending on the capacity that the individual has for producing fluent speech, and the demands placed upon the person by the speaking situation. Capacity for fluent speech, which may affected by a predisposition to the disorder, auditory processing or motor speech deficits, and cognitive or affective issues. Demands may be increased by internal factors such as lack of confidence or self esteem or inadequate language skills or external factors such as peer pressure, time pressure, stressful speaking situations, insistence on perfect speech etc. In stuttering, the severity of the disorder is seen as likely to increase when demands placed on the person's speech and language system is exceeded by their capacity to deal with these pressures.[33]
# Differential Diagnosis
- Adult-onset dysfluencies
- Medication side effects
- Normal speech dysfluencies
- Sensory deficits
- Tourette’s disorder[34]
# Epidemiology
The lifetime prevalence, or the proportion of individuals expected to stutter at one time in their lives, is about 5%,[35] and overall males are affected two to five times more often than females.[36][13][37] Most stuttering begins in early childhood and according studies suggest 2.5% of children under the age of 5 stutter.[38][39] The sex ratio appears to widen as children grow: among preschoolers, boys who stutter outnumber girls who stutter about two to one, or less.[39][37] but widens to three to one at first grade and five to one at fifth grade,[40] due to higher recovery rates in girls.[41] Due to high (approximately 65–75%) rates of early recovery,[36][42] the overall prevalence of stuttering is generally considered to be approximately 1%.[43][13]
Stuttering occurs in all cultures and races,[23] and at similar rates.[13] A US-based study indicated that there were no racial or ethnic differences in the incidence of stuttering in preschool children.[38][39] Summarizing prevalence studies, E. Cooper and C. Cooper conclude: “On the basis of the data currently available, it appears the prevalence of fluency disorders varies among the cultures of the world, with some indications that the prevalence of fluency disorders labeled as stuttering is higher among black populations than white or Asian populations” (Cooper & Cooper, 1993:197)
# Risk Factors
- First-degree biological relatives with stuttering[34]
# Diagnosis
## Diagnostic criteria
### DSM-V Diagnostic Criteria for Stuttering[44]
# Treatment
## Fluency shaping therapy
Fluency shaping therapy, also known as "speak more fluently", "prolonged speech" or "connected speech", trains stutterers to speak fluently by controlling their breathing, phonation, and articulation (lips, jaw, and tongue). It is based on operant conditioning techniques.[45]
Stutterers are trained to reduce their speaking rate by stretching vowels and consonants, and using other fluency techniques such as continuous airflow and soft speech contacts. The result is very slow, monotonic, but fluent speech used only in the speech clinic. After the stutterer masters these fluency skills, the speaking rate and intonation are increased gradually. This more normal-sounding, fluent speech is then transferred to daily life outside the speech clinic, though lack of speech naturalness at the end of treatment remains a frequent criticism. Fluency shaping approaches are often taught in intensive group therapy programs, which may take two to three weeks to complete, but more recently the Camperdown program, using a much shorter schedule, has been shown to be effective.[46]
## Stuttering modification therapy
The goal of stuttering modification therapy is not to eliminate stuttering but to modify it so that stuttering is easier and less effortful.[47] The rationale is that since fear and anxiety causes increased stuttering, using easier stuttering and with less fear and avoidance, stuttering will decrease. The most widely known approach was published by Charles Van Riper in 1973 and is also known as block modification therapy.[48]
As proposed by Van Riper, stuttering modification therapy has four overlapping stages:[49]
- In the first stage, called identification, the stutterer and clinician identify the core behaviors, secondary behaviors, and feelings and attitudes that characterize the stuttering.
- In the second stage, called desensitization, the stutterer works to reduce fear and anxiety by freezing stuttering behaviors, confronting difficult sounds, words and situations, and intentionally stuttering ("voluntary stuttering").
- In the third stage, called modification, the stutterer learns "easy stuttering." This is done by "cancellations" (stopping in a dysfluency, pausing a few moments, and saying the word again); "pull-outs," or pulling out of a dysfluency into fluent speech; and "preparatory sets," or looking ahead for words one may stutter on, and using "easy stuttering" on those words.
- In the fourth stage, called stabilization, the stutterer prepares practice assignments, makes preparatory sets and pull-outs automatic, and changes their self-concept from being a person who stutters to being a person who speaks fluently most of the time but who occasionally stutters mildly.
## Electronic fluency devices
Template:Seealso
Altered auditory feedback, so that stutterers hear their voice differently, have been used for over 50 years in the treatment of stuttering.[50] Altered auditory feedback effect can be produced by speaking in chorus with another person, by providing blocking out the stutterer's voice while talking (masking), by delaying the stutterer's voice slightly (delayed auditory feedback) and/or by altering the frequency of the feedback (frequency altered feedback). Studies of these techniques have had mixed results, with some stutterers showing substantial reductions in stuttering, while others improved only slightly or not at all.[50] In a 2006 review of the efficacy of stuttering treatments, none of the studies on altered auditory feedback met the criteria for experimental quality, such as the presence of control groups.[51]
## Anti-stuttering medications
The effectiveness of pharmacological agents, such as anti-convulsants, anti-depressants, antipsychotic and antihypertensive medications, and dopamine antagonists in the treatment of stuttering has been evaluated in studies involving both adults and children.[52]
A comprehensive review of pharmacological treatments of stuttering in 2006 concluded that few of the drug trials were methodologically sound.[52] Of those that were, only one, not unflawed study,[53] showed a reduction in the frequency stuttering to less than 5% of words spoken. In addition, potentially serious side effects of pharmacological treatments were noted.[52]
## Support Groups and the Self-Help Movement
With existing behavioral, prosthetic, and pharmaceutical treatments providing limited relief from the overt symptoms of stuttering, support groups and the self-help movement continues to gain popularity and support by professionals and people who stutter. One of the basic tenets behind the self-help movement is that since a cure does not exist, quality of living can be improved by improved acceptance of self and stuttering.
# Prognosis
Among preschoolers, the prognosis for recovery is good. Based on research, about 65% of preschoolers who stutter recover spontaneously in the first two years of stuttering,[14][54] and about 74% recover by their early teens.[41] In particular, girls seem to recover well.[41][55] For others, early intervention is effective in helping the child achieve normal fluency.[56]
Once stuttering has become established, and the child has developed secondary behaviors, the prognosis is more guarded,[56] and only 18% of children who stutter after five years recover spontaneously.[57] However, with treatment young children may be left with little evidence of stuttering.[56]
With adult stutterers, there is no known cure,[41] though they may make partial recovery with intervention. Stutterers often learn to stutter less severely and be less affected emotionally, though others may make no progress with therapy.[56]
# Related Chapters
- Developmental dysfluency
- Dyslexia
- Speech processing
- Basal ganglia | https://www.wikidoc.org/index.php/Childhood-onset_fluency_disorder | |
f724b7f22728a88d5675ab9a07a59c13371cdd91 | wikidoc | Chimpanzee | Chimpanzee
# Overview
Chimpanzee, often shortened to chimp, is the common name for the two extant species of apes in the genus Pan. The better known chimpanzee is Pan troglodytes, the Common Chimpanzee, living primarily in West, and Central Africa. Its cousin, the Bonobo or "Pygmy Chimpanzee" as it is known archaically, Pan paniscus, is found in the forests of the Democratic Republic of the Congo. The Congo River forms the boundary between the two species. Chimpanzees are members of the Hominidae family, along with gorillas, humans, and orangutans, and the two chimpanzee species are the closest living relatives to humans.
# Measurements
A fully grown adult male chimpanzee can weigh from 35-70 kilograms (75-155 lb) and stand 0.9-1.2 metres (3-4 ft) tall, while females usually weigh 26-50 kg (57-110 lb) and stand 0.66-1 m (2-3½ ft) tall.
# Lifespan
Chimpanzees rarely live past the age of 40 in the wild, but have been known to reach the age of more than 60 in captivity. Cheeta, star of Tarzan is still alive as of 2008 at the age of 76, making him the oldest known chimpanzee in the world.
# Chimpanzee differences
Anatomical differences between the Common Chimpanzee and the Bonobo are slight, but in sexual and social behaviour there are marked differences. Common Chimpanzees have an omnivorous diet, a troop hunting culture based on beta males led by an alpha male, and highly complex social relationships. Bonobos, on the other hand, have a mostly frugivorous diet and an egalitarian, nonviolent, matriarchal, sexually receptive behaviour. The exposed skin of the face, hands and feet varies from pink to very dark in both species, but is generally lighter in younger individuals, darkening as maturity is reached. Bonobos have proportionately longer upper limbs and tend to walk upright more often than the Common Chimpanzee. A University of Chicago Medical Centre study has found significant genetic differences between chimpanzee populations. Different groups of Chimpanzees also have different cultural behaviour with preferences for types of tools.
# History of human interaction
Africans have had contact with chimpanzees for millennia. Chimpanzees have been kept as domesticated pets for centuries in a few African villages, especially in Congo. The first recorded contact of Europeans with chimps took place in present-day Angola during the 1600s. The diary of Portuguese explorer Duarte Pacheco Pereira (1506), preserved in the Portuguese National Archive (Torre do Tombo), is probably the first European document to acknowledge that chimpanzees built their own rudimentary tools.
The first use of the name "chimpanzee", however, did not occur until 1738. The name is derived from a Tshiluba language term "kivili-chimpenze", which is the local name for the animal and translates loosely as "mockman" or possibly just "ape". The colloquialism "chimp" was most likely coined some time in the late 1870s. Biologists applied Pan as the genus name of the animal. Chimps as well as other apes had also been purported to have been known to Western writers in ancient times, but mainly as myths and legends on the edge of Euro-Arabic societal consciousness, mainly through fragmented and sketchy accounts of European adventurers. Apes are mentioned variously by Aristotle, as well as the Bible, where apes and baboons are described as having been collected by Solomon in 1 Kings 10:22.
When chimpanzees first began arriving on the European continent, European scientists noted the inaccuracy of some ancient descriptions, which often reported that chimpanzees had horns and hooves. The first of these early transcontinental chimpanzees came from Angola and were presented as a gift to Frederick Henry, Prince of Orange in 1640, and were followed by a few of its brethren over the next several years. Scientists who examined these rare specimens were baffled, and described these first chimpanzees as "pygmies", and noted the animals' distinct similarities to humans. The next two decades would see a number of the creatures imported into Europe, mainly acquired by various zoological gardens as entertainment for visitors.
Darwin's theory of evolution (published in 1859) spurred scientific interest in chimpanzees, as in much of life science, leading eventually to numerous studies of the animals in the wild and captivity. The observers of chimpanzees at the time were mainly interested in behaviour as it related to that of humans. This was less strictly and disinterestedly scientific than it might sound, with much attention being focused on whether or not the animals had traits that could be considered 'good'; the intelligence of chimpanzees was often significantly exaggerated. At one point there was even a scheme drawn up to domesticate chimpanzees in order to have them perform various menial tasks (i.e. factory work). By the end of the 1800s chimpanzees remained very much a mystery to humans, with very little factual scientific information available.
The 20th century saw a new age of scientific research into chimpanzee behaviour. Before 1960, almost nothing was known about chimpanzee behaviour in their natural habitat. In July of that year, Jane Goodall set out to Tanzania's Gombe forest to live among the chimpanzees. Her discovery that chimpanzees made and used tools was groundbreaking, as humans were previously believed to be the only species to do so. The most progressive early studies on chimpanzees were spearheaded primarily by Wolfgang Köhler and Robert Yerkes, both of whom were renowned psychologists. Both men and their colleagues established laboratory studies of chimpanzees focused specifically on learning about the intellectual abilities of chimpanzees, particularly problem-solving. This typically involved basic, practical tests on laboratory chimpanzees, which required a fairly high intellectual capacity (such as how to solve the problem of acquiring an out-of-reach banana). Notably, Yerkes also made extensive observations of chimpanzees in the wild which added tremendously to the scientific understanding of chimpanzees and their behaviour. Yerkes studied chimpanzees until World War II, while Köhler concluded five years of study and published his famous Mentality of Apes in 1925 (which is coincidentally when Yerkes began his analyses), eventually concluding that "chimpanzees manifest intelligent behaviour of the general kind familiar in human beings ... a type of behaviour which counts as specifically human" (1925).
Common Chimpanzees have been known to attack humans on occasion. There have been many attacks in Uganda by chimpanzees against human children; the results are sometimes fatal for the children. Some of these attacks are presumed to be due to chimpanzees being intoxicated (from alcohol obtained from rural brewing operations) and mistaking human children for the Western Red Colobus, one of their favourite meals. The dangers of careless human interactions with chimpanzees are only aggravated by the fact that many chimpanzees perceive humans as potential rivals, and by the fact that the average chimpanzee has over 5 times the upper-body strength of a human male. As a result virtually any angered chimpanzee can easily overpower and potentially kill even a fully grown man, as shown by the attack and near death of former NASCAR driver Saint James Davis.
# Intelligence
Chimpanzees make tools and use them to acquire foods and for social displays; they have sophisticated hunting strategies requiring cooperation, influence and rank; they are status conscious, manipulative and capable of deception; they can learn to use symbols and understand aspects of human language including some relational syntax, concepts of number and numerical sequence. Young chimpanzees have outperformed human college students in tasks requiring remembering numbers.
## Tool use
Modern chimpanzees use tools, and recent research indicates that chimpanzee stone tool use dates to at least 4300 years ago. A recent study revealed the use of such advanced tools as spears, which Common Chimpanzees in Senegal sharpen with their teeth, being used to spear Senegal Bushbabies out of small holes in trees. Before the discovery of tool use in chimps, it was believed that humans were the only species to make and use tools, but several other tool-using species are now known.
## Altruism
Recent studies have shown that chimpanzees engage in apparently altruistic behaviour.
## Studies of language
Scientists have long been fascinated with the studies of language, as it was potentially the most uniquely human cognitive ability. To test the hypothesis of the human uniqueness of language, scientists have attempted to teach several species of great apes language. One early attempt was performed by Allen and Beatrice Gardner in the 1960s, in which they spent 51 months attempting to teach a chimpanzee, named Washoe, American Sign Language. Washoe reportedly learned 151 signs in those 51 months. Over a longer period of time, Washoe reportedly learned over 800 signs. Numerous other studies including one involving a chimpanzee named Nim Chimpsky have been conducted since with varying levels of success. There is ongoing debate among some scientists, notably Noam Chomsky and David Premack, about the great apes' ability to learn language.
## Laughter in apes
Laughter might not be confined or unique to humans, despite Aristotle's observation that "only the human animal laughs". The differences between chimpanzee and human laughter may be the result of adaptations that have evolved to enable human speech. Self-awareness of one's situation such as the monkey-mirror experiments below, or the ability to identify with another's predicament (see mirror neurons), are prerequisites for laughter, so animals may be laughing in the same way that we do.
Chimpanzees, gorillas, and orangutans show laughterlike vocalizations in response to physical contact, such as wrestling, play chasing, or tickling. This is documented in wild and captive chimpanzees. Chimpanzee laughter is not readily recognizable to humans as such, because it is generated by alternating inhalations and exhalations that sound more like breathing and panting. There are instances in which non-human primates have been reported to have expressed joy. One study analysed and recorded sounds made by human babies and bonobos (also known as pygmy chimpanzees) when tickled. It found, that although the bonobo’s laugh was a higher frequency, the laugh followed a pattern similar to that of human babies and included similar facial expressions. Humans and chimpanzees share similar ticklish areas of the body, such as the armpits and belly. The enjoyment of tickling in chimpanzees does not diminish with age.
# Chimps in laboratories
As of November 2007, there were 1,300 chimpanzees housed in 10 U.S. laboratories (out of 3,000 great apes living in captivity there), either wild-caught, or acquired from circuses, animal trainers, or zoos. Most of the labs either conduct or make the chimps available for invasive research, defined as "inoculation with an infectious agent, surgery or biopsy conducted for the sake of research and not for the sake of the chimpanzee, and/or drug testing". Two federally funded laboratories use chimps: Yerkes National Primate Research Laboratory at Emory University in Atlanta, Georgia, and the Southwest National Primate Center in San Antonio, Texas. Five hundred chimps have been retired from laboratory use in the U.S. and live in sanctuaries in the U.S. or Canada.
Chimpanzees used in biomedical research tend to be used repeatedly over decades, rather than used and killed as with most laboratory animals. Some individual chimps currently in U.S. laboratories have been used in experiments for over 40 years. According to Project R&R, a campaign to release chimps held in U.S. labs — run by the New England Anti-Vivisection Society in conjunction with Jane Goodall and other primate researchers — the oldest known chimp in a U.S. lab is Wenka, who was born in a laboratory in Florida on May 21, 1954. She was removed from her mother on the day of birth to be used in a vision experiment that lasted 17 months, then sold as a pet to a family in North Carolina. She was returned to the Yerkes National Primate Research Center in 1957 when she became too big to handle. Since then, she has given birth six times, and has been used in research into alcohol use, oral contraceptives, ageing, and cognitive studies.
With the publication of the chimpanzee genome, there are reportedly plans to increase the use of chimps in labs, with some scientists arguing that the federal moratorium on breeding chimps for research should be lifted. A five-year moratorium was imposed by the U.S. National Institutes of Health (NIH) in 1996, because too many chimps had been bred for HIV research, and it has been extended annually since 2001.
Other researchers argue that chimps are unique animals and either should not be used in research, or should be treated differently. Pascal Gagneux, an evolutionary biologist and primate expert at the University of California, San Diego, argues that, given chimpanzees' sense of self, tool use, and genetic similarity to human beings, studies using chimps should follow the ethical guidelines that are used for human subjects unable to give consent. Stuart Zola, director of the Yerkes National Primate Research Laboratory, disagrees. He told National Geographic: "I don't think we should make a distinction between our obligation to treat humanely any species, whether it's a rat or a monkey or a chimpanzee. No matter how much we may wish it, chimps are not human."
An increasing number of governments are enacting a Great Ape research ban forbidding the use of chimpanzees and other great apes in research or toxicology testing. As of 2006, Austria, New Zealand, the Netherlands, Sweden, and the UK had introduced such bans.
# Taxonomic relationships
The genus Pan is now considered to be part of the subfamily Homininae to which humans also belong. These two species are the closest living evolutionary relatives to humans. Humans shared a common ancestor with chimpanzees five to eight million years ago. Groundbreaking research by Mary-Claire King in 1973 found 99% identical DNA between human beings and chimpanzees, although research since has modified that finding to about 94% commonality, with at least some of the difference occurring in 'junk' DNA. It has even been proposed that troglodytes and paniscus belong with sapiens in the genus Homo, rather than in Pan. One argument for this is that other species have been reclassified to belong to the same genus on the basis of less genetic similarity than that between humans and chimpanzees.
A study published by Clark and Nielsen of Cornell University in the December 2003 issue of the journal Science highlights differences related to one of humankind's defining qualities — the ability to understand language and to communicate through speech. These macro-phenotypic differences, however, may owe less to physiology than might be assumed given that Homo sapiens developed modern cultural features long after the modern physiological features were in place and indeed competed averagely against other species of Homo with regard to tools, etc. for many millennia. Differences also exist in the genes for smell, in genes that regulate the metabolism of amino acids and in genes that may affect the ability to digest various proteins. See the history of hominoid taxonomy for more about the history of the classification of chimpanzees. See Human evolutionary genetics for more information on the speciation of humans and great apes.
## Fossils
Many human fossils have been found, but chimpanzee fossils were not described until 2005. Existing chimpanzee populations in West and Central Africa do not overlap with the major human fossil sites in East Africa. However, chimpanzee fossils have now been reported from Kenya. This would indicate that both humans and members of the Pan clade were present in the East African Rift Valley during the Middle Pleistocene. | Chimpanzee
# Overview
Chimpanzee, often shortened to chimp, is the common name for the two extant species of apes in the genus Pan. The better known chimpanzee is Pan troglodytes, the Common Chimpanzee, living primarily in West, and Central Africa. Its cousin, the Bonobo or "Pygmy Chimpanzee" as it is known archaically, Pan paniscus, is found in the forests of the Democratic Republic of the Congo. The Congo River forms the boundary between the two species.[2] Chimpanzees are members of the Hominidae family, along with gorillas, humans, and orangutans, and the two chimpanzee species are the closest living relatives to humans.
# Measurements
A fully grown adult male chimpanzee can weigh from 35-70 kilograms (75-155 lb) and stand 0.9-1.2 metres (3-4 ft) tall, while females usually weigh 26-50 kg (57-110 lb) and stand 0.66-1 m (2-3½ ft) tall.
# Lifespan
Chimpanzees rarely live past the age of 40 in the wild, but have been known to reach the age of more than 60 in captivity. Cheeta, star of Tarzan is still alive as of 2008 at the age of 76, making him the oldest known chimpanzee in the world.[3]
# Chimpanzee differences
Anatomical differences between the Common Chimpanzee and the Bonobo are slight, but in sexual and social behaviour there are marked differences. Common Chimpanzees have an omnivorous diet, a troop hunting culture based on beta males led by an alpha male, and highly complex social relationships. Bonobos, on the other hand, have a mostly frugivorous diet and an egalitarian, nonviolent, matriarchal, sexually receptive behaviour.[4] The exposed skin of the face, hands and feet varies from pink to very dark in both species, but is generally lighter in younger individuals, darkening as maturity is reached. Bonobos have proportionately longer upper limbs and tend to walk upright more often than the Common Chimpanzee. A University of Chicago Medical Centre study has found significant genetic differences between chimpanzee populations.[5] Different groups of Chimpanzees also have different cultural behaviour with preferences for types of tools.[6]
# History of human interaction
Africans have had contact with chimpanzees for millennia. Chimpanzees have been kept as domesticated pets for centuries in a few African villages, especially in Congo. The first recorded contact of Europeans with chimps took place in present-day Angola during the 1600s. The diary of Portuguese explorer Duarte Pacheco Pereira (1506), preserved in the Portuguese National Archive (Torre do Tombo), is probably the first European document to acknowledge that chimpanzees built their own rudimentary tools.
The first use of the name "chimpanzee", however, did not occur until 1738. The name is derived from a Tshiluba language term "kivili-chimpenze", which is the local name for the animal and translates loosely as "mockman" or possibly just "ape". The colloquialism "chimp" was most likely coined some time in the late 1870s[citation needed]. Biologists applied Pan as the genus name of the animal. Chimps as well as other apes had also been purported to have been known to Western writers in ancient times, but mainly as myths and legends on the edge of Euro-Arabic societal consciousness, mainly through fragmented and sketchy accounts of European adventurers. Apes are mentioned variously by Aristotle, as well as the Bible, where apes and baboons are described as having been collected by Solomon in 1 Kings 10:22.
When chimpanzees first began arriving on the European continent, European scientists noted the inaccuracy of some ancient descriptions, which often reported that chimpanzees had horns and hooves[citation needed]. The first of these early transcontinental chimpanzees came from Angola and were presented as a gift to Frederick Henry, Prince of Orange in 1640, and were followed by a few of its brethren over the next several years. Scientists who examined these rare specimens were baffled[citation needed], and described these first chimpanzees as "pygmies", and noted the animals' distinct similarities to humans. The next two decades would see a number of the creatures imported into Europe, mainly acquired by various zoological gardens as entertainment for visitors.
Darwin's theory of evolution (published in 1859) spurred scientific interest in chimpanzees, as in much of life science, leading eventually to numerous studies of the animals in the wild and captivity. The observers of chimpanzees at the time were mainly interested in behaviour as it related to that of humans. This was less strictly and disinterestedly scientific than it might sound, with much attention being focused on whether or not the animals had traits that could be considered 'good'; the intelligence of chimpanzees was often significantly exaggerated.[citation needed] At one point there was even a scheme drawn up to domesticate chimpanzees in order to have them perform various menial tasks (i.e. factory work)[citation needed]. By the end of the 1800s chimpanzees remained very much a mystery to humans, with very little factual scientific information available.
The 20th century saw a new age of scientific research into chimpanzee behaviour. Before 1960, almost nothing was known about chimpanzee behaviour in their natural habitat. In July of that year, Jane Goodall set out to Tanzania's Gombe forest to live among the chimpanzees. Her discovery that chimpanzees made and used tools was groundbreaking, as humans were previously believed to be the only species to do so. The most progressive early studies on chimpanzees were spearheaded primarily by Wolfgang Köhler and Robert Yerkes, both of whom were renowned psychologists. Both men and their colleagues established laboratory studies of chimpanzees focused specifically on learning about the intellectual abilities of chimpanzees, particularly problem-solving. This typically involved basic, practical tests on laboratory chimpanzees, which required a fairly high intellectual capacity (such as how to solve the problem of acquiring an out-of-reach banana). Notably, Yerkes also made extensive observations of chimpanzees in the wild which added tremendously to the scientific understanding of chimpanzees and their behaviour. Yerkes studied chimpanzees until World War II, while Köhler concluded five years of study and published his famous Mentality of Apes in 1925 (which is coincidentally when Yerkes began his analyses), eventually concluding that "chimpanzees manifest intelligent behaviour of the general kind familiar in human beings ... a type of behaviour which counts as specifically human" (1925).[7]
Common Chimpanzees have been known to attack humans on occasion.[8][9] There have been many attacks in Uganda by chimpanzees against human children; the results are sometimes fatal for the children. Some of these attacks are presumed to be due to chimpanzees being intoxicated (from alcohol obtained from rural brewing operations) and mistaking human children[10] for the Western Red Colobus, one of their favourite meals.[11] The dangers of careless human interactions with chimpanzees are only aggravated by the fact that many chimpanzees perceive humans as potential rivals,[12] and by the fact that the average chimpanzee has over 5 times the upper-body strength of a human male.[13][14] As a result virtually any angered chimpanzee can easily overpower and potentially kill even a fully grown man, as shown by the attack and near death of former NASCAR driver Saint James Davis.[15][16]
# Intelligence
Chimpanzees make tools and use them to acquire foods and for social displays; they have sophisticated hunting strategies requiring cooperation, influence and rank; they are status conscious, manipulative and capable of deception; they can learn to use symbols and understand aspects of human language including some relational syntax, concepts of number and numerical sequence. [17] Young chimpanzees have outperformed human college students in tasks requiring remembering numbers.[18]
## Tool use
Modern chimpanzees use tools, and recent research indicates that chimpanzee stone tool use dates to at least 4300 years ago.[19] A recent study revealed the use of such advanced tools as spears, which Common Chimpanzees in Senegal sharpen with their teeth, being used to spear Senegal Bushbabies out of small holes in trees.[20][21] Before the discovery of tool use in chimps, it was believed that humans were the only species to make and use tools, but several other tool-using species are now known.[22][23]
## Altruism
Recent studies have shown that chimpanzees engage in apparently altruistic behaviour.[24][25]
## Studies of language
Scientists have long been fascinated with the studies of language, as it was potentially the most uniquely human cognitive ability. To test the hypothesis of the human uniqueness of language, scientists have attempted to teach several species of great apes language. One early attempt was performed by Allen and Beatrice Gardner in the 1960s, in which they spent 51 months attempting to teach a chimpanzee, named Washoe, American Sign Language. Washoe reportedly learned 151 signs in those 51 months.[26] Over a longer period of time, Washoe reportedly learned over 800 signs.[27] Numerous other studies including one involving a chimpanzee named Nim Chimpsky have been conducted since with varying levels of success. There is ongoing debate among some scientists, notably Noam Chomsky and David Premack, about the great apes' ability to learn language.
## Laughter in apes
Laughter might not be confined or unique to humans, despite Aristotle's observation that "only the human animal laughs". The differences between chimpanzee and human laughter may be the result of adaptations that have evolved to enable human speech. Self-awareness of one's situation such as the monkey-mirror experiments below, or the ability to identify with another's predicament (see mirror neurons), are prerequisites for laughter, so animals may be laughing in the same way that we do.
Chimpanzees, gorillas, and orangutans show laughterlike vocalizations in response to physical contact, such as wrestling, play chasing, or tickling. This is documented in wild and captive chimpanzees. Chimpanzee laughter is not readily recognizable to humans as such, because it is generated by alternating inhalations and exhalations that sound more like breathing and panting. There are instances in which non-human primates have been reported to have expressed joy. One study analysed and recorded sounds made by human babies and bonobos (also known as pygmy chimpanzees) when tickled. It found, that although the bonobo’s laugh was a higher frequency, the laugh followed a pattern similar to that of human babies and included similar facial expressions. Humans and chimpanzees share similar ticklish areas of the body, such as the armpits and belly. The enjoyment of tickling in chimpanzees does not diminish with age. [28]
# Chimps in laboratories
As of November 2007, there were 1,300 chimpanzees housed in 10 U.S. laboratories (out of 3,000 great apes living in captivity there), either wild-caught, or acquired from circuses, animal trainers, or zoos.[29] Most of the labs either conduct or make the chimps available for invasive research,[30] defined as "inoculation with an infectious agent, surgery or biopsy conducted for the sake of research and not for the sake of the chimpanzee, and/or drug testing".[31] Two federally funded laboratories use chimps: Yerkes National Primate Research Laboratory at Emory University in Atlanta, Georgia, and the Southwest National Primate Center in San Antonio, Texas.[32] Five hundred chimps have been retired from laboratory use in the U.S. and live in sanctuaries in the U.S. or Canada.[30]
Chimpanzees used in biomedical research tend to be used repeatedly over decades, rather than used and killed as with most laboratory animals. Some individual chimps currently in U.S. laboratories have been used in experiments for over 40 years.[33] According to Project R&R, a campaign to release chimps held in U.S. labs — run by the New England Anti-Vivisection Society in conjunction with Jane Goodall and other primate researchers — the oldest known chimp in a U.S. lab is Wenka, who was born in a laboratory in Florida on May 21, 1954. She was removed from her mother on the day of birth to be used in a vision experiment that lasted 17 months, then sold as a pet to a family in North Carolina. She was returned to the Yerkes National Primate Research Center in 1957 when she became too big to handle. Since then, she has given birth six times, and has been used in research into alcohol use, oral contraceptives, ageing, and cognitive studies.[34]
With the publication of the chimpanzee genome, there are reportedly plans to increase the use of chimps in labs, with some scientists arguing that the federal moratorium on breeding chimps for research should be lifted.[35][32] A five-year moratorium was imposed by the U.S. National Institutes of Health (NIH) in 1996, because too many chimps had been bred for HIV research, and it has been extended annually since 2001.[32]
Other researchers argue that chimps are unique animals and either should not be used in research, or should be treated differently. Pascal Gagneux, an evolutionary biologist and primate expert at the University of California, San Diego, argues that, given chimpanzees' sense of self, tool use, and genetic similarity to human beings, studies using chimps should follow the ethical guidelines that are used for human subjects unable to give consent.[32] Stuart Zola, director of the Yerkes National Primate Research Laboratory, disagrees. He told National Geographic: "I don't think we should make a distinction between our obligation to treat humanely any species, whether it's a rat or a monkey or a chimpanzee. No matter how much we may wish it, chimps are not human."[32]
An increasing number of governments are enacting a Great Ape research ban forbidding the use of chimpanzees and other great apes in research or toxicology testing.[36] As of 2006, Austria, New Zealand, the Netherlands, Sweden, and the UK had introduced such bans.[37]
# Taxonomic relationships
The genus Pan is now considered to be part of the subfamily Homininae to which humans also belong. These two species are the closest living evolutionary relatives to humans. Humans shared a common ancestor with chimpanzees five to eight million years ago.[38] Groundbreaking research by Mary-Claire King in 1973 found 99% identical DNA between human beings and chimpanzees,[39] although research since has modified that finding to about 94%[40] commonality, with at least some of the difference occurring in 'junk' DNA. It has even been proposed that troglodytes and paniscus belong with sapiens in the genus Homo, rather than in Pan. One argument for this is that other species have been reclassified to belong to the same genus on the basis of less genetic similarity than that between humans and chimpanzees.
A study published by Clark and Nielsen of Cornell University in the December 2003 issue of the journal Science highlights differences related to one of humankind's defining qualities — the ability to understand language and to communicate through speech. These macro-phenotypic differences, however, may owe less to physiology than might be assumed given that Homo sapiens developed modern cultural features long after the modern physiological features were in place and indeed competed averagely against other species of Homo with regard to tools, etc. for many millennia. Differences also exist in the genes for smell, in genes that regulate the metabolism of amino acids and in genes that may affect the ability to digest various proteins. See the history of hominoid taxonomy for more about the history of the classification of chimpanzees. See Human evolutionary genetics for more information on the speciation of humans and great apes.
## Fossils
Many human fossils have been found, but chimpanzee fossils were not described until 2005. Existing chimpanzee populations in West and Central Africa do not overlap with the major human fossil sites in East Africa. However, chimpanzee fossils have now been reported from Kenya. This would indicate that both humans and members of the Pan clade were present in the East African Rift Valley during the Middle Pleistocene.[38] | https://www.wikidoc.org/index.php/Chimpanzee | |
bde1058aa588c7ddecdfca36b8df62506448f21e | wikidoc | Chitinozoa | Chitinozoa
Chitinozoa (singular: chitinozoan, plural: chitinozoans) are a taxon of flask-shaped, organic walled marine microfossils produced by an as yet unknown animal. Common from the Ordovician to Devonian periods, the millimetre-scale organisms are found across the globe in almost all types of marine sediment, which renders them useful biostratigraphic markers.
Their bizarre form has made classification and ecological reconstruction difficult. Suggestions of protist, plant, and fungal affinities have all been entertained, although there is mounting evidence to suggest that they represent either eggs or the juvenile stage of a marine animal.
# Appearance
Chitinozoa range in length from around 50 to 2000 micrometres. They appear dark to almost opaque when viewed under an optical microscope. They often have external ornament, in the form of hairs, loops or protrusions, sometimes as large as the chamber itself. The range and complexity of ornament displayed increased with time against a backdrop of decreasing organism size, with the earliest Ordovician species being large and smooth-walled; by the mid-Ordovician a large and expanding variety of ornament, and of hollow appendages, was evident. While shorter appendages are generally solid, larger protrusions tend to be hollow, with some of the largest displaying a spongy internal structure. However, even hollow appendages leave no mark on the inner wall of the organisms: this may suggest that they were secreted or attached from the outside. There is some debate about the number of layers present in the organisms' walls: up to three layers have been reported, with the internal wall often ornamented; some specimens only appear to display one. This may be a genuine phenomenon or a result of the preservational process.
"Immature" or juvenile examples of Chitinozoans have not been found; this may suggest that they didn't "grow", that they were moults (unlikely), or that the fossilisable test only formed after the developmental process was complete.
Most chitinozoans are found as isolated fossils, but chains of multiple tests, joined from aperture to base, have been reported from all genera. Very long chains tend to take the form of a spring. Occasionally, clusters or condensed chains are found, packed in an organic "cocoon".
# Classification
Alfred Eisenack's original description of the Chitinozoans placed them in three families, spanning seven genera, based on morphological grounds. Further genera were identified, at first on an annual basis, as time progressed. Eisenack's original classification has been much honed by these additional discoveries, as well as advances in microscopy. The advent of the scanning electron microscope in the 1970s allowed the improved detection of surface ornamentation which is hugely important in identification - as can be appreciated by a comparison of the images on this page. Even the light microscope image here is of far greater quality than could have been achieved earlier in the century, using poorly preserved specimens and less advanced microscopes.
The original three families proposed by Eisenack represented the best classification possible with available data, based largely on the presence or absence of chains of organisms and the chamber's shape. They have, however, since been revised as scientific advances, and the appearance of distinctive traits in disparate groups, have made construction of a "natural order," reflecting relatedness rather than similarity, more feasible. Features of the base and neck, the presence of spines, and perforations or connections are now considered to be more useful diagnostic features.
# Relationships
What are the Chitinozoans? This question has been asked since their discovery in 1930, and we are little closer to an answer today. In order to address the issue, a combination of ecological, taphonomical and practical factors have to be considered.
## Amoebæ
Eisenack's original guess was that the Chitinozoa were of the rhizopod order Testacea, since similar chitin-based tests were produced by the extant members of this group. However, the chemistry of these tests differs from that of the fossils, and modern Testacea are almost exclusively fresh-water - an extremely different environment. Within a year, he'd abandoned this initial idea.
## Photosynthesisers
Arguments put forwards by Obut (1973) proposed that the organisms were one-celled "plants", which would now be grouped into the chromalveolata; however, as mentioned previously, spines and appendages are attached from the exterior of the vessel: only animals have the cellular machinery necessary to perform such a feat. Further, no analogy for the cocoon envelope can be found in this kingdom.
## Young graptolites
The graptolites are colonial organic walled fossils which also occurred from the Ordovician to the Devonian; only part of their life cycle is known and it is not clear how they reproduced. It has been suggested that the Chitinozoa may represent the pre-sicula stages of graptolites - the period between the colony's sexual reproduction, and the formation of a new colony. This hypothesis appears to be supported by the co-occurrence of graptolite and chitinozoan fossils, whose abundances appear to mirror one another. The similar chemical composition of the fossils has been seized by both sides of the argument. Proponents suggest that the use of the same chemical framework is an indicator that the two may be related. However, this factor means that situations favouring the preservation of one will also tend to preserve the other - and preparation techniques will also favour or disfavour the two groups equally. Therefore, the apparent co-occurrence of the two fossils may merely be an artifact of their similar composition. Further doubt must creep in when the continuing abundance of chitinozoans after the middle Devonian, when graptolites were becoming increasingly rare, is taken into account.
## Eggs
The test of the Chitinozoa was fixed - there was no scope for any parts of it to move or rotate. This makes it seem likely that the tests were containers, to protect whatever was inside - whether that was a "hibernating" or encysted organism, or a clutch of hatching eggs.
There are several arguments behind an association of the chitinozoans with annelids or gastropods, and it is not impossible that the chitinozoans are a convergent phenomenon laid by both groups. In fact, the spirally coiled nature of chitinozoan chains has been used to suggest that they were laid by a spirally coiled organism, such as the gastropods; were this inference true, uncoiled chains could be to be attributed to the (straight) annelid worms or other organisms.
Recent excavations of the Soom Shale, an Ordovician konservat-lagerstätten in South Africa, have yielded chitinozoans alongside a wide range of other organisms. It has been suggested that if whatever organism created the Chitinozoa was fossilisable, it would be present in the Soom biota — from which gastropods and graptolites are notable in their absence. Most organisms present in the shale can be ruled out for a variety of reasons, but polychaete worms, Promissum conodonts and orthocone cephalopods remain as likely candidates. However, further evidence connecting chitinozoans to any of these groups is circumstantial at best.
# Ecology
It is not immediately clear what mode of life was occupied by these improbably shaped fossils, and several lines of argument must be invoked to approach an answer.
The fossils' restriction to marine sediments can be taken as sound evidence that the organisms dwelt in the Palæozoic seas - which presents three main modes of life:
- Infaunal — living within the sediment - the "burrowers"
- Benthic — dwelling upon the sea floor, perhaps anchored in place - the "sitters"
- Pelagic — free-floating in the water column - the "drifters"
An infaunal mode of life can be quickly ruled out, as the fossils are sometimes found in alignment with the depositing current; as nothing attached them to the bottom, they must have fallen from the water column.
The ornament of the chitinozoans may cast light on the question. Whilst in some cases a defensive role - by making the vessel larger, and thus less digestible by would-be predators - seems probable, it is not impossible that the protrusions may have anchored the organisms to the sea floor. However, their low-density construction makes this unlikely: perhaps more plausible is that they acted to attach to other organisms. Longer spines also make the organisms more buoyant, by decreasing their rayleigh number — it is therefore possible that at least the long-spined chitinozoans were planktonic "floaters". On the other hand, the walls of some chitinozoans were probably too thick and dense to allow them to float.
Whilst little is known about their interactions with other organisms, small holes in the tests of some chitinozoans are evidence that they were hosts to some parasites. Although some forms have been reinterpreted as "pock-marks" caused by the disintegration of the diagenetic mineral pyrite, the clustering of cylindrical holes around the chamber — where the flesh of the organism was likely to be concentrated — is evidence for a biological cause.
Amazingly, corals in Gotland with daily growth markings have been found in association with abundant chitinozoans, which allow the detection of seasonal variation in chitinozoan abundance. A peak in abundance during the late autumn months is observed, with the maxima for different species occurring on different dates. Such a pattern is also observed in modern-day tropical zooplankton. The diversity of living habits is also reflected by the depth of water, and distance from the shore, where different species are found in highest abundance; while deepish waters around 40 km from the shoreline are generally the optimal environment, some species appear to prefer very shallow water. On the whole, chitinozoans are less abundant in turbulent waters or reef environments, implying an aversion to such regimes when alive, if it is not an effect of sedimentary focusing.
# Stratigraphic application
Since Alfred Eisenack first recognised and named the group in 1930, the Chitinozoa have proven incredibly useful as as stratigraphic markers in biostratigraphy during the Ordovician, Silurian and Devonian periods. Their utility is due to the rapidity of their morphological evolution, their abundance — the most productive samples bearing almost a thousand tests per gram — and the easy identification (due largely to the large variation in shapes) and short lifetimes (<10 million years) of most species. They are also widely distributed and appear in a variety of marine depositional settings, making correlation easier; better still, they can often be recognised in even quite strongly metamorphosed rocks. However, convergence of morphological form to similar environments sometimes leads to the mistaken identification of a species in several areas separated by vast differences in space and time, but sharing a similar depositional environment; clearly, this can cause major problems if the organisms are interpreted as being the same species. Aside from the acritarchs, chitinozoans were the only reliable means of correlating palæozoic units until the late 1960s, when the detailed study of conodonts and graptolites fully unleashed their stratigraphic potential. | Chitinozoa
Chitinozoa (singular: chitinozoan, plural: chitinozoans) are a taxon of flask-shaped, organic walled marine microfossils produced by an as yet unknown animal.[2] Common from the Ordovician to Devonian periods, the millimetre-scale organisms are found across the globe in almost all types of marine sediment,[3] which renders them useful biostratigraphic markers.
Their bizarre form has made classification and ecological reconstruction difficult. Suggestions of protist, plant, and fungal affinities have all been entertained, although there is mounting evidence to suggest that they represent either eggs or the juvenile stage of a marine animal.[4]
# Appearance
Chitinozoa range in length from around 50 to 2000 micrometres.[3] They appear dark to almost opaque when viewed under an optical microscope. They often have external ornament, in the form of hairs, loops or protrusions, sometimes as large as the chamber itself. The range and complexity of ornament displayed increased with time against a backdrop of decreasing organism size, with the earliest Ordovician species being large and smooth-walled;[1] by the mid-Ordovician a large and expanding variety of ornament, and of hollow appendages, was evident. While shorter appendages are generally solid, larger protrusions tend to be hollow, with some of the largest displaying a spongy internal structure.[5] However, even hollow appendages leave no mark on the inner wall of the organisms: this may suggest that they were secreted or attached from the outside.[5] There is some debate about the number of layers present in the organisms' walls: up to three layers have been reported, with the internal wall often ornamented; some specimens only appear to display one. This may be a genuine phenomenon or a result of the preservational process.[5]
Template:Annotated image/Chitinozoan
"Immature" or juvenile examples of Chitinozoans have not been found; this may suggest that they didn't "grow", that they were moults (unlikely), or that the fossilisable test only formed after the developmental process was complete.[1]
Most chitinozoans are found as isolated fossils, but chains of multiple tests, joined from aperture to base, have been reported from all genera.[1] Very long chains tend to take the form of a spring. Occasionally, clusters or condensed chains are found, packed in an organic "cocoon".
# Classification
Alfred Eisenack's original description of the Chitinozoans placed them in three families, spanning seven genera,[6] based on morphological grounds. Further genera were identified, at first on an annual basis, as time progressed.[7] Eisenack's original classification has been much honed by these additional discoveries, as well as advances in microscopy. The advent of the scanning electron microscope in the 1970s allowed the improved detection of surface ornamentation which is hugely important in identification - as can be appreciated by a comparison of the images on this page. Even the light microscope image here is of far greater quality than could have been achieved earlier in the century, using poorly preserved specimens and less advanced microscopes.[7]
The original three families proposed by Eisenack represented the best classification possible with available data, based largely on the presence or absence of chains of organisms and the chamber's shape. They have, however, since been revised as scientific advances, and the appearance of distinctive traits in disparate groups, have made construction of a "natural order," reflecting relatedness rather than similarity, more feasible. Features of the base and neck, the presence of spines, and perforations or connections are now considered to be more useful diagnostic features.[1][7]
# Relationships
What are the Chitinozoans? This question has been asked since their discovery in 1930, and we are little closer to an answer today. In order to address the issue, a combination of ecological, taphonomical and practical factors have to be considered.
## Amoebæ
Eisenack's original guess was that the Chitinozoa were of the rhizopod order Testacea, since similar chitin-based tests were produced by the extant members of this group. However, the chemistry of these tests differs from that of the fossils, and modern Testacea are almost exclusively fresh-water - an extremely different environment. Within a year, he'd abandoned this initial idea.[3]
## Photosynthesisers
Arguments put forwards by Obut (1973) proposed that the organisms were one-celled "plants", which would now be grouped into the chromalveolata; however, as mentioned previously, spines and appendages are attached from the exterior of the vessel: only animals have the cellular machinery necessary to perform such a feat.[5] Further, no analogy for the cocoon envelope can be found in this kingdom.[8]
## Young graptolites
The graptolites are colonial organic walled fossils which also occurred from the Ordovician to the Devonian; only part of their life cycle is known and it is not clear how they reproduced. It has been suggested that the Chitinozoa may represent the pre-sicula stages of graptolites - the period between the colony's sexual reproduction, and the formation of a new colony.[1] This hypothesis appears to be supported by the co-occurrence of graptolite and chitinozoan fossils, whose abundances appear to mirror one another. The similar chemical composition of the fossils has been seized by both sides of the argument. Proponents suggest that the use of the same chemical framework is an indicator that the two may be related. However, this factor means that situations favouring the preservation of one will also tend to preserve the other - and preparation techniques will also favour or disfavour the two groups equally. Therefore, the apparent co-occurrence of the two fossils may merely be an artifact of their similar composition.[1][5] Further doubt must creep in when the continuing abundance of chitinozoans after the middle Devonian, when graptolites were becoming increasingly rare, is taken into account.[5]
## Eggs
The test of the Chitinozoa was fixed - there was no scope for any parts of it to move or rotate. This makes it seem likely that the tests were containers, to protect whatever was inside - whether that was a "hibernating" or encysted organism, or a clutch of hatching eggs.[5]
There are several arguments behind an association of the chitinozoans with annelids or gastropods,[8] and it is not impossible that the chitinozoans are a convergent phenomenon laid by both groups. In fact, the spirally coiled nature of chitinozoan chains has been used to suggest that they were laid by a spirally coiled organism, such as the gastropods; were this inference true, uncoiled chains could be to be attributed to the (straight) annelid worms or other organisms.[5]
Recent excavations of the Soom Shale, an Ordovician konservat-lagerstätten in South Africa, have yielded chitinozoans alongside a wide range of other organisms. It has been suggested that if whatever organism created the Chitinozoa was fossilisable, it would be present in the Soom biota — from which gastropods and graptolites are notable in their absence. Most organisms present in the shale can be ruled out for a variety of reasons,[4] but polychaete worms, Promissum conodonts and orthocone cephalopods remain as likely candidates. However, further evidence connecting chitinozoans to any of these groups is circumstantial at best.
# Ecology
It is not immediately clear what mode of life was occupied by these improbably shaped fossils, and several lines of argument must be invoked to approach an answer.
The fossils' restriction to marine sediments can be taken as sound evidence that the organisms dwelt in the Palæozoic seas - which presents three main modes of life:
- Infaunal — living within the sediment - the "burrowers"
- Benthic — dwelling upon the sea floor, perhaps anchored in place - the "sitters"
- Pelagic — free-floating in the water column - the "drifters"
An infaunal mode of life can be quickly ruled out, as the fossils are sometimes found in alignment with the depositing current; as nothing attached them to the bottom, they must have fallen from the water column.[5]
The ornament of the chitinozoans may cast light on the question. Whilst in some cases a defensive role - by making the vessel larger, and thus less digestible by would-be predators - seems probable, it is not impossible that the protrusions may have anchored the organisms to the sea floor. However, their low-density construction makes this unlikely:[5] perhaps more plausible is that they acted to attach to other organisms.[5] Longer spines also make the organisms more buoyant, by decreasing their rayleigh number — it is therefore possible that at least the long-spined chitinozoans were planktonic "floaters". On the other hand, the walls of some chitinozoans were probably too thick and dense to allow them to float.[5]
Whilst little is known about their interactions with other organisms, small holes in the tests of some chitinozoans are evidence that they were hosts to some parasites.[5][9][10] Although some forms have been reinterpreted as "pock-marks" caused by the disintegration of the diagenetic mineral pyrite,[11] the clustering of cylindrical holes around the chamber — where the flesh of the organism was likely to be concentrated — is evidence for a biological cause.
Amazingly, corals in Gotland with daily growth markings have been found in association with abundant chitinozoans, which allow the detection of seasonal variation in chitinozoan abundance. A peak in abundance during the late autumn months is observed, with the maxima for different species occurring on different dates.[5] Such a pattern is also observed in modern-day tropical zooplankton.[12] The diversity of living habits is also reflected by the depth of water, and distance from the shore, where different species are found in highest abundance; while deepish waters around 40 km from the shoreline are generally the optimal environment, some species appear to prefer very shallow water. On the whole, chitinozoans are less abundant in turbulent waters or reef environments, implying an aversion to such regimes when alive, if it is not an effect of sedimentary focusing.[3]
# Stratigraphic application
Since Alfred Eisenack first recognised and named the group[13] in 1930, the Chitinozoa have proven incredibly useful as as stratigraphic markers in biostratigraphy during the Ordovician, Silurian and Devonian periods. Their utility is due to the rapidity of their morphological evolution, their abundance — the most productive samples bearing almost a thousand tests per gram[3] — and the easy identification (due largely to the large variation in shapes) and short lifetimes (<10 million years) of most species. They are also widely distributed and appear in a variety of marine depositional settings, making correlation easier; better still, they can often be recognised in even quite strongly metamorphosed rocks. However, convergence of morphological form to similar environments sometimes leads to the mistaken identification of a species in several areas separated by vast differences in space and time, but sharing a similar depositional environment; clearly, this can cause major problems if the organisms are interpreted as being the same species. Aside from the acritarchs, chitinozoans were the only reliable means of correlating palæozoic units until the late 1960s, when the detailed study of conodonts and graptolites fully unleashed their stratigraphic potential.[1]
# External links
- Commission Internationale de Microflore du Paléozoique (CIMP), international commission for Palaeozoic palynology. | https://www.wikidoc.org/index.php/Chitinozoa | |
b814f3593d323a085dd42b0bed5c1b9195f8aa2b | wikidoc | Chlamydiae | Chlamydiae
# Overview
Chlamydiae is a bacterial phylum whose members are obligate intracellular pathogens. Many Chlamydiae coexist in an asymptomatic state within specific hosts, and it is widely believed that these hosts provide a natural reservoir for these species.
All Chlamydiae grow by infecting eukaryotic host cells. They are as small or smaller than many viruses. Inside the cells Chlamydiae take on an intracellular replicative form; outside of cells they survive only in an extracellular infectious form. Chlamydiae can be grown only where their host cells grow, leading to two consequences in the laboratory: Chlamydiae cannot be propagated in bacterial culture media, and Chlamydiae are most successfully isolated while still inside the host cell.
Cavalier-Smith has postulated that the Chlamydiae fall into the clade Planctobacteria in the larger clade Gracilicutes.
# History
Chlamydia-like disease affecting the eyes of people was first described in ancient Chinese and Egyptian manuscripts. A modern description of Chlamydia-like organisms was provided by Halberstaedter and von Prowazek in 1907. Chlamydial isolates cultured in the yolk sacs of embryonating eggs were obtained from a human pneumonitis outbreak in the late 1920s and early 1930s, and by the mid-20th Century isolates had been obtained from dozens of vertebrate species. The term Chlamydia (a cloak) appeared in the literature in 1945, although other names continued to be used, including Bedsonia, Miyagawanella, ornithosis-, TRIC-, and PLT-agents.
# Nomenclature
In 1966, Chlamydiae were recognized as bacteria and the genus Chlamydia was validated. The Order Chlamydiales was created by Storz and Page in 1971. Between 1989 and 1999, new families, genera, and species were recognized. The phylum Chlamydiae was established in Bergey's Manual of Systematic Bacteriology.
By 2006, genetic data for over 350 chlamydial lineages had been reported (), four chlamydial families recognized (Chlamydiaceae, Parachlamydiaceae, Simkaniaceae, and Waddliaceae), and another family proposed (Rhabdochlamydiaceae).
# Structure
Chlamydiae can be either parasites or endosymbionts, depending on the eukaryotic host and chlamydial species. The infectious, extracellular form is an elementary body (EB, a term borrowed from virologists) is electron-dense, typically 0.2-0.6 μm in diameter. The EB wall is held together with disulfide bonds. EBs that have been endocytosed by eukaryotic cells typically remain in vacuolar inclusions (a virology term), where the disulfide bonds are reduced and EBs transform into reticulate bodies, (RBs; the contents of each RB were ‘reticulated,’ i.e., homogeneous). RBs range up to 1.5 μm, take up nutrients from the host cell, and undergo multiple rounds of binary division. Binary division may involve ring structures comprised of a transitory type of peptidoglycan. Using electron microscopy, both EBs and RBs can be seen during replication in the inclusion. Inclusions do not undergo acidification or lysosomal fusion and do not correspond to canonical endocytic vesicles, being essentially dissociated from the endocytic pathway and having some similarities with recycling endosomes. After several days of replication, the RBs transform back into metabolically inactive EBs that are released through host cell rupture or fusion of the inclusion/plasma membranes. Chlamydiae are spread by aerosol or by contact and require no alternate vector.
# Genomics
Chlamydiae is a unique bacterial evolutionary group that separated from other bacteria approximately a billion years ago. Reports have varied as to whether Chlamydiae is related to Planctomycetales or Spirochaetes. Genome sequencing, however, indicates that 11% of the genes in Candidatus Protochlamydia amoebophila UWE25 and 4% in Chlamydiaceae are most similar to chloroplast, plant, and cyanobacterial genes. Comparison of ribosomal RNA genes has provided a phylogeny of known strains within Chlamydiae. The unique status of Chlamydiae has enabled the use of DNA analysis for chlamydial diagnostics.
There are three described species of chlamydiae that commonly infect humans:
- Chlamydia trachomatis, which causes the eye-disease trachoma and the sexually transmitted infection chlamydia;
- Chlamydophila pneumoniae, which causes a form of pneumonia;
- Chlamydophila psittaci, which causes psittacosis. | Chlamydiae
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chlamydiae is a bacterial phylum whose members are obligate intracellular pathogens.[1] Many Chlamydiae coexist in an asymptomatic state within specific hosts, and it is widely believed that these hosts provide a natural reservoir for these species.[2]
All Chlamydiae grow by infecting eukaryotic host cells. They are as small or smaller than many viruses. Inside the cells Chlamydiae take on an intracellular replicative form; outside of cells they survive only in an extracellular infectious form. Chlamydiae can be grown only where their host cells grow, leading to two consequences in the laboratory: Chlamydiae cannot be propagated in bacterial culture media, and Chlamydiae are most successfully isolated while still inside the host cell.
Cavalier-Smith has postulated that the Chlamydiae fall into the clade Planctobacteria in the larger clade Gracilicutes.
# History
Chlamydia-like disease affecting the eyes of people was first described in ancient Chinese and Egyptian manuscripts. A modern description of Chlamydia-like organisms was provided by Halberstaedter and von Prowazek in 1907. Chlamydial isolates cultured in the yolk sacs of embryonating eggs were obtained from a human pneumonitis outbreak in the late 1920s and early 1930s, and by the mid-20th Century isolates had been obtained from dozens of vertebrate species. The term Chlamydia (a cloak) appeared in the literature in 1945, although other names continued to be used, including Bedsonia, Miyagawanella, ornithosis-, TRIC-, and PLT-agents.
# Nomenclature
In 1966, Chlamydiae were recognized as bacteria and the genus Chlamydia was validated.[3] The Order Chlamydiales was created by Storz and Page in 1971.[4] Between 1989 and 1999, new families, genera, and species were recognized. The phylum Chlamydiae was established in Bergey's Manual of Systematic Bacteriology.[5]
By 2006, genetic data for over 350 chlamydial lineages had been reported ([2]), four chlamydial families recognized (Chlamydiaceae, Parachlamydiaceae, Simkaniaceae, and Waddliaceae), and another family proposed (Rhabdochlamydiaceae).[6][7]
# Structure
Chlamydiae can be either parasites or endosymbionts, depending on the eukaryotic host and chlamydial species. The infectious, extracellular form is an elementary body (EB, a term borrowed from virologists) is electron-dense, typically 0.2-0.6 μm in diameter. The EB wall is held together with disulfide bonds. EBs that have been endocytosed by eukaryotic cells typically remain in vacuolar inclusions (a virology term), where the disulfide bonds are reduced and EBs transform into reticulate bodies, (RBs; the contents of each RB were ‘reticulated,’ i.e., homogeneous). RBs range up to 1.5 μm, take up nutrients from the host cell, and undergo multiple rounds of binary division. Binary division may involve ring structures comprised of a transitory type of peptidoglycan.[8] Using electron microscopy, both EBs and RBs can be seen during replication in the inclusion. Inclusions do not undergo acidification or lysosomal fusion and do not correspond to canonical endocytic vesicles, being essentially dissociated from the endocytic pathway and having some similarities with recycling endosomes.[9] After several days of replication, the RBs transform back into metabolically inactive EBs that are released through host cell rupture or fusion of the inclusion/plasma membranes. Chlamydiae are spread by aerosol or by contact and require no alternate vector.
# Genomics
Chlamydiae is a unique bacterial evolutionary group that separated from other bacteria approximately a billion years ago.[10][11] Reports have varied as to whether Chlamydiae is related to Planctomycetales or Spirochaetes.[12][13] Genome sequencing, however, indicates that 11% of the genes in Candidatus Protochlamydia amoebophila UWE25 and 4% in Chlamydiaceae are most similar to chloroplast, plant, and cyanobacterial genes.[11] Comparison of ribosomal RNA genes has provided a phylogeny of known strains within Chlamydiae.[14] The unique status of Chlamydiae has enabled the use of DNA analysis for chlamydial diagnostics.[15]
There are three described species of chlamydiae that commonly infect humans:
- Chlamydia trachomatis, which causes the eye-disease trachoma and the sexually transmitted infection chlamydia;
- Chlamydophila pneumoniae, which causes a form of pneumonia;
- Chlamydophila psittaci, which causes psittacosis. | https://www.wikidoc.org/index.php/Chlamydiae | |
86a6a13859a4257d786d8c6835374f9de29b1f67 | wikidoc | Chlorobium | Chlorobium
Chlorobium is a genus of green sulfur bacteria. They are photolithotrophic oxidizers of sulfur and most notably utilise a noncyclic electron transport chain to reduce NAD+. Hydrogen sulfide is used as an electron source and carbon dioxide its carbon source.
Chlorobium species exhibit a dark green color; in a Winogradsky column, the green layer often observed is composed of Chlorobium. This genus lives in strictly anaerobic conditions below the surface of a body of water, commonly the anaerobic zone of a eutrophic lake.
The complete C. tepidum genome, which consists of 2.15 megabases (Mb), has recently been published. It synthesizes chlorophyll a and bacteriochlorophylls (BChls) a and c, of which the model organism has been used to ellucidate the biosynthesis of BChl c. Several of its carotenoid metabolic pathways (including a novel lycopene cyclase) have similar counterparts in cyanobacteria. | Chlorobium
Chlorobium is a genus of green sulfur bacteria. They are photolithotrophic oxidizers of sulfur and most notably utilise a noncyclic electron transport chain to reduce NAD+. Hydrogen sulfide is used as an electron source and carbon dioxide its carbon source.[1]
Chlorobium species exhibit a dark green color; in a Winogradsky column, the green layer often observed is composed of Chlorobium. This genus lives in strictly anaerobic conditions below the surface of a body of water, commonly the anaerobic zone of a eutrophic lake.[1]
The complete C. tepidum genome, which consists of 2.15 megabases (Mb), has recently been published.[2] It synthesizes chlorophyll a and bacteriochlorophylls (BChls) a and c, of which the model organism has been used to ellucidate the biosynthesis of BChl c.[3] Several of its carotenoid metabolic pathways (including a novel lycopene cyclase) have similar counterparts in cyanobacteria.[4][5] | https://www.wikidoc.org/index.php/Chlorobium | |
84f391607d87320f049ba481f8fe2144a4485bb1 | wikidoc | Chlorodyne | Chlorodyne
Chlorodyne was the name for one of the most famous patent medicines sold in the British Isles. It was invented in the 19th century by a Dr. J. Collis Browne, a doctor in the British Indian Army; its original purpose was in the treatment of cholera. Browne sold his formula to a pharmacist named Davenport, who advertised it widely, as a treatment for cholera, diarrhea, insomnia, neuralgia, migraines, etc. As its principal ingredients were a mixture of laudanum (an alcoholic solution of opium), tincture of cannabis, and chloroform, it readily lived up to its claims of relieving pain, as a sedative, and for the treatment of diarrhea.
# Imitations
Chlorodyne sold extremely well for many years; as its active ingredients were well known, local chemists' shops would also make up cheaper generic versions for sale to their customers. Here is an example of such a generic formulation, from Materia Medica by William Hale-White & A.H. Douthwaite, 21st edition (1932):
"Tinctura Chloroformi et Morphinæ Composita intended to be an imitation of the proprietary medicine called chlorodyne. Mix chloroform 75, tincture of capsicum 25, tincture of Indian hemp 100, oil of peppermint 2 and glycerin 250 with alcohol (20 per cent) 450. Dissolve morphine hydrochloride 10 in the mixture. Add to it diluted hydrocyanic acid 50 and enough alcohol (90 per cent) to make 1000. Strength. 1 millilitre contains chloroform 7.5 centimils; morphine hydrochloride 1 centigram; acidum hydrocyanicum dilutum 5 centimils.
Dose 5 to 15 minims - 0.2 to 1ml
Besides the generics, a number of rival sellers marketed their own branded versions of the formula, brands such as "Freeman's", "Teasdale's", and "Towle's". It can be seen from the illustrations that the authenticity of these rival brands was hotly contested.
# Decline
Though the drug was effective in many ways, its high opiate content also made it very addictive, and deaths from overdoses, either accidental or deliberate, became a frequent occurrence. A common feature of the coroner's report in such cases would be the description of the deceased's body being found in a flat or bedsit littered with empty Chlorodyne bottles. Over the decades of the twentieth century, the cannabis was removed from the formulation, and the amount of opiates in the medicine were progressively reduced. The name of Collis Browne lives on in Britain in a mixture sold under the trade name "J Collis Browne's Mixture" for the relief of coughs and diarrhea. This modern formulation contains morphine and peppermint oil. | Chlorodyne
Chlorodyne was the name for one of the most famous patent medicines sold in the British Isles. It was invented in the 19th century by a Dr. J. Collis Browne, a doctor in the British Indian Army; its original purpose was in the treatment of cholera. Browne sold his formula to a pharmacist named Davenport, who advertised it widely, as a treatment for cholera, diarrhea, insomnia, neuralgia, migraines, etc. As its principal ingredients were a mixture of laudanum (an alcoholic solution of opium), tincture of cannabis, and chloroform, it readily lived up to its claims of relieving pain, as a sedative, and for the treatment of diarrhea.
# Imitations
Chlorodyne sold extremely well for many years; as its active ingredients were well known, local chemists' shops would also make up cheaper generic versions for sale to their customers. Here is an example of such a generic formulation, from Materia Medica by William Hale-White & A.H. Douthwaite, 21st edition (1932):
"Tinctura Chloroformi et Morphinæ Composita intended to be an imitation of the proprietary medicine called chlorodyne. Mix chloroform 75, tincture of capsicum 25, tincture of Indian hemp 100, oil of peppermint 2 and glycerin 250 with alcohol (20 per cent) 450. Dissolve morphine hydrochloride 10 in the mixture. Add to it diluted hydrocyanic acid 50 and enough alcohol (90 per cent) to make 1000. Strength. 1 millilitre contains chloroform 7.5 centimils; morphine hydrochloride 1 centigram; acidum hydrocyanicum dilutum 5 centimils.
Dose 5 to 15 minims - 0.2 to 1ml
Besides the generics, a number of rival sellers marketed their own branded versions of the formula, brands such as "Freeman's", "Teasdale's", and "Towle's". It can be seen from the illustrations that the authenticity of these rival brands was hotly contested.
# Decline
Though the drug was effective in many ways, its high opiate content also made it very addictive, and deaths from overdoses, either accidental or deliberate, became a frequent occurrence. A common feature of the coroner's report in such cases would be the description of the deceased's body being found in a flat or bedsit littered with empty Chlorodyne bottles. Over the decades of the twentieth century, the cannabis was removed from the formulation, and the amount of opiates in the medicine were progressively reduced. The name of Collis Browne lives on in Britain in a mixture sold under the trade name "J Collis Browne's Mixture" for the relief of coughs and diarrhea. This modern formulation contains morphine and peppermint oil.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Chlorodyne | |
a6753e847e4f0d5888119ef75820b070d90b9ea0 | wikidoc | Chloroform | Chloroform
# Overview
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered hazardous. Several million tons are produced annually as a precursor to PTFE and refrigerants, but its use for refrigerants is being phased out. The hydrogen attached to carbon in chloroform participates in hydrogen bonding.
# Natural occurrence
The total global flux of chloroform through the environment is approximately 660 000 tonnes per year, and about 90% of emissions are natural in origin. Many kinds of seaweed produce chloroform, and fungi are believed to produce chloroform in soil.
Chloroform volatilizes readily from soil and surface water and undergoes degradation in air to produce phosgene, dichloromethane, formyl chloride, carbon monoxide, carbon dioxide, and hydrogen chloride. Its halflife in air ranges from 55 to 620 days. Biodegradation in water and soil is slow. Chloroform does not bioaccumulate to any significant extent in aquatic organisms.
# History
Trichloromethane was synthesized independently by two groups in 1831: Liebig carried out the alkaline cleavage of chloral, whereas Soubeirain obtained the compound by the action of chlorine bleach on both ethanol and acetone. In 1835, Dumas prepared the substance by the alkaline cleavage of trichloroacetic acid. Regnault prepared trichloromethane by chlorination of monochloromethane. By the 1850s, chloroform was being produced on a commercial basis by using the Liebig procedure, which retained its importance until the 1960s. Today, trichloromethane — along with dichloromethane — is prepared exclusively and on a massive scale by the chlorination of methane and monochloromethane.
## Production
In industry, chloroform is produced by heating a mixture of chlorine and either chloromethane or methane. At 400–500 °C, a free radical halogenation occurs, converting these precursors to progressively more chlorinated compounds:
Chloroform undergoes further chlorination to yield carbon tetrachloride (CCl4):
The output of this process is a mixture of the four chloromethanes (chloromethane, dichloromethane, chloroform, and carbon tetrachloride), which can then be separated by distillation.
## Deuterochloroform
Deuterated chloroform is an isotopologue of chloroform with a single deuterium atom. CDCl3 is a common solvent used in NMR spectroscopy. Deuterochloroform is produced by the haloform reaction, the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite. The haloform process is now obsolete for the production of ordinary chloroform. Deuterochloroform can also be prepared by the reaction of sodium deuteroxide with chloral hydrate, or from ordinary chloroform.
## Inadvertent formation of chloroform
The haloform reaction can also occur inadvertently in domestic settings. Bleaching with hypochlorite generates halogenated compounds in side reactions; chloroform is the main byproduct. Sodium hypochlorite solution (chlorine bleach) mixed with common household liquids such as acetone, butanone, ethanol, or isopropyl alcohol can produce some chloroform, in addition to other compounds such as chloroacetone or dichloroacetone.
# Uses
The major use of chloroform today is in the production of the chlorodifluoromethane, a major precursor to tetrafluoroethylene:
The reaction is conducted in the presence of a catalytic amount of antimony pentafluoride. Chlorodifluoromethane is then converted into tetrafluoroethylene, the main precursor to Teflon. Before the Montreal Protocol, chlorodifluoromethane (designated as R-22) was also a popular refrigerant.
## Solvent
Worldwide, chloroform is also used in pesticide formulations, as a solvent for fats, oils, rubber, alkaloids, waxes, gutta-percha, and resins, as a cleansing agent, grain fumigant, in fire extinguishers, and in the rubber industry. CDCl3 is a common solvent used in NMR spectroscopy.
## Reagent
As a reagent, chloroform serves as a source of the dichlorocarbene CCl2 group. It reacts with aqueous sodium hydroxide usually in the presence of a phase transfer catalyst to produce dichlorocarbene, CCl2. This reagent affects ortho-formylation of activated aromatic rings such as phenols, producing aryl aldehydes in a reaction known as the Reimer-Tiemann reaction. Alternatively the carbene can be trapped by an alkene to form a cyclopropane derivative. In the Kharasch addition chloroform forms the CHCl2 free radical in addition to alkenes.
The most important reaction of chloroform is that with hydrogen fluoride in the presence of antimony pentahalides to give monochlorodifluoromethane (CFC 22), a precursor in the production of polytetrafluoroethylene (Teflon).
## Anaesthetic
Chloroform was once a widely used anesthetic. On 4 November 1847, the Scottish obstetrician James Young Simpson first used the anaesthetic qualities of chloroform on a human, two guests at his dinner party. This was done as an entertainment and not as a medical procedure.
This was followed, only three days later, by the first use of chloroform on an actual patient, for a dental procedure, by Francis Brodie Imlach (1819-1891), also in Edinburgh, who, under other circumstances, may have gained the same fame as Simpson.
The use of chloroform during surgery expanded rapidly thereafter in Europe. In the 1850s, chloroform was used during the birth of Queen Victoria's last two children. In the United States, chloroform began to replace ether as an anesthetic at the beginning of the 20th century; however, it was quickly abandoned in favor of ether upon discovery of its toxicity, especially its tendency to cause fatal cardiac arrhythmia analogous to what is now termed "sudden sniffer's death". Some people used chloroform as a recreational drug or to attempt suicide. One possible mechanism of action for chloroform is that it increases movement of potassium ions through certain types of potassium channels in nerve cells. Chloroform could also be mixed with other anesthetic agents such as ether to make C.E. mixture, or ether and alcohol to make A.C.E. mixture.
In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anesthetic. A number of physically fit patients died after inhaling it. However, in 1848 John Snow developed an inhaler that regulated the dosage and so successfully reduced the number of deaths.
The opponents and supporters of chloroform were mainly at odds with the question of whether the complications were solely due to respiratory disturbance or whether chloroform had a specific effect on the heart. Between 1864 and 1910 numerous commissions in UK studied chloroform, but failed to come to any clear conclusions. It was only in 1911 that Levy proved in experiments with animals that chloroform can cause cardiac fibrillation. The reservations about chloroform could not halt its soaring popularity. Between about 1865 and 1920, chloroform was used in 80 to 95% of all narcoses performed in UK and German-speaking countries. In America, however, there was less enthusiasm for chloroform narcosis. In Germany the first comprehensive surveys of the fatality rate during anaesthesia were made by Gurlt between 1890 and 1897. In 1934, Killian gathered all the statistics compiled until then and found that the chances of suffering fatal complications under ether were between 1: 14,000 and 1: 28,000, whereas under chloroform the chances were between 1: 3,000 and 1: 6,000. The rise of gas anaesthesia using nitrous oxide, improved equipment for administering anaesthetics and the discovery of hexobarbital in 1932 led to the gradual decline of chloroform narcosis.
## Criminal use
Chloroform has been reputed to be used by criminals to knock out, daze or even murder their victims. Joseph Harris was charged in 1894 with using chloroform to rob people. In 1901, chloroform was also implicated in the murder of the American businessman William Marsh Rice, the namesake of the institution now known as Rice University. Chloroform was also deemed to be a factor in the alleged murder of a woman in 1991 when she was asphyxiated while sleeping. In a 2007 plea bargain a man confessed to using stun guns and chloroform to sexually assault minors. Use of chloroform as an incapacitating agent has become widely recognized, bordering on clichéd, due to the popularity of crime fiction authors having criminals use chloroform-soaked rags to render victims unconscious. However, it is nearly impossible to incapacitate someone using chloroform. It takes at least five minutes of inhaling an item soaked in chloroform to render a person unconscious. Most criminal cases involving chloroform also involve another drug being co-administered, such as alcohol or diazepam, or the victim being found to have been complicit in its administration. After a person has lost consciousness due to chloroform inhalation, a continuous volume must be administered and the chin must be supported in order to keep the tongue from obstructing the airway, a difficult procedure even for an anesthesiologist. In 1865 as a direct result of the criminal reputation chloroform had gained, medical journal The Lancet offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility" using chloroform, and as of 1998 no such demonstration has been forthcoming.
# Safety
Chloroform is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation. Prolonged dermal exposure can result in the development of sores as a result of defatting. Elimination is primarily from lungs in the form of chloroform and carbon dioxide; less than 1% is excreted in urine.
Chloroform is metabolized in the liver by the cytochrome P-450 enzymes, by oxidation to phosgene and by reduction to the dichloromethyl free radical. Other metabolites of chloroform include chloromethanol, hydrochloric acid, hydrogen chloride, and digluathionyl dithiocarbonate, with carbon dioxide as the predominant end product of metabolism.
Chloroform causes depression of the central nervous system (CNS), ultimately producing deep coma and respiratory center depression. When ingested, chloroform caused symptoms similar to those seen following inhalation. Serious illness has followed ingestion of 7.5 g. The mean lethal oral dose for an adult is estimated to be about 45 g.
The anesthetic use of chloroform has been discontinued because it caused deaths due to respiratory and cardiac arrhythmias and failure. Following chloroform-induced anesthesia, some patients suffered nausea, vomiting, prostration, jaundice, and coma due to hepatic dysfunction. At autopsy, liver necrosis and degeneration have been observed.
Chloroform has induced liver tumors in mice and kidney tumors in mice and rats. The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene.
## Conversion to phosgene
During prolonged storage in the presence of oxygen, chloroform converts slowly to phosgene, releasing HCl in the process. To prevent accidents, commercial chloroform is stabilized with ethanol or amylene, but samples that have been recovered or dried no longer contain any stabilizer. Amylene has been found ineffective, and the phosgene can affect analytes in samples, lipids, and nucleic acids dissolved in or extracted with chloroform. Phosgene and HCl can be removed from chloroform by washing with saturated aqueous carbonate solutions, such as sodium bicarbonate. This procedure is simple and results in harmless products. Phosgene reacts with water to form carbon dioxide and HCl, and the carbonate salt neutralizes the resulting acid.
Suspected samples can be tested for phosgene using filter paper (treated with 5% diphenylamine, 5% dimethylaminobenzaldehyde in alcohol, and then dried), which turns yellow in phosgene vapor. There are several colorimetric and fluorometric reagents for phosgene, and it can also be quantified with mass spectrometry. | Chloroform
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes.[2] The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered hazardous. Several million tons are produced annually as a precursor to PTFE and refrigerants, but its use for refrigerants is being phased out.[2] The hydrogen attached to carbon in chloroform participates in hydrogen bonding.[3][4]
# Natural occurrence
The total global flux of chloroform through the environment is approximately 660 000 tonnes per year, and about 90% of emissions are natural in origin. Many kinds of seaweed produce chloroform, and fungi are believed to produce chloroform in soil.
Chloroform volatilizes readily from soil and surface water and undergoes degradation in air to produce phosgene, dichloromethane, formyl chloride, carbon monoxide, carbon dioxide, and hydrogen chloride. Its halflife in air ranges from 55 to 620 days. Biodegradation in water and soil is slow. Chloroform does not bioaccumulate to any significant extent in aquatic organisms.[5]
# History
Trichloromethane was synthesized independently by two groups in 1831: Liebig carried out the alkaline cleavage of chloral, whereas Soubeirain obtained the compound by the action of chlorine bleach on both ethanol and acetone. In 1835, Dumas prepared the substance by the alkaline cleavage of trichloroacetic acid. Regnault prepared trichloromethane by chlorination of monochloromethane. By the 1850s, chloroform was being produced on a commercial basis by using the Liebig procedure, which retained its importance until the 1960s. Today, trichloromethane — along with dichloromethane — is prepared exclusively and on a massive scale by the chlorination of methane and monochloromethane.[2]
## Production
In industry, chloroform is produced by heating a mixture of chlorine and either chloromethane or methane.[2] At 400–500 °C, a free radical halogenation occurs, converting these precursors to progressively more chlorinated compounds:
Chloroform undergoes further chlorination to yield carbon tetrachloride (CCl4):
The output of this process is a mixture of the four chloromethanes (chloromethane, dichloromethane, chloroform, and carbon tetrachloride), which can then be separated by distillation.[2]
## Deuterochloroform
Deuterated chloroform is an isotopologue of chloroform with a single deuterium atom. CDCl3 is a common solvent used in NMR spectroscopy. Deuterochloroform is produced by the haloform reaction[citation needed], the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite.[2] The haloform process is now obsolete for the production of ordinary chloroform. Deuterochloroform can also be prepared by the reaction of sodium deuteroxide with chloral hydrate,[citation needed] or from ordinary chloroform.[6]
## Inadvertent formation of chloroform
The haloform reaction can also occur inadvertently in domestic settings. Bleaching with hypochlorite generates halogenated compounds in side reactions; chloroform is the main byproduct.[7] Sodium hypochlorite solution (chlorine bleach) mixed with common household liquids such as acetone, butanone, ethanol, or isopropyl alcohol can produce some chloroform, in addition to other compounds such as chloroacetone or dichloroacetone.
# Uses
The major use of chloroform today is in the production of the chlorodifluoromethane, a major precursor to tetrafluoroethylene:
The reaction is conducted in the presence of a catalytic amount of antimony pentafluoride. Chlorodifluoromethane is then converted into tetrafluoroethylene, the main precursor to Teflon. Before the Montreal Protocol, chlorodifluoromethane (designated as R-22) was also a popular refrigerant.
## Solvent
Worldwide, chloroform is also used in pesticide formulations, as a solvent for fats, oils, rubber, alkaloids, waxes, gutta-percha, and resins, as a cleansing agent, grain fumigant, in fire extinguishers, and in the rubber industry.[5][8] CDCl3 is a common solvent used in NMR spectroscopy.
## Reagent
As a reagent, chloroform serves as a source of the dichlorocarbene CCl2 group.[9] It reacts with aqueous sodium hydroxide usually in the presence of a phase transfer catalyst to produce dichlorocarbene, CCl2.[10][11] This reagent affects ortho-formylation of activated aromatic rings such as phenols, producing aryl aldehydes in a reaction known as the Reimer-Tiemann reaction. Alternatively the carbene can be trapped by an alkene to form a cyclopropane derivative. In the Kharasch addition chloroform forms the CHCl2 free radical in addition to alkenes.
The most important reaction of chloroform is that with hydrogen fluoride in the presence of antimony pentahalides to give monochlorodifluoromethane (CFC 22), a precursor in the production of polytetrafluoroethylene (Teflon).[2]
## Anaesthetic
Chloroform was once a widely used anesthetic. On 4 November 1847, the Scottish obstetrician James Young Simpson first used the anaesthetic qualities of chloroform on a human,[12] two guests at his dinner party. This was done as an entertainment and not as a medical procedure.
This was followed, only three days later, by the first use of chloroform on an actual patient, for a dental procedure, by Francis Brodie Imlach (1819-1891), also in Edinburgh, who, under other circumstances, may have gained the same fame as Simpson.[13]
The use of chloroform during surgery expanded rapidly thereafter in Europe. In the 1850s, chloroform was used during the birth of Queen Victoria's last two children.[14] In the United States, chloroform began to replace ether as an anesthetic at the beginning of the 20th century; however, it was quickly abandoned in favor of ether upon discovery of its toxicity, especially its tendency to cause fatal cardiac arrhythmia analogous to what is now termed "sudden sniffer's death". Some people used chloroform as a recreational drug or to attempt suicide.[15] One possible mechanism of action for chloroform is that it increases movement of potassium ions through certain types of potassium channels in nerve cells.[16] Chloroform could also be mixed with other anesthetic agents such as ether to make C.E. mixture, or ether and alcohol to make A.C.E. mixture.
In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anesthetic.[17] A number of physically fit patients died after inhaling it. However, in 1848 John Snow developed an inhaler that regulated the dosage and so successfully reduced the number of deaths.[18]
The opponents and supporters of chloroform were mainly at odds with the question of whether the complications were solely due to respiratory disturbance or whether chloroform had a specific effect on the heart. Between 1864 and 1910 numerous commissions in UK studied chloroform, but failed to come to any clear conclusions. It was only in 1911 that Levy proved in experiments with animals that chloroform can cause cardiac fibrillation. The reservations about chloroform could not halt its soaring popularity. Between about 1865 and 1920, chloroform was used in 80 to 95% of all narcoses performed in UK and German-speaking countries. In America, however, there was less enthusiasm for chloroform narcosis. In Germany the first comprehensive surveys of the fatality rate during anaesthesia were made by Gurlt between 1890 and 1897. In 1934, Killian gathered all the statistics compiled until then and found that the chances of suffering fatal complications under ether were between 1: 14,000 and 1: 28,000, whereas under chloroform the chances were between 1: 3,000 and 1: 6,000. The rise of gas anaesthesia using nitrous oxide, improved equipment for administering anaesthetics and the discovery of hexobarbital in 1932 led to the gradual decline of chloroform narcosis.[19]
## Criminal use
Chloroform has been reputed to be used by criminals to knock out, daze or even murder their victims. Joseph Harris was charged in 1894 with using chloroform to rob people.[20] In 1901, chloroform was also implicated in the murder of the American businessman William Marsh Rice, the namesake of the institution now known as Rice University. Chloroform was also deemed to be a factor in the alleged murder of a woman in 1991 when she was asphyxiated while sleeping.[21] In a 2007 plea bargain a man confessed to using stun guns and chloroform to sexually assault minors.[22] Use of chloroform as an incapacitating agent has become widely recognized, bordering on clichéd, due to the popularity of crime fiction authors having criminals use chloroform-soaked rags to render victims unconscious. However, it is nearly impossible to incapacitate someone using chloroform.[23] It takes at least five minutes of inhaling an item soaked in chloroform to render a person unconscious. Most criminal cases involving chloroform also involve another drug being co-administered, such as alcohol or diazepam, or the victim being found to have been complicit in its administration. After a person has lost consciousness due to chloroform inhalation, a continuous volume must be administered and the chin must be supported in order to keep the tongue from obstructing the airway, a difficult procedure even for an anesthesiologist. In 1865 as a direct result of the criminal reputation chloroform had gained, medical journal The Lancet offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility" using chloroform,[24] and as of 1998[update] no such demonstration has been forthcoming.[23]
# Safety
Chloroform is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation.[5] Prolonged dermal exposure can result in the development of sores as a result of defatting. Elimination is primarily from lungs in the form of chloroform and carbon dioxide; less than 1% is excreted in urine.[8]
Chloroform is metabolized in the liver by the cytochrome P-450 enzymes, by oxidation to phosgene and by reduction to the dichloromethyl free radical. Other metabolites of chloroform include chloromethanol, hydrochloric acid, hydrogen chloride, and digluathionyl dithiocarbonate, with carbon dioxide as the predominant end product of metabolism.[25]
Chloroform causes depression of the central nervous system (CNS), ultimately producing deep coma and respiratory center depression.[25] When ingested, chloroform caused symptoms similar to those seen following inhalation. Serious illness has followed ingestion of 7.5 g. The mean lethal oral dose for an adult is estimated to be about 45 g.[5]
The anesthetic use of chloroform has been discontinued because it caused deaths due to respiratory and cardiac arrhythmias and failure. Following chloroform-induced anesthesia, some patients suffered nausea, vomiting, prostration, jaundice, and coma due to hepatic dysfunction. At autopsy, liver necrosis and degeneration have been observed.[5]
Chloroform has induced liver tumors in mice and kidney tumors in mice and rats.[5] The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene.[25]
## Conversion to phosgene
During prolonged storage in the presence of oxygen, chloroform converts slowly to phosgene, releasing HCl in the process. To prevent accidents, commercial chloroform is stabilized with ethanol or amylene, but samples that have been recovered or dried no longer contain any stabilizer. Amylene has been found ineffective, and the phosgene can affect analytes in samples, lipids, and nucleic acids dissolved in or extracted with chloroform.[26] Phosgene and HCl can be removed from chloroform by washing with saturated aqueous carbonate solutions, such as sodium bicarbonate. This procedure is simple and results in harmless products. Phosgene reacts with water to form carbon dioxide and HCl,[27] and the carbonate salt neutralizes the resulting acid.
Suspected samples can be tested for phosgene using filter paper (treated with 5% diphenylamine, 5% dimethylaminobenzaldehyde in alcohol, and then dried), which turns yellow in phosgene vapor. There are several colorimetric and fluorometric reagents for phosgene, and it can also be quantified with mass spectrometry. | https://www.wikidoc.org/index.php/Chloroform | |
85629db64ddb9de3e3b33153d46398de7f5cb7b0 | wikidoc | Chloroxine | Chloroxine
# Overview
Chloroxine (trade name Capitrol; Kloroxin, Dichlorchinolinol, chlorquinol, halquinol(s)); Latin cloroxinum, dichlorchinolinolum) is an antibacterial drug. Oral formulations (under trade name such as Endiaron) are used in infectious diarrhea, disorders of the intestinal microflora (e.g. after antibiotic treatment), giardiasis, inflammatory bowel disease. It is also useful for dandruff and seborrheic dermatitis., as used in shampoos (Capitrol) and dermal creams like (Valpeda, Triaderm).
# Mechanism of action
Chloroxine has bacteriostatic, fungistatic and antiprotozoal properties. It is effective against Streptococci, Staphylococci, Candida, Candida albicans, Shigella and Trichomonads.
The pharma reference also says that it does not adversely affects the natural intestinal microflora, however this claim is unsourced.
# Adverse effects
Rarely occurs, but may cause nausea and vomiting associated with oral administration. It may also cause skin irritation.
# Pregnancy and lactation
The FDA lists chloroxine in Pregnancy Category C (risk cannot be ruled out) because no pregnancy studies on the medication have been performed with animals or humans. For this reason, use of chloroxine oral or topical during pregnancy or when breast-feeding is not recommended.
# History
First prepared in 1888 by A. Hebebrand. | Chloroxine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Chloroxine (trade name Capitrol; Kloroxin, Dichlorchinolinol, chlorquinol, halquinol(s));[citation needed] Latin cloroxinum, dichlorchinolinolum) is an antibacterial drug.[1] Oral formulations (under trade name such as Endiaron[2]) are used in infectious diarrhea, disorders of the intestinal microflora (e.g. after antibiotic treatment), giardiasis, inflammatory bowel disease. It is also useful for dandruff and seborrheic dermatitis.,[3] as used in shampoos (Capitrol) and dermal creams like (Valpeda, Triaderm).
# Mechanism of action
Chloroxine has bacteriostatic, fungistatic and antiprotozoal properties. It is effective against Streptococci, Staphylococci, Candida, Candida albicans, Shigella and Trichomonads.
The pharma reference also says that it does not adversely affects the natural intestinal microflora, however this claim is unsourced.
# Adverse effects
Rarely occurs, but may cause nausea and vomiting associated with oral administration. It may also cause skin irritation.
# Pregnancy and lactation
The FDA lists chloroxine in Pregnancy Category C (risk cannot be ruled out) because no pregnancy studies on the medication have been performed with animals or humans. For this reason, use of chloroxine oral or topical during pregnancy or when breast-feeding is not recommended.[4]
# History
First prepared in 1888 by A. Hebebrand.[5] | https://www.wikidoc.org/index.php/Chloroxine | |
ddd7ad24d20c918869c2d57ebaf6c1c299f18b11 | wikidoc | Chromosome | Chromosome
# Overview
A chromosome is a single large macromolecule of DNA, and constitutes a physically organized form of DNA in a cell. It is a very long, continuous piece of DNA (a single DNA molecule), which contains many genes, regulatory elements and other intervening nucleotide sequences.
A broader definition of "chromosome" also includes the DNA-bound proteins which serve to package and manage the DNA. The word chromosome comes from the Greek Template:Polytonic (chroma, color) and Template:Polytonic (soma, body) due to its capacity to be stained very strongly with vital and supravital dyes.
Chromosomes vary extensively between different organisms. The DNA molecule may be circular or linear, and can contain anything from tens of kilobase pairs to hundreds of megabase pairs.
Typically eukaryotic cells (cells with nuclei) have large linear chromosomes and prokaryotic cells (cells without nuclei) smaller circular chromosomes, although there are many exceptions to this rule. Furthermore, cells may contain more than one type of chromosome; for example mitochondria in most eukaryotes and chloroplasts in plants have their own small chromosome in addition to the nuclear chromosomes.
In eukaryotes nuclear chromosomes are packaged by proteins (particularly histones) into chromatin to fit the massive molecules into the nucleus.
The structure of chromatin varies through the cell cycle, and is responsible for the compaction of DNA into the classic four-arm structure during mitosis and meiosis. Prokaryotes do not form chromatin, because the cells lack proteins required and the circular configuration of the molecule prevents this.
"Chromosome" is a rather loosely defined term. In prokaryotes, a small circular DNA molecule may be called either a plasmid or a small chromosome. In viruses, mitochondria, and chloroplasts their DNA molecules are commonly referred to as chromosomes, despite being naked molecules, as they constitute the complete genome of the organism or organelle.
# History
Chromosomes were first observed in plant cells by a Swiss botanist named Karl Wilhelm von Nägeli in 1842, and independently in Ascaris worms by Belgian scientist Edouard Van Beneden (1846-1910).
The use of basophilic aniline dyes was a fundamentally new technique for effectively staining the chromatin material in the nucleus. Their behavior in animal (salamander) cells was later described in detail by German cytologist and professor of anatomy Walther Flemming, the discoverer of mitosis, in 1882.
The name was invented later by another German anatomist, Heinrich von Waldeyer in 1888.
# Chromosomes in eukaryotes
Eukaryotes (cells with nuclei such as plants, yeast, and animals) possess multiple large linear chromosomes contained in the cell's nucleus. Each chromosome has one centromere, with one or two arms projecting from the centromere, although under most circumstances these arms are not visible as such.
In addition most eukaryotes have a small circular mitochondrial genome, and some eukaryotes may have additional small circular or linear cytoplasmic chromosomes.
In the nuclear chromosomes of eukaryotes, the uncondensed DNA exists in a semi-ordered structure, where it is wrapped around histones (structural proteins), forming a composite material called chromatin.
- Figure 1: A representation of a condensed eukaryotic chromosome, as seen during cell division.
## Chromatin
Chromatin is the complex of DNA and protein found in the eukaryotic nucleus which packages chromosomes. The structure of chromatin varies significantly between different stages of the cell cycle, according to the requirements of the DNA.
- Fig. 2: The major structures in DNA compaction; DNA, the nucleosome, the 10nm "beads-on-a-string" fibre, the 30nm fibre and the metaphase chromosome.
### Interphase chromatin
During interphase (the period of the cell cycle where the cell is not dividing) two types of chromatin can be distinguished:
- Euchromatin, which consists of DNA that is active, e.g., expressed as protein.
- Heterochromatin, which consists of mostly inactive DNA. It seems to serve structural purposes during the chromosomal stages. Heterochromatin can be further distinguished into two types:
Constitutive heterochromatin, which is never expressed. It is located around the centromere and usually contains repetitive sequences.
Facultative heterochromatin, which is sometimes expressed.
- Constitutive heterochromatin, which is never expressed. It is located around the centromere and usually contains repetitive sequences.
- Facultative heterochromatin, which is sometimes expressed.
Individual chromosomes cannot be distinguished at this stage - they appear in the nucleus as a homogeneous tangled mix of DNA and protein.
### Metaphase chromatin and division
In the early stages of mitosis or meiosis (cell division), the chromatin strands become more and more condensed. They cease to function as accessible genetic material (transcription stops) and become a compact transportable form. This compact form makes the individual chromosomes visible, and they form the classic four arm structure, a pair of sister chromatids attached to each other at the centromere. The shorter arms are called p arms (from the French petit, small) and the longer arms are called q arms (q follows p in the Latin alphabet). This is the only natural context in which individual chromosomes are visible with an optical microscope.
During divisions long microtubules attach to the centromere and the two opposite ends of the cell. The microtubules then pull the chromatids apart, so that each daughter cell inherits one set of chromatids. Once the cells have divided, the chromatids are uncoiled and can function again as chromatin. In spite of their appearance, chromosomes are structurally highly condensed which enables these giant DNA structures to be contained within a cell nucleus (Fig. 2).
The self assembled microtubules form the spindle, which attaches to chromosomes at specialized structures called kinetochores, one of which is present on each sister chromatid. A special DNA base sequence in the region of the kinetochores provides, along with special proteins, longer-lasting attachment in this region.
- Human chromosomes during metaphase.
# Chromosomes in prokaryotes
Prokaryotes (eg. Bacteria) typically have a single circular chromosome, but many variations do exist.
Bacterial DNA also exists as plasmids, essentially miniature chromosomes, which are small circular pieces of DNA that are readily transmitted between bacteria. The distinction between plasmids and chromosomes is poorly defined, though size and necessity are generally taken into account.
## Structure in sequences
Prokaryotes chromosomes have less sequence-based structure than eukaryotes. They do, however, typically have a single point, the origin of replication, from which replication starts.
The genes in prokaryotes are often organised in operons, and do not contain introns, unlike eukaryotes.
## Location in the cell
Bacterial chromosomes tend to be tethered to the plasma membrane of the bacteria. In molecular biology application, this allows for its isolation from plasmid DNA by centrifugation of lysed bacteria and pelleting of the membranes (and the attached DNA).
## DNA packaging
Prokaryotes do not possess histones or nuclei, and so do not possess chromatin like eukaryotes. There is, however, thought to be some structural organisation to help condense the large molecule into the small prokaryotic cell.
Prokaryotic chromosomes and plasmids are, like eukaryotic DNA, generally supercoiled. The DNA must first be released into its relaxed state for access for transcription, regulation, and replication.
# Number of chromosomes in various organisms
## Eukaryotes | Chromosome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
A chromosome is a single large macromolecule of DNA, and constitutes a physically organized form of DNA in a cell. It is a very long, continuous piece of DNA (a single DNA molecule), which contains many genes, regulatory elements and other intervening nucleotide sequences.
A broader definition of "chromosome" also includes the DNA-bound proteins which serve to package and manage the DNA. The word chromosome comes from the Greek Template:Polytonic (chroma, color) and Template:Polytonic (soma, body) due to its capacity to be stained very strongly with vital and supravital dyes.
Chromosomes vary extensively between different organisms. The DNA molecule may be circular or linear, and can contain anything from tens of kilobase pairs to hundreds of megabase pairs.
Typically eukaryotic cells (cells with nuclei) have large linear chromosomes and prokaryotic cells (cells without nuclei) smaller circular chromosomes, although there are many exceptions to this rule. Furthermore, cells may contain more than one type of chromosome; for example mitochondria in most eukaryotes and chloroplasts in plants have their own small chromosome in addition to the nuclear chromosomes.
In eukaryotes nuclear chromosomes are packaged by proteins (particularly histones) into chromatin to fit the massive molecules into the nucleus.
The structure of chromatin varies through the cell cycle, and is responsible for the compaction of DNA into the classic four-arm structure during mitosis and meiosis. Prokaryotes do not form chromatin, because the cells lack proteins required and the circular configuration of the molecule prevents this.
"Chromosome" is a rather loosely defined term. In prokaryotes, a small circular DNA molecule may be called either a plasmid or a small chromosome. In viruses, mitochondria, and chloroplasts their DNA molecules are commonly referred to as chromosomes, despite being naked molecules, as they constitute the complete genome of the organism or organelle.
# History
Chromosomes were first observed in plant cells by a Swiss botanist named Karl Wilhelm von Nägeli in 1842, and independently in Ascaris worms by Belgian scientist Edouard Van Beneden (1846-1910).
The use of basophilic aniline dyes was a fundamentally new technique for effectively staining the chromatin material in the nucleus. Their behavior in animal (salamander) cells was later described in detail by German cytologist and professor of anatomy Walther Flemming, the discoverer of mitosis, in 1882.
The name was invented later by another German anatomist, Heinrich von Waldeyer in 1888.
# Chromosomes in eukaryotes
Eukaryotes (cells with nuclei such as plants, yeast, and animals) possess multiple large linear chromosomes contained in the cell's nucleus. Each chromosome has one centromere, with one or two arms projecting from the centromere, although under most circumstances these arms are not visible as such.
In addition most eukaryotes have a small circular mitochondrial genome, and some eukaryotes may have additional small circular or linear cytoplasmic chromosomes.
In the nuclear chromosomes of eukaryotes, the uncondensed DNA exists in a semi-ordered structure, where it is wrapped around histones (structural proteins), forming a composite material called chromatin.
- Figure 1: A representation of a condensed eukaryotic chromosome, as seen during cell division.
## Chromatin
Chromatin is the complex of DNA and protein found in the eukaryotic nucleus which packages chromosomes. The structure of chromatin varies significantly between different stages of the cell cycle, according to the requirements of the DNA.
- Fig. 2: The major structures in DNA compaction; DNA, the nucleosome, the 10nm "beads-on-a-string" fibre, the 30nm fibre and the metaphase chromosome.
### Interphase chromatin
During interphase (the period of the cell cycle where the cell is not dividing) two types of chromatin can be distinguished:
- Euchromatin, which consists of DNA that is active, e.g., expressed as protein.
- Heterochromatin, which consists of mostly inactive DNA. It seems to serve structural purposes during the chromosomal stages. Heterochromatin can be further distinguished into two types:
Constitutive heterochromatin, which is never expressed. It is located around the centromere and usually contains repetitive sequences.
Facultative heterochromatin, which is sometimes expressed.
- Constitutive heterochromatin, which is never expressed. It is located around the centromere and usually contains repetitive sequences.
- Facultative heterochromatin, which is sometimes expressed.
Individual chromosomes cannot be distinguished at this stage - they appear in the nucleus as a homogeneous tangled mix of DNA and protein.
### Metaphase chromatin and division
Template:Seealso
In the early stages of mitosis or meiosis (cell division), the chromatin strands become more and more condensed. They cease to function as accessible genetic material (transcription stops) and become a compact transportable form. This compact form makes the individual chromosomes visible, and they form the classic four arm structure, a pair of sister chromatids attached to each other at the centromere. The shorter arms are called p arms (from the French petit, small) and the longer arms are called q arms (q follows p in the Latin alphabet). This is the only natural context in which individual chromosomes are visible with an optical microscope.
During divisions long microtubules attach to the centromere and the two opposite ends of the cell. The microtubules then pull the chromatids apart, so that each daughter cell inherits one set of chromatids. Once the cells have divided, the chromatids are uncoiled and can function again as chromatin. In spite of their appearance, chromosomes are structurally highly condensed which enables these giant DNA structures to be contained within a cell nucleus (Fig. 2).
The self assembled microtubules form the spindle, which attaches to chromosomes at specialized structures called kinetochores, one of which is present on each sister chromatid. A special DNA base sequence in the region of the kinetochores provides, along with special proteins, longer-lasting attachment in this region.
- Human chromosomes during metaphase.
# Chromosomes in prokaryotes
Prokaryotes (eg. Bacteria) typically have a single circular chromosome, but many variations do exist.
Bacterial DNA also exists as plasmids, essentially miniature chromosomes, which are small circular pieces of DNA that are readily transmitted between bacteria. The distinction between plasmids and chromosomes is poorly defined, though size and necessity are generally taken into account.
## Structure in sequences
Prokaryotes chromosomes have less sequence-based structure than eukaryotes. They do, however, typically have a single point, the origin of replication, from which replication starts.
The genes in prokaryotes are often organised in operons, and do not contain introns, unlike eukaryotes.
## Location in the cell
Bacterial chromosomes tend to be tethered to the plasma membrane of the bacteria. In molecular biology application, this allows for its isolation from plasmid DNA by centrifugation of lysed bacteria and pelleting of the membranes (and the attached DNA).
## DNA packaging
Prokaryotes do not possess histones or nuclei, and so do not possess chromatin like eukaryotes. There is, however, thought to be some structural organisation to help condense the large molecule into the small prokaryotic cell.
Prokaryotic chromosomes and plasmids are, like eukaryotic DNA, generally supercoiled. The DNA must first be released into its relaxed state for access for transcription, regulation, and replication.
# Number of chromosomes in various organisms
## Eukaryotes | https://www.wikidoc.org/index.php/Chromosomal | |
8cc220eb700395d1dace40623725e58afa7a6f23 | wikidoc | Chronotype | Chronotype
Chronotype is an attribute of human beings reflecting whether they are alert and prefer to be active early or late in the day. The continuum is often referred to as “morningness/eveningness” or “larks” and “owls” where morning people wake up early and are most alert in the first part of the day and evening people are most alert in the evening hours and prefer to go to bed late. Chronotype is also referred to as circadian type, diurnal preference or diurnal variation.
Humans are diurnal animals, active in the daytime. As with most other diurnal animals, human activity-rest patterns are endogenously controlled by circadian rhythms.
Normal variation in chronotypes encompasses sleep/wake cycles that are from about two hours earlier to about two hours later than average. Extremes outside of this range can cause a person difficulty in participating in normal work, school, and social activities. If a person's "lark" or (more commonly) "owl" tendencies are strong and intractable to the point of disallowing normal participation in society, the person is considered to have a circadian rhythm sleep disorder.
# History
The 20th century saw greatly increased interest in and research on all questions about sleep. Tremendous strides have been made in molecular, neural and medical aspects of biological rhythmicity. Physiology professor Nathaniel Kleitman's book Sleep and Wakefulness, 1939, revised 1963, summarized the existing knowledge of sleep, and it was he who proposed the existence of a basic rest-activity cycle. Kleitman, with his students including William C. Dement and Eugene Aserinsky, continued his research throughout the 1900s.
O. Öquist’s thesis, 1970, at the Department of Psychology, University of Göteborg, Sweden, introduces the modern research into chronotypes. It is entitled “Kartläggning av individuella dygnsrytmer”, Charting Individual Circadian Rhythms. O. Östberg modified Öquist’s questionnaire and in 1976, together with J. A. Horne, he published the Morningness - Eveningness Questionnaire, MEQ, which still is used and referred to in virtually all research on this topic. A short version can be found online.
Researchers in many countries have worked on validating the MEQ with regard to their local cultures. A revision of the scoring of the MEQ as well as a component analysis was done by Jacques Taillard et al in 2004, working with employed people over the age of 50, as the MEQ previously had been validated only for subjects of university age.
Several other assessment tools have been developed including the Circadian Type Inventory (Folkard 1987); Composite Morningness Questionnaire (Smith 1989); the Lark-Owl Chronotype Indicator, LOCI (Roberts 1999), and Munich Chronotype Questionnaire, MCTQ (Roenneberg 2003). Some of these are designed with particular situations in mind, such as shift work scheduling, travel fatigue and jet lag, athletic performance or best timing of medical procedures.
# Characteristics
Most people are neither evening nor morning types but lie somewhere in between. Estimates vary, but up to half are either morning or evening people. People who share a chronotype, morningness or eveningness, have similar activity-pattern timing: sleep, appetite, exercise, study etc. Researchers in the field of chronobiology look for objective markers by which to measure the chronotype spectrum.
- Horne and Östberg, 1976, found that morning types had a higher daytime temperature with an earlier peak time than evening types and that they went to sleep and awoke earlier, while no differences in sleep lengths were found. They also note that age should be considered in assessments of morningness and eveningness, noting how a "bed time of 23:30 may be indicative of a Morning type within a student population, but might be more related to an Evening type in the 40-60 years age group" (Horne & Östberg, 1976, p109).
- Clodoré et al, France, 1986, find differences in alertness between morning and evening types after a two hour sleep reduction.
- Gibertini et al, USA, 1999, assessed blood levels of the hormone melatonin, finding that the melatonin acrophase (the time at which the peak of a rhythm occurs) was strongly related to circadian type while amplitude was not. They note that morning types evidence a more rapid decline in melatonin levels after the peak than do evening types.
- Duffy et al, USA, 1999, found that while evening types woke at a later clock hour than morning types, morning types woke at a later circadian phase; that is, the interval between circadian phase and usual wake time was longer in morning types.
- Baehr et al, USA, 2000, found that the daily body temperature minimum occurred at about 4 in the morning for morning types and at about 6 for evening types in young adults. This minimum occurred at approximately the middle of the eight hour sleep period, but closer to wake in evening types. Evening types had a lower nocturnal temperature. The temperature minimum occurred about a half hour earlier in women than in men. Similar results were found by Mongrain et al in Canada, 2004.
- Zavada et al, The Netherlands, 2005, show that the time of mid-sleep on free (non-work) days may be the best marker for sleep-based assessments of chronotype, correlating well with such physiological markers as Dim-Light Melatonin Onset (DLMO) and the minimum of the daily cortisol rhythm. They also state that each chronotype category “contains a similar portion of short and long sleepers”.
- Giampietro and Cavallera, Italy, 2006, refer to many studies in their examination of the relationship between chronotypes, personality and creative thinking.
- Paine et al, New Zealand, 2006, conclude that “morningness/eveningness preference is largely independent of ethnicity, gender, and socioeconomic position, indicating that it is a stable characteristic that may be better explained by endogenous factors.”
# Notes
- ↑ Logie, Bruce. "Larks and Owls". Retrieved 2007-11-02..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}
- ↑ American Academy of Sleep Medicine International Classification of Sleep Disorders, Revised Edition 2001.
- ↑ Kleitman, Nathaniel. Sleep and Wakefulness. The University of Chicago Press.
- ↑ Horne, J.A. (1976). "A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms". International Journal of Chronobiology. 4: 97–110. Unknown parameter |coauthors= ignored (help)
- ↑ adapted from Horne & Östberg. "Morningness-Eveningness Scale". Bruce Logie. Retrieved 2007-11-02.
- ↑ Taillard, Jacques; et al. (2004). "Validation of Horne and Ostberg Morningness-Eveningness Questionnaire in a Middle-Aged Population of French Workers". Journal of Biological Rhythms. 19 (1): 76–86. Retrieved 2007-11-02.CS1 maint: Explicit use of et al. (link)
- ↑ Clodoré, M. (1986). "Diurnal variation in subjective and objective measures of sleepiness: the effects of sleep reduction and circadian type". Chronobiol Int. 3 (4): 255–63. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Gibertini, M. (1999). "Self-report of circadian type reflects the phase of the melatonin rhythm". Biol psychol. 50 (1): 19–33. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ "Dictionary of Circadian Physiology". Circadian Rhythm Laboratory, University of South Carolina Salkehatchie, Walterboro campus.
- ↑ Duffy, J.F. (1999). "Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young and older people". J Investig Med. 47 (3): 141–50. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Baehr, E.K. (2000). "Individual differences in the phase and amplitude of the human circadian temperature rhythm: with an emphasis on morningness-eveningness". J Sleep Res. 9 (2): 117–27. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Mongrain, V. (2004). "Phase relationships between sleep-wake cycle and underlying circadian rhythms in Morningness-Eveningness". J Biol Rhythms. 19 (3): 248–57. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Zavada, Andrei (2005). "Comparison of the Munich Chronotype Questionnaire with the Horne-Östberg's Morningness-Eveningness Score" (PDF). Chronobiol. Int. 22: 267–78. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Giampietro, M. (2006). "Morning and evening types and creative thinking". Elsevier Ltd. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Paine, Sarah-Jane (2006). "The Epidemology of Morningness/Eveningness: Influence of Age, Gender, Ethnicity, and Socioeconomic Factors in Adults (30-49 Years)". Journal of Biological Rhythms. 21 (1): 68–76. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
da:A-mennesker og B-mennesker | Chronotype
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Chronotype is an attribute of human beings reflecting whether they are alert and prefer to be active early or late in the day. The continuum is often referred to as “morningness/eveningness” or “larks” and “owls” where morning people wake up early and are most alert in the first part of the day and evening people are most alert in the evening hours and prefer to go to bed late. Chronotype is also referred to as circadian type, diurnal preference or diurnal variation.
Humans are diurnal animals, active in the daytime. As with most other diurnal animals, human activity-rest patterns are endogenously controlled by circadian rhythms.
Normal variation in chronotypes encompasses sleep/wake cycles that are from about two hours earlier to about two hours later than average.[1] Extremes outside of this range can cause a person difficulty in participating in normal work, school, and social activities. If a person's "lark" or (more commonly) "owl" tendencies are strong and intractable to the point of disallowing normal participation in society, the person is considered to have a circadian rhythm sleep disorder.[2]
# History
The 20th century saw greatly increased interest in and research on all questions about sleep. Tremendous strides have been made in molecular, neural and medical aspects of biological rhythmicity. Physiology professor Nathaniel Kleitman's book Sleep and Wakefulness, 1939, revised 1963,[3] summarized the existing knowledge of sleep, and it was he who proposed the existence of a basic rest-activity cycle. Kleitman, with his students including William C. Dement and Eugene Aserinsky, continued his research throughout the 1900s.
O. Öquist’s thesis, 1970, at the Department of Psychology, University of Göteborg, Sweden, introduces the modern research into chronotypes. It is entitled “Kartläggning av individuella dygnsrytmer”, Charting Individual Circadian Rhythms. O. Östberg modified Öquist’s questionnaire and in 1976, together with J. A. Horne, he published the Morningness - Eveningness Questionnaire, MEQ,[4] which still is used and referred to in virtually all research on this topic. A short version can be found online.[5]
Researchers in many countries have worked on validating the MEQ with regard to their local cultures. A revision of the scoring of the MEQ as well as a component analysis was done by Jacques Taillard et al in 2004,[6] working with employed people over the age of 50, as the MEQ previously had been validated only for subjects of university age.
Several other assessment tools have been developed including the Circadian Type Inventory (Folkard 1987); Composite Morningness Questionnaire (Smith 1989); the Lark-Owl Chronotype Indicator, LOCI (Roberts 1999), and Munich Chronotype Questionnaire, MCTQ (Roenneberg 2003). Some of these are designed with particular situations in mind, such as shift work scheduling, travel fatigue and jet lag, athletic performance or best timing of medical procedures.
# Characteristics
Most people are neither evening nor morning types but lie somewhere in between. Estimates vary, but up to half are either morning or evening people. People who share a chronotype, morningness or eveningness, have similar activity-pattern timing: sleep, appetite, exercise, study etc. Researchers in the field of chronobiology look for objective markers by which to measure the chronotype spectrum.
- Horne and Östberg, 1976, found that morning types had a higher daytime temperature with an earlier peak time than evening types and that they went to sleep and awoke earlier, while no differences in sleep lengths were found. They also note that age should be considered in assessments of morningness and eveningness, noting how a "bed time of 23:30 may be indicative of a Morning type within a student population, but might be more related to an Evening type in the 40-60 years age group" (Horne & Östberg, 1976, p109).
- Clodoré et al, France, 1986,[7] find differences in alertness between morning and evening types after a two hour sleep reduction.
- Gibertini et al, USA, 1999,[8] assessed blood levels of the hormone melatonin, finding that the melatonin acrophase (the time at which the peak of a rhythm occurs[9]) was strongly related to circadian type while amplitude was not. They note that morning types evidence a more rapid decline in melatonin levels after the peak than do evening types.
- Duffy et al, USA, 1999,[10] found that while evening types woke at a later clock hour than morning types, morning types woke at a later circadian phase; that is, the interval between circadian phase and usual wake time was longer in morning types.
- Baehr et al, USA, 2000,[11] found that the daily body temperature minimum occurred at about 4 in the morning for morning types and at about 6 for evening types in young adults. This minimum occurred at approximately the middle of the eight hour sleep period, but closer to wake in evening types. Evening types had a lower nocturnal temperature. The temperature minimum occurred about a half hour earlier in women than in men. Similar results were found by Mongrain et al in Canada, 2004.[12]
- Zavada et al, The Netherlands, 2005,[13] show that the time of mid-sleep on free (non-work) days may be the best marker for sleep-based assessments of chronotype, correlating well with such physiological markers as Dim-Light Melatonin Onset (DLMO) and the minimum of the daily cortisol rhythm. They also state that each chronotype category “contains a similar portion of short and long sleepers”.
- Giampietro and Cavallera, Italy, 2006,[14] refer to many studies in their examination of the relationship between chronotypes, personality and creative thinking.
- Paine et al, New Zealand, 2006,[15] conclude that “morningness/eveningness preference is largely independent of ethnicity, gender, and socioeconomic position, indicating that it is a stable characteristic that may be better explained by endogenous factors.”
# Notes
- ↑ Logie, Bruce. "Larks and Owls". Retrieved 2007-11-02..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}
- ↑ American Academy of Sleep Medicine International Classification of Sleep Disorders, Revised Edition 2001.
- ↑ Kleitman, Nathaniel. Sleep and Wakefulness. The University of Chicago Press.
- ↑ Horne, J.A. (1976). "A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms". International Journal of Chronobiology. 4: 97–110. Unknown parameter |coauthors= ignored (help)
- ↑ adapted from Horne & Östberg. "Morningness-Eveningness Scale". Bruce Logie. Retrieved 2007-11-02.
- ↑ Taillard, Jacques; et al. (2004). "Validation of Horne and Ostberg Morningness-Eveningness Questionnaire in a Middle-Aged Population of French Workers". Journal of Biological Rhythms. 19 (1): 76–86. Retrieved 2007-11-02.CS1 maint: Explicit use of et al. (link)
- ↑ Clodoré, M. (1986). "Diurnal variation in subjective and objective measures of sleepiness: the effects of sleep reduction and circadian type". Chronobiol Int. 3 (4): 255–63. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Gibertini, M. (1999). "Self-report of circadian type reflects the phase of the melatonin rhythm". Biol psychol. 50 (1): 19–33. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ "Dictionary of Circadian Physiology". Circadian Rhythm Laboratory, University of South Carolina Salkehatchie, Walterboro campus.
- ↑ Duffy, J.F. (1999). "Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young and older people". J Investig Med. 47 (3): 141–50. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Baehr, E.K. (2000). "Individual differences in the phase and amplitude of the human circadian temperature rhythm: with an emphasis on morningness-eveningness". J Sleep Res. 9 (2): 117–27. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Mongrain, V. (2004). "Phase relationships between sleep-wake cycle and underlying circadian rhythms in Morningness-Eveningness". J Biol Rhythms. 19 (3): 248–57. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Zavada, Andrei (2005). "Comparison of the Munich Chronotype Questionnaire with the Horne-Östberg's Morningness-Eveningness Score" (PDF). Chronobiol. Int. 22: 267–78. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Giampietro, M. (2006). "Morning and evening types and creative thinking". Elsevier Ltd. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
- ↑ Paine, Sarah-Jane (2006). "The Epidemology of Morningness/Eveningness: Influence of Age, Gender, Ethnicity, and Socioeconomic Factors in Adults (30-49 Years)". Journal of Biological Rhythms. 21 (1): 68–76. Retrieved 2007-11-02. Unknown parameter |coauthors= ignored (help)
Template:SleepSeries2
da:A-mennesker og B-mennesker
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Chronotype | |
1dfb4e7c761da942e0735e244bf169196c21cce5 | wikidoc | Chrysiasis | Chrysiasis
Chrysiasis is a dermatological condition caused by the prolonged ingestion of gold.
Similar to silver, a gold preparation used parenterally for a long period may rarely produce a permanent skin pigmentation - especially if the skin is exposed to sunlight or artificial ultraviolet radiation.
The skin's pigmentation has been described as uniformly gray, grayish purple, slate gray, or grayish blue, and is usually limited to exposed portions of the body. It may involve the conjunctivae over the scleras but usually not the oral mucosa. Location of pigment predominantly in the upper dermis leads to the blue component of skin color through the scattering phenomenon. It is much less likely to be deposited in the nails and hair.
Chrysiasis was said to have been much more common when medicines containing traces of gold were used for treatment of tuberculosis (commonplace forms of treatment nearly fifty years ago). Treatments containing gold traces were also used to treat cases of rheumatoid arthritis - but because the dose used for tuberculosis was higher than for arthritis, it has not afflicted many subscribing to such treatments. Gold can be identified in the skin chemically by light microscopy, electron microscopy, and spectroscopy. There is no treatment or way to reverse chrysiasis. | Chrysiasis
Chrysiasis is a dermatological condition caused by the prolonged ingestion of gold.
Similar to silver, a gold preparation used parenterally for a long period may rarely produce a permanent skin pigmentation - especially if the skin is exposed to sunlight or artificial ultraviolet radiation.
The skin's pigmentation has been described as uniformly gray, grayish purple, slate gray, or grayish blue, and is usually limited to exposed portions of the body. It may involve the conjunctivae over the scleras but usually not the oral mucosa. Location of pigment predominantly in the upper dermis leads to the blue component of skin color through the scattering phenomenon. It is much less likely to be deposited in the nails and hair.
Chrysiasis was said to have been much more common when medicines containing traces of gold were used for treatment of tuberculosis (commonplace forms of treatment nearly fifty years ago). Treatments containing gold traces were also used to treat cases of rheumatoid arthritis - but because the dose used for tuberculosis was higher than for arthritis, it has not afflicted many subscribing to such treatments. Gold can be identified in the skin chemically by light microscopy, electron microscopy, and spectroscopy. There is no treatment or way to reverse chrysiasis. | https://www.wikidoc.org/index.php/Chrysiasis | |
1f652f85ccb385d00000bdced1cd13b5e15d33b9 | wikidoc | Ciclopirox | Ciclopirox
# 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
Ciclopirox is an antifungal agent that is FDA approved for the {{{indicationType}}} of tinea pedis, tinea cruris, tinea corporis, candidiasis and tinea versicolor. Common adverse reactions include erythema, pruritus, and sensation of burning of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ciclopirox Cream is indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; candidiasis (moniliasis) due to Candida albicans; and tinea (pityriasis) versicolor due to Malassezia furfur.
- Gently massage Ciclopirox Cream 0.77% into the affected and surrounding skin areas twice daily, in the morning and evening. Clinical improvement with relief of pruritus and other symptoms usually occurs within the first week of treatment. If a patient shows no clinical improvement after four weeks of treatment with Ciclopirox Cream the diagnosis should be redetermined. Patients with tinea versicolor usually exhibit clinical and mycological clearing after two weeks of treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ciclopirox in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ciclopirox in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients below the age of 10 years have not been established.
- Ciclopirox Cream is indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; candidiasis (moniliasis) due to Candida albicans; and tinea (pityriasis) versicolor due to Malassezia furfur.
- Gently massage Ciclopirox Cream 0.77% into the affected and surrounding skin areas twice daily, in the morning and evening. Clinical improvement with relief of pruritus and other symptoms usually occurs within the first week of treatment. If a patient shows no clinical improvement after four weeks of treatment with Ciclopirox Cream the diagnosis should be redetermined. Patients with tinea versicolor usually exhibit clinical and mycological clearing after two weeks of treatment.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ciclopirox in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ciclopirox in pediatric patients.
# Contraindications
- Ciclopirox Cream is contraindicated in individuals who have shown hypersensitivity to any of its components.
# Warnings
- Ciclopirox Cream is not for ophthalmic use. Keep out of reach of children.
### Precautions
- If a reaction suggesting sensitivity or chemical irritation should occur with the use of Ciclopirox Cream, treatment should be discontinued and appropriate therapy instituted.
# Adverse Reactions
## Clinical Trials Experience
- In all controlled clinical studies with 514 patients using Ciclopirox Cream and in 296 patients using the vehicle cream, the incidence of adverse reactions was low. This included pruritus at the site of application in one patient and worsening of the clinical signs and symptoms in another patient using ciclopirox cream and burning in one patient and worsening of the clinical signs and symptoms in another patient using the vehicle cream.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ciclopirox in the drug label.
# Drug Interactions
There is limited information regarding Ciclopirox Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Reproduction studies have been performed in the mouse, rat, rabbit, and monkey (via various routes of administration) at doses 10 times or more the topical human dose and have revealed no significant evidence of impaired fertility or harm to the fetus due to ciclopirox. There are, however, no adequate or well-controlled studies in pregnant 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):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ciclopirox in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ciclopirox 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 Ciclopirox Cream 0.77% is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 10 years have not been established.
### Geriatic Use
There is no FDA guidance on the use of Ciclopirox with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Ciclopirox with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ciclopirox with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ciclopirox in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ciclopirox in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ciclopirox in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ciclopirox in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Ciclopirox in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ciclopirox in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ciclopirox in the drug label.
# Pharmacology
## Mechanism of Action
- Ciclopirox is a broad-spectrum, antifungal agent that inhibits the growth of pathogenic dermatophytes, yeasts, and Malassezia furfur. Ciclopirox exhibits fungicidal activity in vitro against isolates of Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, and Candida albicans.
## Structure
- Ciclopirox Cream 0.77% is for topical use.
- Each gram of Ciclopirox cream 0.77% contains 7.70 mg of Ciclopirox (as Ciclopirox Olamine) in a water miscible vanishing cream base consisting of purified water USP, cetyl alcohol NF, mineral oil USP, octyldodecanol NF, stearyl alcohol NF, cocamide DEA, polysorbate 60 NF, myristyl alcohol, sorbitan monostearate NF, lactic acid USP, and benzyl alcohol NF (1%) as preservative.
- Ciclopirox Cream contains a synthetic, broad-spectrum, antifungal agent ciclopirox (as ciclopirox olamine).
- The chemical name is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt.
- The CAS Registry Number is 41621-49-2.
- The chemical structure is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ciclopirox in the drug label.
## Pharmacokinetics
- Pharmacokinetic studies in men with tagged ciclopirox solution in polyethylene glycol 400 showed an average of 1.3% absorption of the dose when it was applied topically to 750 cm2 on the back followed by occlusion for 6 hours. The biological half-life was 1.7 hours and excretion occurred via the kidney. Two days after application only 0.01% of the dose applied could be found in the urine. Fecal excretion was negligible.
- Penetration studies in human cadaverous skin from the back, with ciclopirox cream 0.77% with tagged ciclopirox showed the presence of 0.8 to 1.6% of the dose in the stratum corneum 1.5 to 6 hours after application. The levels in the dermis were still 10 to 15 times above the minimum inhibitory concentrations.
- Autoradiographic studies with human cadaverous skin showed that ciclopirox penetrates into the hair and through the epidermis and hair follicles into the sebaceous glands and dermis, while a portion of the drug remains in the stratum corneum.
- Draize Human Sensitization Assay, 21-Day Cumulative Irritancy study, Phototoxicity study, and Phot-Draize study conducted in a total of 142 healthy male subjects showed no contact sensitization of the delayed hypersensitivity type, no irritation, no phototoxicity, and no photo-contact sensitization due to Ciclopirox Cream 0.77%.
## Nonclinical Toxicology
- A carcinogenicity study in female mice dosed cutaneously twice per week for 50 weeks followed by a 6-month drug-free observation period prior to necropsy revealed no evidence of tumors at the application site. The following in vitro and in vivo genotoxicity tests have been conducted with ciclopirox olamine: studies to evaluate gene mutation in the Ames SalmonellaIMammalian Microsome Assay (negative) and Yeast Saccharomyces Cerevisiae Assay (negative) and studies to evaluate chromosome aberrations in vivo in the Mouse Dominant Lethal Assay and in the Mouse Micronucleus Assay at 500 mg/kg (negative). The following battery of in vitro genotoxicity tests were conducted with ciclopirox: a chromosome aberration assay in V79 Chinese Hamster Cells, with and without metabolic activation (positive); a gene mutation assay in the HGPRT - test with V79 Chinese Hamster Cells (negative); and a primary DNA damage assay (i.e., unscheduled DNA Synthesis Assay in A549 Human Cells (negative)). An in vitro Cell Transformation Assay in BALB/C3T3 Cells was negative for cell transformation. In an in vivo Chinese Hamster Bone Marrow Cytogenetic Assay, ciclopirox was negative for chromosome aberrations at 5000 mg/kg.
# Clinical Studies
There is limited information regarding Clinical Studies of Ciclopirox in the drug label.
# How Supplied
- Ciclopirox Cream 0.77% (Ciclopirox Olamine Cream USP) is supplied in:
- NDC 0168-0313-15 15 gram tube
- NDC 0168-0313-30 30 gram tube
- NDC 0168-0313-90 90 gram tube
- Store at 20°-25°C (68°-77°F).
## Storage
There is limited information regarding Ciclopirox Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The patient should be told to:
- Use the medication for the full treatment time even though symptoms may have improved and notify the physician if there is no improvement after four weeks.
- Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, or oozing) indicative of possible sensitization.
- Avoid the use of occlusive wrappings or dressings.
# Precautions with Alcohol
- Alcohol-Ciclopirox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CICLOPIROX OLAMINE ®
# Look-Alike Drug Names
There is limited information regarding Ciclopirox Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ciclopirox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [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
Ciclopirox is an antifungal agent that is FDA approved for the {{{indicationType}}} of tinea pedis, tinea cruris, tinea corporis, candidiasis and tinea versicolor. Common adverse reactions include erythema, pruritus, and sensation of burning of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ciclopirox Cream is indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; candidiasis (moniliasis) due to Candida albicans; and tinea (pityriasis) versicolor due to Malassezia furfur.
- Gently massage Ciclopirox Cream 0.77% into the affected and surrounding skin areas twice daily, in the morning and evening. Clinical improvement with relief of pruritus and other symptoms usually occurs within the first week of treatment. If a patient shows no clinical improvement after four weeks of treatment with Ciclopirox Cream the diagnosis should be redetermined. Patients with tinea versicolor usually exhibit clinical and mycological clearing after two weeks of treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ciclopirox in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ciclopirox in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in pediatric patients below the age of 10 years have not been established.
- Ciclopirox Cream is indicated for the topical treatment of the following dermal infections: tinea pedis, tinea cruris, and tinea corporis due to Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis; candidiasis (moniliasis) due to Candida albicans; and tinea (pityriasis) versicolor due to Malassezia furfur.
- Gently massage Ciclopirox Cream 0.77% into the affected and surrounding skin areas twice daily, in the morning and evening. Clinical improvement with relief of pruritus and other symptoms usually occurs within the first week of treatment. If a patient shows no clinical improvement after four weeks of treatment with Ciclopirox Cream the diagnosis should be redetermined. Patients with tinea versicolor usually exhibit clinical and mycological clearing after two weeks of treatment.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ciclopirox in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ciclopirox in pediatric patients.
# Contraindications
- Ciclopirox Cream is contraindicated in individuals who have shown hypersensitivity to any of its components.
# Warnings
- Ciclopirox Cream is not for ophthalmic use. Keep out of reach of children.
### Precautions
- If a reaction suggesting sensitivity or chemical irritation should occur with the use of Ciclopirox Cream, treatment should be discontinued and appropriate therapy instituted.
# Adverse Reactions
## Clinical Trials Experience
- In all controlled clinical studies with 514 patients using Ciclopirox Cream and in 296 patients using the vehicle cream, the incidence of adverse reactions was low. This included pruritus at the site of application in one patient and worsening of the clinical signs and symptoms in another patient using ciclopirox cream and burning in one patient and worsening of the clinical signs and symptoms in another patient using the vehicle cream.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ciclopirox in the drug label.
# Drug Interactions
There is limited information regarding Ciclopirox Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
- Reproduction studies have been performed in the mouse, rat, rabbit, and monkey (via various routes of administration) at doses 10 times or more the topical human dose and have revealed no significant evidence of impaired fertility or harm to the fetus due to ciclopirox. There are, however, no adequate or well-controlled studies in pregnant 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):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ciclopirox in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ciclopirox 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 Ciclopirox Cream 0.77% is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 10 years have not been established.
### Geriatic Use
There is no FDA guidance on the use of Ciclopirox with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Ciclopirox with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ciclopirox with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ciclopirox in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ciclopirox in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ciclopirox in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ciclopirox in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Ciclopirox in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ciclopirox in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ciclopirox in the drug label.
# Pharmacology
## Mechanism of Action
- Ciclopirox is a broad-spectrum, antifungal agent that inhibits the growth of pathogenic dermatophytes, yeasts, and Malassezia furfur. Ciclopirox exhibits fungicidal activity in vitro against isolates of Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis, and Candida albicans.
## Structure
- Ciclopirox Cream 0.77% is for topical use.
- Each gram of Ciclopirox cream 0.77% contains 7.70 mg of Ciclopirox (as Ciclopirox Olamine) in a water miscible vanishing cream base consisting of purified water USP, cetyl alcohol NF, mineral oil USP, octyldodecanol NF, stearyl alcohol NF, cocamide DEA, polysorbate 60 NF, myristyl alcohol, sorbitan monostearate NF, lactic acid USP, and benzyl alcohol NF (1%) as preservative.
- Ciclopirox Cream contains a synthetic, broad-spectrum, antifungal agent ciclopirox (as ciclopirox olamine).
- The chemical name is 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt.
- The CAS Registry Number is 41621-49-2.
- The chemical structure is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Ciclopirox in the drug label.
## Pharmacokinetics
- Pharmacokinetic studies in men with tagged ciclopirox solution in polyethylene glycol 400 showed an average of 1.3% absorption of the dose when it was applied topically to 750 cm2 on the back followed by occlusion for 6 hours. The biological half-life was 1.7 hours and excretion occurred via the kidney. Two days after application only 0.01% of the dose applied could be found in the urine. Fecal excretion was negligible.
- Penetration studies in human cadaverous skin from the back, with ciclopirox cream 0.77% with tagged ciclopirox showed the presence of 0.8 to 1.6% of the dose in the stratum corneum 1.5 to 6 hours after application. The levels in the dermis were still 10 to 15 times above the minimum inhibitory concentrations.
- Autoradiographic studies with human cadaverous skin showed that ciclopirox penetrates into the hair and through the epidermis and hair follicles into the sebaceous glands and dermis, while a portion of the drug remains in the stratum corneum.
- Draize Human Sensitization Assay, 21-Day Cumulative Irritancy study, Phototoxicity study, and Phot-Draize study conducted in a total of 142 healthy male subjects showed no contact sensitization of the delayed hypersensitivity type, no irritation, no phototoxicity, and no photo-contact sensitization due to Ciclopirox Cream 0.77%.
## Nonclinical Toxicology
- A carcinogenicity study in female mice dosed cutaneously twice per week for 50 weeks followed by a 6-month drug-free observation period prior to necropsy revealed no evidence of tumors at the application site. The following in vitro and in vivo genotoxicity tests have been conducted with ciclopirox olamine: studies to evaluate gene mutation in the Ames SalmonellaIMammalian Microsome Assay (negative) and Yeast Saccharomyces Cerevisiae Assay (negative) and studies to evaluate chromosome aberrations in vivo in the Mouse Dominant Lethal Assay and in the Mouse Micronucleus Assay at 500 mg/kg (negative). The following battery of in vitro genotoxicity tests were conducted with ciclopirox: a chromosome aberration assay in V79 Chinese Hamster Cells, with and without metabolic activation (positive); a gene mutation assay in the HGPRT - test with V79 Chinese Hamster Cells (negative); and a primary DNA damage assay (i.e., unscheduled DNA Synthesis Assay in A549 Human Cells (negative)). An in vitro Cell Transformation Assay in BALB/C3T3 Cells was negative for cell transformation. In an in vivo Chinese Hamster Bone Marrow Cytogenetic Assay, ciclopirox was negative for chromosome aberrations at 5000 mg/kg.
# Clinical Studies
There is limited information regarding Clinical Studies of Ciclopirox in the drug label.
# How Supplied
- Ciclopirox Cream 0.77% (Ciclopirox Olamine Cream USP) is supplied in:
- NDC 0168-0313-15 15 gram tube
- NDC 0168-0313-30 30 gram tube
- NDC 0168-0313-90 90 gram tube
- Store at 20°-25°C (68°-77°F).
## Storage
There is limited information regarding Ciclopirox Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The patient should be told to:
- Use the medication for the full treatment time even though symptoms may have improved and notify the physician if there is no improvement after four weeks.
- Inform the physician if the area of application shows signs of increased irritation (redness, itching, burning, blistering, swelling, or oozing) indicative of possible sensitization.
- Avoid the use of occlusive wrappings or dressings.
# Precautions with Alcohol
- Alcohol-Ciclopirox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CICLOPIROX OLAMINE ®[1]
# Look-Alike Drug Names
There is limited information regarding Ciclopirox Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ciclopirox | |
0200d708ac08f1d64c03167872baf75bc3d10c95 | wikidoc | Cigar Dave | Cigar Dave
David Zeplowitz (nicknamed Cigar Dave and The General), is the creator and host of Smoke This!-- a nationally syndicated radio program devoted entirely to cigar smoking and its accompanying lifestyle.
# Biography
Cigar Dave was born in Buffalo, New York, and graduated from Syracuse University in 1986. He currently lives in Tampa, Florida, and "traces his love of cigars to his grandfather, 'Cigar Abe,' who faithfully enjoyed Gold Label Cigars for many years."
# Smoke This!
## History
Cigar Dave hosted the first broadcast of Smoke This! in July, 1995. The broadcast ran for one hour on the Tampa radio station WSUN. The show quickly gained listeners that Dave, The General, refers to as Cigar Lieutenants. In December, 1995, Smoke This! began its two hour long broadcast.
## Broadcast time
Smoke This! broadcasts on Saturday afternoons from noon to 2:00 p.m. Eastern time on WFLA, and on Sirius Satellite Radio, XM Satellite Radio, and the overseas Shortwave Radio. The recording is broadcast tape-delayed on over 90 radio stations across the United States via the Talk Shows USA network, and can be listened to live at the Cigar Dave website.
A brief attempt at a "third hour" spinoff, Poker Boulevard, took place on WFLA in 2005, but was effectively cancelled after a short run when an infomercial took the slot.
## Content
Cigar Dave opens his show with the greeting "Long Ashes!" and the "national cigar-lighting ritual," a time when both Dave and his listeners light up their cigars. Dave routinely discusses cigars, spirits, and current events with his listeners. The General promotes the enjoyment of cigars and spirits in moderation.
### Orwell's 1984
Always "truthful" (as he says) and usually politically incorrect, the General "leads his troops" and "wages battle" in the fight against America's self-anointed "Pleasure Police" and "Big Pleasure." The "Pleasure Police" and "Big Pleasure" are plays on George Orwell's "Thought Police" and "Big Brother" themes from the novel 1984, where governments and corporations combine mass surveillance assets to oversee all aspects of an individual's professional and personal life.
In Cigar Dave's broadcasts, "Pleasure Police" refers to politicians and other public figures who The General portrays as striving to set (and strictly enforce) laws that would outlaw personal pursuit of otherwise legal pleasures-- such as smoking cigars, pipes, and other tobacco products, and imbibing "adult beverages" such as beers, wines, spirits, and even coffee, in public.
"Big Pleasure" refers to employers, insurance companies, and other organizations that, for example, discriminate against employees, customers, or other guests whom might happen to legally smoke or drink, on their own time-- due to the perception of increased health risks to themselves and others they may come into contact with. These "Pleasure Police," according to The General, use outdated, flawed, and repudiated scientific studies to "prove" various health issues claimed to be caused by "second hand smoke," among others.
### "Cigar Draft"
One of the features of the Smoke This! broadcast is the annual "Cigar Draft," which mimics the annual sports drafts conducted by Major League Baseball and the National Football League. Listeners to the live program call in to the show, and select their favorite cigar by brand, version, size, shape, and vintage.
### Tasting Events
Cigar Dave also occasionally hosts on-air tasting events of various alcoholic beverages, usually accompanied by a professional sommelier, with the idea of pairing beverages with cigars of appropriate strength and character so they complement each other.
## Nicknames
- The King of Coronas
- The Pope of Panatelas
- The Rabbi of Robustos
- The Sultan of Smoke
- The Professor of Puff
- The Prince of Pleasure
- The Cigar Sommelier
- The Connoisseur-in-Chief.
# The Cigar Dave Show
In 2006, Cigar Dave began hosting his own television show called "The Cigar Dave Show." It currently airs on ABC Action News (WFTS) in Tampa, Florida on Saturday nights at 11:35pm and focuses on cigars, fine wines, grilling, and music around the Tampa Bay area. | Cigar Dave
David Zeplowitz (nicknamed Cigar Dave and The General), is the creator and host of Smoke This!-- a nationally syndicated radio program devoted entirely to cigar smoking and its accompanying lifestyle.
# Biography
Cigar Dave was born in Buffalo, New York, and graduated from Syracuse University in 1986. He currently lives in Tampa, Florida, and "traces his love of cigars to his grandfather, 'Cigar Abe,' who faithfully enjoyed Gold Label Cigars for many years."[1]
# Smoke This!
## History
Cigar Dave hosted the first broadcast of Smoke This! in July, 1995. The broadcast ran for one hour on the Tampa radio station WSUN. The show quickly gained listeners that Dave, The General, refers to as Cigar Lieutenants. In December, 1995, Smoke This! began its two hour long broadcast.
## Broadcast time
Smoke This! broadcasts on Saturday afternoons from noon to 2:00 p.m. Eastern time on WFLA, and on Sirius Satellite Radio, XM Satellite Radio, and the overseas Shortwave Radio. The recording is broadcast tape-delayed on over 90 radio stations across the United States via the Talk Shows USA network, and can be listened to live at the Cigar Dave website.
A brief attempt at a "third hour" spinoff, Poker Boulevard, took place on WFLA in 2005, but was effectively cancelled after a short run when an infomercial took the slot.
## Content
Cigar Dave opens his show with the greeting "Long Ashes!" and the "national cigar-lighting ritual,"[1] a time when both Dave and his listeners light up their cigars. Dave routinely discusses cigars, spirits, and current events with his listeners. The General promotes the enjoyment of cigars and spirits in moderation.
### Orwell's 1984
Always "truthful" (as he says) and usually politically incorrect, the General "leads his troops" and "wages battle" in the fight against America's self-anointed "Pleasure Police" and "Big Pleasure." The "Pleasure Police" and "Big Pleasure" are plays on George Orwell's "Thought Police" and "Big Brother" themes from the novel 1984, where governments and corporations combine mass surveillance assets to oversee all aspects of an individual's professional and personal life.
In Cigar Dave's broadcasts, "Pleasure Police" refers to politicians and other public figures who The General portrays as striving to set (and strictly enforce) laws that would outlaw personal pursuit of otherwise legal pleasures-- such as smoking cigars, pipes, and other tobacco products, and imbibing "adult beverages" such as beers, wines, spirits, and even coffee, in public.
"Big Pleasure" refers to employers, insurance companies, and other organizations that, for example, discriminate against employees, customers, or other guests whom might happen to legally smoke or drink, on their own time-- due to the perception of increased health risks to themselves and others they may come into contact with. These "Pleasure Police," according to The General, use outdated, flawed, and repudiated scientific studies to "prove" various health issues claimed to be caused by "second hand smoke," among others.
### "Cigar Draft"
One of the features of the Smoke This! broadcast is the annual "Cigar Draft," [2][3] which mimics the annual sports drafts conducted by Major League Baseball and the National Football League. Listeners to the live program call in to the show, and select their favorite cigar by brand, version, size, shape, and vintage.
### Tasting Events
Cigar Dave also occasionally hosts on-air tasting events of various alcoholic beverages, usually accompanied by a professional sommelier, with the idea of pairing beverages with cigars of appropriate strength and character so they complement each other.
## Nicknames
- The King of Coronas
- The Pope of Panatelas
- The Rabbi of Robustos
- The Sultan of Smoke
- The Professor of Puff
- The Prince of Pleasure
- The Cigar Sommelier
- The Connoisseur-in-Chief.
# The Cigar Dave Show
In 2006, Cigar Dave began hosting his own television show called "The Cigar Dave Show." It currently airs on ABC Action News (WFTS) in Tampa, Florida on Saturday nights at 11:35pm and focuses on cigars, fine wines, grilling, and music around the Tampa Bay area. | https://www.wikidoc.org/index.php/Cigar_Dave | |
d559636db10b99802249942a517b9a4661c9354c | wikidoc | Ciliopathy | Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies.
# History
Although non-motile or primary cilia were first described in 1898, "cell biologists largely ignored them." But "microscopists continued to document their presence in the cells of most vertebrate organisms." The "primary cilium was long considered--with few exceptions--to be a largely useless evolutionary vestige, a vestigial organelle. Recent research has revealed an initial understanding that cilia are essential to many of the body's organs".
Recent advances in mammalian genetic research have facilitated the elucidation of a molecular basis for a number of dysfunctional mechanisms in both motile and primary cilia structures of the cell. "Numerous critical developmental signaling pathways" essential to cellular development have been discovered. These are principally but not exclusively found in the non-motile or primary cilia. A number of common observable characteristics of mamallian genetic disorders and diseases are caused by ciliary dysgenesis and dysfunction. Once identified, these characteristics thus describe a set of hallmarks of a ciliopathy.
Cilia have recently been implicated in a wide variety of human genetic diseases by "the discovery that numerous proteins involved in mammalian disease localize to the basal bodies and cilia." For example, in just a single area of human disease physiology, cystic renal disease, cilia-related genes and proteins have been identified to have causal effect in polycystic kidney disease, nephronophthisis, Senior-Loken syndrome type 5, orofaciodigital syndrome type 1 and Bardet-Biedl syndrome.
# Similar genes can result in a range of different diseases
"Just as different genes can contribute to similar diseases, so the same genes and families of genes can play a part in a range of different diseases." For example, in just two of the diseases caused by malfunctioning cilia, Meckel-Gruber syndrome and Bardet-Biedl syndrome, patients who carry mutations in genes associated with both diseases "have unique symptoms that are not seen in either condition alone." The genes linked to the two different conditions "interact with each other during development." Systems biologists are endeavoring to define functional modules containing multiple genes and then look at disorders whose phenotypes fit into such modules.
# Ciliopathies
"The phenotypic parameters that define a ciliopathy may be used to both recognize the cellular basis of a number of genetic disorders and to facilitate the diagnosis and treatment of some diseases of unknown etiology".
## Syndromes and diseases with a known cilia-based causal mechanism
- Alstrom syndrome
- Bardet-Biedl syndrome,
- early embryonic death (some cases)
- hydrocephalus (some cases)
- Joubert syndrome
- Meckel-Gruber syndrome
- nephronophthisis,
- orofaciodigital syndrome type 1
- polycystic kidney disease,
- polycystic liver disease
- primary ciliary dyskinesia
- retinal degeneration (some forms)
- Senior-Loken syndrome
## Implied or suspected ciliopathies
- agenesis of the corpus callosum
- anencephaly
- breathing abnomalities
- cerebellar vermis hypoplasia
- Dandy-Walker malformation
- diabetes
- Ellis-van Creveld syndrome
- exencephaly
- eye movement abnormalities
- liver disease
- hypoplasia of the corpus callosum
- hypotonia
- reproductive sterility
- Jeune asphyxiating thoracic dystrophy
- Juvenile myoclonic epilepsy (JME)
- Kartagener syndrome
- Marden-Walker syndrome
- "mental retardation/developmental delay" or "other cognitive defects"
- obesity
- polydactyly
- posterior encephalocele
- respiratory dysfunction
- "recurent respiratory infections"
- renal cystic disease
- retinitis pigmentosa
- sensorineural deafness
- situs inversus/Isomerism
- spina bifida
# Clinical symptoms
A wide variety of symptoms are potential clinical features of ciliopathy.
- Defective thermosensation or mechanosensation.
- (add to the list, with citations, here) | Ciliopathy
A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies.
# History
Although non-motile or primary cilia were first described in 1898, "cell biologists largely ignored them." But "microscopists continued to document their presence in the cells of most vertebrate organisms." The "primary cilium was long considered--with few exceptions--to be a largely useless evolutionary vestige, a vestigial organelle. Recent research has revealed an initial understanding that cilia are essential to many of the body's organs"[1].
Recent advances in mammalian genetic research have facilitated the elucidation of a molecular basis for a number of dysfunctional mechanisms in both motile and primary cilia structures of the cell. "Numerous critical developmental signaling pathways" essential to cellular development have been discovered. These are principally but not exclusively found in the non-motile or primary cilia. A number of common observable characteristics of mamallian genetic disorders and diseases are caused by ciliary dysgenesis and dysfunction. Once identified, these characteristics thus describe a set of hallmarks of a ciliopathy[2].
Cilia have recently been implicated in a wide variety of human genetic diseases by "the discovery that numerous proteins involved in mammalian disease localize to the basal bodies and cilia." For example, in just a single area of human disease physiology, cystic renal disease, cilia-related genes and proteins have been identified to have causal effect in polycystic kidney disease, nephronophthisis, Senior-Loken syndrome type 5, orofaciodigital syndrome type 1 and Bardet-Biedl syndrome[3].
# Similar genes can result in a range of different diseases
"Just as different genes can contribute to similar diseases, so the same genes and families of genes can play a part in a range of different diseases." For example, in just two of the diseases caused by malfunctioning cilia, Meckel-Gruber syndrome and Bardet-Biedl syndrome, patients who carry mutations in genes associated with both diseases "have unique symptoms that are not seen in either condition alone." The genes linked to the two different conditions "interact with each other during development." Systems biologists are endeavoring to define functional modules containing multiple genes and then look at disorders whose phenotypes fit into such modules.
# Ciliopathies
"The phenotypic parameters that define a ciliopathy may be used to both recognize the cellular basis of a number of genetic disorders and to facilitate the diagnosis and treatment of some diseases of unknown etiology"[2].
## Syndromes and diseases with a known cilia-based causal mechanism
- Alstrom syndrome[2]
- Bardet-Biedl syndrome[2],[3]
- early embryonic death (some cases)[2]
- hydrocephalus (some cases)[2]
- Joubert syndrome[2]
- Meckel-Gruber syndrome[2]
- nephronophthisis[2],[3]
- orofaciodigital syndrome type 1[3]
- polycystic kidney disease[2],[3]
- polycystic liver disease[2]
- primary ciliary dyskinesia[2]
- retinal degeneration (some forms)[2]
- Senior-Loken syndrome[3]
## Implied or suspected ciliopathies
- agenesis of the corpus callosum[2]
- anencephaly[2]
- breathing abnomalities[2]
- cerebellar vermis hypoplasia[2]
- Dandy-Walker malformation[2]
- diabetes[2]
- Ellis-van Creveld syndrome[2]
- exencephaly[2]
- eye movement abnormalities[2]
- liver disease[2]
- hypoplasia of the corpus callosum[2]
- hypotonia[2]
- reproductive sterility[2]
- Jeune asphyxiating thoracic dystrophy[2]
- Juvenile myoclonic epilepsy (JME) [4]
- Kartagener syndrome[2]
- Marden-Walker syndrome[2]
- "mental retardation/developmental delay" or "other cognitive defects"[2]
- obesity[2]
- polydactyly[2]
- posterior encephalocele[2]
- respiratory dysfunction[2]
- "recurent respiratory infections"[2]
- renal cystic disease[2]
- retinitis pigmentosa[2]
- sensorineural deafness[2]
- situs inversus/Isomerism[2]
- spina bifida[2]
# Clinical symptoms
A wide variety of symptoms are potential clinical features of ciliopathy.
- Defective thermosensation or mechanosensation[5].
- (add to the list, with citations, here) | https://www.wikidoc.org/index.php/Ciliopathy | |
8f416a8894c538885684139000dbe23f9829c8e5 | wikidoc | Cilostazol | Cilostazol
# Disclaimer
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# Black Box Warning
# Overview
Cilostazol is a phosphodiesterase 3 (PDE3) inhibitor and platelet aggregation inhibitor that is FDA approved for the {{{indicationType}}} of intermittent claudication, as indicated by an increased walking distance. There is a Black Box Warning for this drug as shown here. Common adverse reactions include palpitations, peripheral edema, tachyarrhythmia, abdominal pain, diarrhea, indigestion, decreased platelet aggregation, backache, myalgia, dizziness, headache, cough, pharyngitis, and rhinitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 100 mg PO bid, taken at least half an hour before or two hours after breakfast and dinner.
- A dose of 50 mg PO bid should be considered during coadministration of such inhibitors of CYP3A4 as ketoconazole, itraconazole, erythromycin and diltiazem, and during coadministration of such inhibitors of CYP2C19 as omeprazole.
- Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.
- Discontinuation of Therapy
- The available data suggest that the dosage of Cilostazol can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Chest Physicians (ACCP)
- Dosing Information
- In patients with a history of noncardioembolic ischemic stroke or TIA, ACCP recommends long-term treatment with aspirin (75-100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended-release dipyridamole (25 mg/200 mg bid), or Cilostazol (100 mg bid) over no antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), the combination of clopidogrel plus aspirin (Grade 1B), or triflusal (Grade 2B).
- Of the recommended antiplatelet regimens, ACCP suggests clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or Cilostazol (Grade 2C).
- Developed by: American College of Chest Physicians (ACCP)
- Dosing Information
- Use of low-dose aspirin 75 to 100 mg daily and clopidogrel 75 mg daily alone is recommended, rather than Cilostazol in addition to these drugs (Grade 1B).
- Aspirin 75 to 100 mg daily and clopidogrel 75 mg daily as part of dual antiplatelet therapy is suggested, rather than the use of either drug with Cilostazol (Grade 1B).
- Cilostazol 100 mg twice daily as substitute for either low-dose aspirin 75 to 100 mg daily or clopidogrel 75 mg daily as part of a dual antiplatelet regimen is suggested in patients with an allergy or intolerance of either drug class (Grade 2C).
### Non–Guideline-Supported Use
- Dosing Information
- 100–200 mg PO qd
- Dosing Information
- Cilostazol 200 mg/day plus aspirin 100 mg/day significantly reduced the rate of restenosis of femoropopliteal lesions, and significantly improved event-free survival at 12 months after percutaneous transluminal angioplasty with provisional nitinol stenting when compared with use of aspirin alone.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of Cilostazole in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cilostazol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cilostazol in pediatric patients.
# Contraindications
- Congestive heart failure of any severity
- Hemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer and intracranial bleeding
- Hypersensitivity to any of its components
# Warnings
### Precautions
- Hematologic Adverse Reactions
- Rare cases have been reported of thrombocytopenia or leukopenia progressing to agranulocytosis when Cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of Cilostazol.
- Use with Clopidogrel
- There is limited information with respect to the efficacy or safety of the concurrent use of Cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with Cilostazol and clopidogrel, caution is advised for checking bleeding times during coadministration.
- Hepatic Impairment
- Patients with moderate or severe hepatic impairment have not been studied in clinical trials. Special caution is advised when Cilostazol is used in such patients.
- Renal Impairment
- Patients on dialysis have not been studied, but, it is unlikely that Cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%).
- Special caution is advised when Cilostazol is used in patients with severe renal impairment: estimated creatinine clearance < 25 mL/min.
- Use with other antiplatelet agents
- Cilostazol inhibits platelet aggregation but in a reversible manner. Caution is advised in patients at risk of bleeding from surgery or pathologic processes. Platelet aggregability returns to normal within 96 hours of stopping Cilostazol. Caution is advised in patients receiving both Cilostazol and any other antiplatelet agent, or in patients with thrombocytopenia.
- Cardiovascular Toxicity
- Repeated oral administration of Cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound Cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg b.i.d. Similar lesions have been reported in dogs following the administration of other positive inotropic agents (including PDE III inhibitors) and/or vasodilating agents. No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of Cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound Cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the MRHD. Cardiovascular lesions were also not seen in rats following 52 weeks of administration of Cilostazol at doses up to 150 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound Cilostazol were about 0.5 and 5 times (male and female rats, respectively) the exposure in humans at the MRHD. In female rats, Cilostazol AUCs were similar at 150 and 1500 mg/kg/day. Cardiovascular lesions were also not observed in monkeys after oral administration of Cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of Cilostazol produced pharmacologic effects in monkeys, plasma Cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated with cardiovascular lesions.
# Adverse Reactions
## Clinical Trials Experience
- Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. Cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on Cilostazol and 134 days for patients on placebo.
- The only adverse event resulting in discontinuation of therapy in ≥ 3% of patients treated with Cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with Cilostazol 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for Cilostazol (all doses) versus 0.1% for placebo.
- The most commonly reported adverse events, occurring in ≥ 2% of patients treated with Cilostazol 50 or 100 mg b.i.d., are shown in the table (below).
- Other events seen with an incidence of ≥ 2%, but occurring in the placebo group at least as frequently as in the 100 mg b.i.d. group were: asthenia, hypertension, vomiting, leg cramps, hypesthesia, paresthesia, dyspnea, rash, hematuria, urinary tract infection, flu syndrome, angina pectoris, arthritis, and bronchitis.
- Less frequent adverse events (<2%) that were experienced by patients exposed to Cilostazol 50 mg b.i.d. or 100 mg b.i.d. in the eight controlled clinical trials and that occurred at a frequency in the 100 mg b.i.d. group greater than in the placebo group, regardless of suspected drug relationship, are listed below.
Chills, face edema, fever, generalized edema, malaise, neck rigidity, pelvic pain, retroperitoneal hemorrhage.
Atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, congestive heart failure, cardiac arrest, hemorrhage, hypotension, myocardial infarction, myocardial ischemia, nodal arrhythmia, postural hypotension, supraventricular tachycardia, syncope, varicose vein, vasodilation, ventricular extrasystoles, ventricular tachycardia.
Anorexia, cholelithiasis, colitis, duodenal ulcer, duodenitis, esophageal hemorrhage, esophagitis, increased GGT, gastritis, gastroenteritis, gum hemorrhage, hematemesis, melena, peptic ulcer, periodontal abscess, rectal hemorrhage, peptic ulcer, tongue edema.
Diabetes mellitus.
Anemia, ecchymosis, iron deficiency anemia, polycythemia, purpura.
Increased creatinine, gout, hyperlipemia, hyperuricemia.
Arthralgia, bone pain, bursitis.
Anxiety, insomnia, neuralgia.
Asthma, epistaxis, hemoptysis, pneumonia, sinusitis.
Dry skin, furunculosis, skin hypertrophy, urticaria.
Amblyopia, blindness, conjunctivitis, diplopia, ear pain, eye hemorrhage, retinal hemorrhage, tinnitus.
Albuminuria, cystitis, urinary frequency, vaginal hemorrhage, vaginitis.
## Postmarketing Experience
The following events have been reported spontaneously from worldwide postmarketing experience since the launch of Cilostazol in the U.S.
Agranulocytosis, aplastic anemia, granulocytopenia, thrombocytopenia, leukopenia, bleeding tendency
Torsades de pointes, QTc prolongation (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, heart failure and bradyarrhythmia, when treated with Cilostazol. Cilostazol was used "off label" due to its positive chronotropic action.)
Gastrointestinal hemorrhage
Pain, chest pain, hot flushes
Hepatic dysfunction/Abnormal liver function tests, jaundice
Extradural hematoma and subdural hematoma
Blood glucose increased, blood uric acid increased, platelet count decreased, white blood cell count decreased, increase in BUN (blood urea nitrogen increased), blood pressure increase
Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident
Pulmonary hemorrhage, interstitial pneumonia
Subcutaneous hemorrhage, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa)
Subacute thrombosis (These cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of Cilostazol for prevention of thrombotic complication after coronary stenting.)
# Drug Interactions
- Since Cilostazol is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when Cilostazol is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole. Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of Cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of Cilostazol among patients concurrently treated with diltiazem, an inhibitor of CYP3A4. Cilostazol does not, however, appear to cause increased blood levels of drugs metabolized by CYP3A4, as it had no effect on lovastatin, a drug with metabolism very sensitive to CYP3A4 inhibition.
- Short-term (≤4 days) coadministration of aspirin with Cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% - 37% when compared to either aspirin or Cilostazol alone. Short-term (≤ 4 days) coadministration of aspirin with Cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to Cilostazol alone and by 48% compared to aspirin alone. However, short-term coadministration of aspirin with Cilostazol had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term coadministration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with Cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75-81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking Cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.
- The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2, and CYP2C19, and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after a single 25 mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and Cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.
- Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of Cilostazol.
Strong Inhibitors of CYP3A4
- A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to coadministration of single doses of ketoconazole 400 mg and Cilostazol 100 mg. This regimen increased Cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, and sertraline, would be expected to have a similar effect.
Moderate Inhibitors of CYP3A4
- Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg q 8 h with a single dose of Cilostazol 100 mg increased Cilostazol Cmax by 47% and AUC by 73%. Inhibition of Cilostazol metabolism by erythromycin increased the AUC of 4 '-trans-hydroxy-Cilostazol by 141%. Other macrolide antibiotics (e.g., clarithromycin), but not all (e.g., azithromycin), would be expected to have a similar effect.
- Diltiazem: Diltiazem 180 mg decreased the clearance of Cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.
- Grapefruit juice: Grapefruit juice increased the Cmax of Cilostazol by ~50%, but had no effect on AUC.
Omeprazole
- Coadministration of omeprazole did not significantly affect the metabolism of Cilostazol, but the systemic exposure to 3,4- dehydro-Cilostazol was increased by 69%, probably the result of omeprazole's potent inhibition of CYP2C19.
Quinidine
- Concomitant administration of quinidine with a single dose of Cilostazol 100 mg did not alter Cilostazol pharmacokinetics.
Lovastatin
- The concomitant administration of lovastatin with Cilostazol decreases Cilostazol Css, max and AUC by 15%. There is also a decrease, although nonsignificant, in Cilostazol metabolite concentrations. Coadministration of Cilostazol with lovastatin increases lovastatin and β-hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- In a rat developmental toxicity study, oral administration of 1000 mg Cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposure to unbound Cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound Cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydro-Cilostazol was barely detectable.
- When Cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).
- There are no adequate and well-controlled studies in pregnant women.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cilostazol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cilostazol during labor and delivery.
### Nursing Mothers
- Transfer of Cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue Cilostazol.
### Pediatric Use
- The safety and effectiveness of Cilostazol in pediatric patients have not been established.
### Geriatic Use
- Of the total number of subjects (n=2274) in clinical studies of Cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of Cilostazol and its metabolites.
### Gender
There is no FDA guidance on the use of Cilostazol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cilostazol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cilostazol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cilostazol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cilostazol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cilostazol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cilostazol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cilostazol in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Information on acute overdosage with Cilostazol in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The oral LD50 of Cilostazol is >5 g/kg in mice and rats and >2 g/kg in dogs.
### Management
- The patient should be carefully observed and given supportive treatment. Since Cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by hemodialysis or peritoneal dialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cilostazol in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of the effects of Cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively. Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking Cilostazol. After 12 weeks, as compared to placebo, Cilostazol 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4 mg/dL (≥10%).
- Cilostazol affects both vascular beds and cardiovascular function. It produces nonhomogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of Cilostazol.
- In dogs or cynomolgous monkeys, Cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more Cilostazol-treated patients had increases in ventricular premature beats and nonsustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related.
## Structure
- Cilostazol is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). The molecular formula of Cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-- 3,4-dihydro-2(1H)-quinolinone. The structural formula is:
- Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in methanol and ethanol, and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.
- Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: carboxymethylcellulose calcium, pregelantized starch, hypromellose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.
## Pharmacodynamics
- Cilostazol is 95 - 98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-Cilostazol is 97.4% and for 4 '-trans-hydroxy-Cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of Cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of Cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.
## Pharmacokinetics
- Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of Cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of Cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).
- The mean ± SEM plasma concentration-time profile at steady state after multiple dosing of Cilostazol 100 mg b.i.d. is shown below:
- Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in Cilostazol's metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-Cilostazol, the most active of the metabolites, is unknown.
- Following oral administration of 100 mg radiolabeled Cilostazol, 56% of the total analytes in plasma was Cilostazol, 15% was 3,4-dehydro-Cilostazol (4-7 times as active as Cilostazol), and 4% was 4 '-trans-hydroxy-Cilostazol (one fifth as active as Cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged Cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3, 4- dehydro-Cilostazol. About 30% of the dose was excreted in urine as 4 '-trans-hydroxy-Cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
- The total and unbound oral clearances, adjusted for body weight, of Cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50-to- 80-year-old age range.
- Population pharmacokinetic analysis suggests that smoking decreased Cilostazol exposure by about 20%.
- The pharmacokinetics of Cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects. Patients with moderate or severe hepatic impairment have not been studied.
- The total pharmacologic activity of Cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it is unlikely that Cilostazol can be removed efficiently by dialysis because of its high protein binding (95 - 98%).
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Dietary administration of Cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.
- Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day.
- At this dose, systemic exposures (AUCs) to unbound Cilostazol were less than 1.5 times in males, and about 5 times in females, the exposure in humans at the MRHD.
# Clinical Studies
- The ability of Cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks' duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998), and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.
- Compared to patients treated with placebo, patients treated with Cilostazol 50 or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of Cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.
- The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.
- Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with Cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%. The corresponding changes in the placebo group were -10% to 41%.
- The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either Cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta-blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.
- A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of Cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8 to 8.4%) on Cilostazol and 6.8% (95% CI of 1.9 to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on Cilostazol, which was the a priori study hypothesis.
# How Supplied
- Cilostazol is supplied as 50 mg and 100 mg tablets. The 50 mg tablets are white, round, debossed with B167 on one side and 50 on the other, and are provided in bottles of 60 tablets (NDC #51991-167-06) and 1000 tablets (NDC #51991-167-10).
- The 100 mg tablets are white, round, debossed with B168 on one side and 100 on the other, and provided in bottles of 60 tablets (NDC #51991-168-06) and 1000 tablets (NDC #51991-168-10).
- Store Cilostazol tablets at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)
## Storage
There is limited information regarding Cilostazol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- What is Cilostazol for?
- Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.
- What is intermittent claudication?
- Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.
- What treatments are available for intermittent claudication?
- The three main treatments available for intermittent claudication are:
- Exercise. Your doctor may advise an exercise program.
- Medication. Your doctor may prescribe a medication such as Cilostazol.
- Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.
- How does Cilostazol work?
- The exact way that many drugs work is not well understood. Although how Cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.
- Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.
- Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from Cilostazol after 12 weeks you and your doctor may wish to discuss other forms of treatment.
- Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.
- Who should not take Cilostazol?
- Patients who have congestive heart failure (CHF) must not take Cilostazol. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.
- How should Cilostazol be taken?
- Follow your doctor's advice about how to take Cilostazol.
- You should take Cilostazol twice a day, at least one half-hour before or two hours after breakfast and dinner. Take Cilostazol at about the same times each day.
- Do not share Cilostazol with anyone else. It was prescribed only for you.
- Keep Cilostazol and all drugs out of the reach of children.
- Can Cilostazol be taken with other drugs?
- Certain drugs and foods can increase the amount of Cilostazol in the blood. Because of this, your doctor may adjust your dose of Cilostazol or even stop it if you are taking or are going to take one of the following medications.
# Precautions with Alcohol
- Alcohol-Cilostazol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Pletal®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Cilostazol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Black Box Warning
# Overview
Cilostazol is a phosphodiesterase 3 (PDE3) inhibitor and platelet aggregation inhibitor that is FDA approved for the {{{indicationType}}} of intermittent claudication, as indicated by an increased walking distance. There is a Black Box Warning for this drug as shown here. Common adverse reactions include palpitations, peripheral edema, tachyarrhythmia, abdominal pain, diarrhea, indigestion, decreased platelet aggregation, backache, myalgia, dizziness, headache, cough, pharyngitis, and rhinitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- 100 mg PO bid, taken at least half an hour before or two hours after breakfast and dinner.
- A dose of 50 mg PO bid should be considered during coadministration of such inhibitors of CYP3A4 as ketoconazole, itraconazole, erythromycin and diltiazem, and during coadministration of such inhibitors of CYP2C19 as omeprazole.
- Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.
- Discontinuation of Therapy
- The available data suggest that the dosage of Cilostazol can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Chest Physicians (ACCP)
- Dosing Information
- In patients with a history of noncardioembolic ischemic stroke or TIA, ACCP recommends long-term treatment with aspirin (75-100 mg once daily), clopidogrel (75 mg once daily), aspirin/extended-release dipyridamole (25 mg/200 mg bid), or Cilostazol (100 mg bid) over no antiplatelet therapy (Grade 1A), oral anticoagulants (Grade 1B), the combination of clopidogrel plus aspirin (Grade 1B), or triflusal (Grade 2B).
- Of the recommended antiplatelet regimens, ACCP suggests clopidogrel or aspirin/extended-release dipyridamole over aspirin (Grade 2B) or Cilostazol (Grade 2C).
- Developed by: American College of Chest Physicians (ACCP)
- Dosing Information
- Use of low-dose aspirin 75 to 100 mg daily and clopidogrel 75 mg daily alone is recommended, rather than Cilostazol in addition to these drugs (Grade 1B).
- Aspirin 75 to 100 mg daily and clopidogrel 75 mg daily as part of dual antiplatelet therapy is suggested, rather than the use of either drug with Cilostazol (Grade 1B).
- Cilostazol 100 mg twice daily as substitute for either low-dose aspirin 75 to 100 mg daily or clopidogrel 75 mg daily as part of a dual antiplatelet regimen is suggested in patients with an allergy or intolerance of either drug class (Grade 2C).
### Non–Guideline-Supported Use
- Dosing Information
- 100–200 mg PO qd[1][2]
- Dosing Information
- Cilostazol 200 mg/day plus aspirin 100 mg/day significantly reduced the rate of restenosis of femoropopliteal lesions, and significantly improved event-free survival at 12 months after percutaneous transluminal angioplasty with provisional nitinol stenting when compared with use of aspirin alone.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of Cilostazole in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cilostazol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cilostazol in pediatric patients.
# Contraindications
- Congestive heart failure of any severity
- Hemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer and intracranial bleeding
- Hypersensitivity to any of its components
# Warnings
### Precautions
- Hematologic Adverse Reactions
- Rare cases have been reported of thrombocytopenia or leukopenia progressing to agranulocytosis when Cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of Cilostazol.
- Use with Clopidogrel
- There is limited information with respect to the efficacy or safety of the concurrent use of Cilostazol and clopidogrel, a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with Cilostazol and clopidogrel, caution is advised for checking bleeding times during coadministration.
- Hepatic Impairment
- Patients with moderate or severe hepatic impairment have not been studied in clinical trials. Special caution is advised when Cilostazol is used in such patients.
- Renal Impairment
- Patients on dialysis have not been studied, but, it is unlikely that Cilostazol can be removed efficiently by dialysis because of its high protein binding (95-98%).
- Special caution is advised when Cilostazol is used in patients with severe renal impairment: estimated creatinine clearance < 25 mL/min.
- Use with other antiplatelet agents
- Cilostazol inhibits platelet aggregation but in a reversible manner. Caution is advised in patients at risk of bleeding from surgery or pathologic processes. Platelet aggregability returns to normal within 96 hours of stopping Cilostazol. Caution is advised in patients receiving both Cilostazol and any other antiplatelet agent, or in patients with thrombocytopenia.
- Cardiovascular Toxicity
- Repeated oral administration of Cilostazol to dogs (30 or more mg/kg/day for 52 weeks, 150 or more mg/kg/day for 13 weeks, and 450 mg/kg/day for 2 weeks), produced cardiovascular lesions that included endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery, and coronary arteritis and periarteritis. At the lowest dose associated with cardiovascular lesions in the 52-week study, systemic exposure (AUC) to unbound Cilostazol was less than that seen in humans at the maximum recommended human dose (MRHD) of 100 mg b.i.d. Similar lesions have been reported in dogs following the administration of other positive inotropic agents (including PDE III inhibitors) and/or vasodilating agents. No cardiovascular lesions were seen in rats following 5 or 13 weeks of administration of Cilostazol at doses up to 1500 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound Cilostazol were only about 1.5 and 5 times (male and female rats, respectively) the exposure seen in humans at the MRHD. Cardiovascular lesions were also not seen in rats following 52 weeks of administration of Cilostazol at doses up to 150 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound Cilostazol were about 0.5 and 5 times (male and female rats, respectively) the exposure in humans at the MRHD. In female rats, Cilostazol AUCs were similar at 150 and 1500 mg/kg/day. Cardiovascular lesions were also not observed in monkeys after oral administration of Cilostazol for 13 weeks at doses up to 1800 mg/kg/day. While this dose of Cilostazol produced pharmacologic effects in monkeys, plasma Cilostazol levels were less than those seen in humans given the MRHD, and those seen in dogs given doses associated with cardiovascular lesions.
# Adverse Reactions
## Clinical Trials Experience
- Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. Cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on Cilostazol and 134 days for patients on placebo.
- The only adverse event resulting in discontinuation of therapy in ≥ 3% of patients treated with Cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with Cilostazol 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included palpitation and diarrhea, both 1.1% for Cilostazol (all doses) versus 0.1% for placebo.
- The most commonly reported adverse events, occurring in ≥ 2% of patients treated with Cilostazol 50 or 100 mg b.i.d., are shown in the table (below).
- Other events seen with an incidence of ≥ 2%, but occurring in the placebo group at least as frequently as in the 100 mg b.i.d. group were: asthenia, hypertension, vomiting, leg cramps, hypesthesia, paresthesia, dyspnea, rash, hematuria, urinary tract infection, flu syndrome, angina pectoris, arthritis, and bronchitis.
- Less frequent adverse events (<2%) that were experienced by patients exposed to Cilostazol 50 mg b.i.d. or 100 mg b.i.d. in the eight controlled clinical trials and that occurred at a frequency in the 100 mg b.i.d. group greater than in the placebo group, regardless of suspected drug relationship, are listed below.
Chills, face edema, fever, generalized edema, malaise, neck rigidity, pelvic pain, retroperitoneal hemorrhage.
Atrial fibrillation, atrial flutter, cerebral infarct, cerebral ischemia, congestive heart failure, cardiac arrest, hemorrhage, hypotension, myocardial infarction, myocardial ischemia, nodal arrhythmia, postural hypotension, supraventricular tachycardia, syncope, varicose vein, vasodilation, ventricular extrasystoles, ventricular tachycardia.
Anorexia, cholelithiasis, colitis, duodenal ulcer, duodenitis, esophageal hemorrhage, esophagitis, increased GGT, gastritis, gastroenteritis, gum hemorrhage, hematemesis, melena, peptic ulcer, periodontal abscess, rectal hemorrhage, peptic ulcer, tongue edema.
Diabetes mellitus.
Anemia, ecchymosis, iron deficiency anemia, polycythemia, purpura.
Increased creatinine, gout, hyperlipemia, hyperuricemia.
Arthralgia, bone pain, bursitis.
Anxiety, insomnia, neuralgia.
Asthma, epistaxis, hemoptysis, pneumonia, sinusitis.
Dry skin, furunculosis, skin hypertrophy, urticaria.
Amblyopia, blindness, conjunctivitis, diplopia, ear pain, eye hemorrhage, retinal hemorrhage, tinnitus.
Albuminuria, cystitis, urinary frequency, vaginal hemorrhage, vaginitis.
## Postmarketing Experience
The following events have been reported spontaneously from worldwide postmarketing experience since the launch of Cilostazol in the U.S.
Agranulocytosis, aplastic anemia, granulocytopenia, thrombocytopenia, leukopenia, bleeding tendency
Torsades de pointes, QTc prolongation (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. complete atrioventricular block, heart failure and bradyarrhythmia, when treated with Cilostazol. Cilostazol was used "off label" due to its positive chronotropic action.)
Gastrointestinal hemorrhage
Pain, chest pain, hot flushes
Hepatic dysfunction/Abnormal liver function tests, jaundice
Extradural hematoma and subdural hematoma
Blood glucose increased, blood uric acid increased, platelet count decreased, white blood cell count decreased, increase in BUN (blood urea nitrogen increased), blood pressure increase
Intracranial hemorrhage, cerebral hemorrhage, cerebrovascular accident
Pulmonary hemorrhage, interstitial pneumonia
Subcutaneous hemorrhage, pruritus, skin eruptions including Stevens-Johnson syndrome, skin drug eruption (dermatitis medicamentosa)
Subacute thrombosis (These cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of Cilostazol for prevention of thrombotic complication after coronary stenting.)
# Drug Interactions
- Since Cilostazol is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when Cilostazol is coadministered with inhibitors of CYP3A4 such as ketoconazole and erythromycin or inhibitors of CYP2C19 such as omeprazole. Pharmacokinetic studies have demonstrated that omeprazole and erythromycin significantly increased the systemic exposure of Cilostazol and/or its major metabolites. Population pharmacokinetic studies showed higher concentrations of Cilostazol among patients concurrently treated with diltiazem, an inhibitor of CYP3A4. Cilostazol does not, however, appear to cause increased blood levels of drugs metabolized by CYP3A4, as it had no effect on lovastatin, a drug with metabolism very sensitive to CYP3A4 inhibition.
- Short-term (≤4 days) coadministration of aspirin with Cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% - 37% when compared to either aspirin or Cilostazol alone. Short-term (≤ 4 days) coadministration of aspirin with Cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to Cilostazol alone and by 48% compared to aspirin alone. However, short-term coadministration of aspirin with Cilostazol had no clinically significant impact on PT, aPTT, or bleeding time compared to aspirin alone. Effects of long-term coadministration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was coadministered with Cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75-81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking Cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.
- The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2, and CYP2C19, and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time, or platelet aggregation) of R- and S-warfarin after a single 25 mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and Cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.
- Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of Cilostazol.
Strong Inhibitors of CYP3A4
- A priming dose of ketoconazole 400 mg (a strong inhibitor of CYP3A4), was given one day prior to coadministration of single doses of ketoconazole 400 mg and Cilostazol 100 mg. This regimen increased Cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, and sertraline, would be expected to have a similar effect.
Moderate Inhibitors of CYP3A4
- Erythromycin and other macrolide antibiotics: Erythromycin is a moderately strong inhibitor of CYP3A4. Coadministration of erythromycin 500 mg q 8 h with a single dose of Cilostazol 100 mg increased Cilostazol Cmax by 47% and AUC by 73%. Inhibition of Cilostazol metabolism by erythromycin increased the AUC of 4 '-trans-hydroxy-Cilostazol by 141%. Other macrolide antibiotics (e.g., clarithromycin), but not all (e.g., azithromycin), would be expected to have a similar effect.
- Diltiazem: Diltiazem 180 mg decreased the clearance of Cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.
- Grapefruit juice: Grapefruit juice increased the Cmax of Cilostazol by ~50%, but had no effect on AUC.
Omeprazole
- Coadministration of omeprazole did not significantly affect the metabolism of Cilostazol, but the systemic exposure to 3,4- dehydro-Cilostazol was increased by 69%, probably the result of omeprazole's potent inhibition of CYP2C19.
Quinidine
- Concomitant administration of quinidine with a single dose of Cilostazol 100 mg did not alter Cilostazol pharmacokinetics.
Lovastatin
- The concomitant administration of lovastatin with Cilostazol decreases Cilostazol Css, max and AUC by 15%. There is also a decrease, although nonsignificant, in Cilostazol metabolite concentrations. Coadministration of Cilostazol with lovastatin increases lovastatin and β-hydroxi lovastatin AUC approximately 70%. This is most likely clinically insignificant.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- In a rat developmental toxicity study, oral administration of 1000 mg Cilostazol/kg/day was associated with decreased fetal weights, and increased incidences of cardiovascular, renal, and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib, and retarded ossification). At this dose, systemic exposure to unbound Cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound Cilostazol was considerably lower than that seen in humans given the MRHD, and exposure to 3,4-dehydro-Cilostazol was barely detectable.
- When Cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).
- There are no adequate and well-controlled studies in pregnant women.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cilostazol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cilostazol during labor and delivery.
### Nursing Mothers
- Transfer of Cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue Cilostazol.
### Pediatric Use
- The safety and effectiveness of Cilostazol in pediatric patients have not been established.
### Geriatic Use
- Of the total number of subjects (n=2274) in clinical studies of Cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism, and elimination of Cilostazol and its metabolites.
### Gender
There is no FDA guidance on the use of Cilostazol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cilostazol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Cilostazol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Cilostazol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cilostazol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cilostazol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Cilostazol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Cilostazol in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Information on acute overdosage with Cilostazol in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The oral LD50 of Cilostazol is >5 g/kg in mice and rats and >2 g/kg in dogs.
### Management
- The patient should be carefully observed and given supportive treatment. Since Cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by hemodialysis or peritoneal dialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cilostazol in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of the effects of Cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively. Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking Cilostazol. After 12 weeks, as compared to placebo, Cilostazol 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4 mg/dL (≥10%).
- Cilostazol affects both vascular beds and cardiovascular function. It produces nonhomogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid or superior mesenteric arteries. Renal arteries were not responsive to the effects of Cilostazol.
- In dogs or cynomolgous monkeys, Cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more Cilostazol-treated patients had increases in ventricular premature beats and nonsustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related.
## Structure
- Cilostazol is a quinolinone derivative that inhibits cellular phosphodiesterase (more specific for phosphodiesterase III). The molecular formula of Cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]- 3,4-dihydro-2(1H)-quinolinone. The structural formula is:
- Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in methanol and ethanol, and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.
- Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: carboxymethylcellulose calcium, pregelantized starch, hypromellose, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.
## Pharmacodynamics
- Cilostazol is 95 - 98% protein bound, predominantly to albumin. The mean percent binding for 3,4-dehydro-Cilostazol is 97.4% and for 4 '-trans-hydroxy-Cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of Cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of Cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.
## Pharmacokinetics
- Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of Cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of Cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).
- The mean ± SEM plasma concentration-time profile at steady state after multiple dosing of Cilostazol 100 mg b.i.d. is shown below:
- Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in Cilostazol's metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-Cilostazol, the most active of the metabolites, is unknown.
- Following oral administration of 100 mg radiolabeled Cilostazol, 56% of the total analytes in plasma was Cilostazol, 15% was 3,4-dehydro-Cilostazol (4-7 times as active as Cilostazol), and 4% was 4 '-trans-hydroxy-Cilostazol (one fifth as active as Cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged Cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3, 4- dehydro-Cilostazol. About 30% of the dose was excreted in urine as 4 '-trans-hydroxy-Cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.
- The total and unbound oral clearances, adjusted for body weight, of Cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50-to- 80-year-old age range.
- Population pharmacokinetic analysis suggests that smoking decreased Cilostazol exposure by about 20%.
- The pharmacokinetics of Cilostazol and its metabolites were similar in subjects with mild hepatic disease as compared to healthy subjects. Patients with moderate or severe hepatic impairment have not been studied.
- The total pharmacologic activity of Cilostazol and its metabolites was similar in subjects with mild to moderate renal impairment and in normal subjects. Severe renal impairment increases metabolite levels and alters protein binding of the parent and metabolites. The expected pharmacologic activity, however, based on plasma concentrations and relative PDE III inhibiting potency of parent drug and metabolites, appeared little changed. Patients on dialysis have not been studied, but, it is unlikely that Cilostazol can be removed efficiently by dialysis because of its high protein binding (95 - 98%).
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Dietary administration of Cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation, and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.
- Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day.
- At this dose, systemic exposures (AUCs) to unbound Cilostazol were less than 1.5 times in males, and about 5 times in females, the exposure in humans at the MRHD.
# Clinical Studies
- The ability of Cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks' duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998), and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.
- Compared to patients treated with placebo, patients treated with Cilostazol 50 or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of Cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.
- The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.
- Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with Cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%. The corresponding changes in the placebo group were -10% to 41%.
- The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either Cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta-blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.
- A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of Cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8 to 8.4%) on Cilostazol and 6.8% (95% CI of 1.9 to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on Cilostazol, which was the a priori study hypothesis.
# How Supplied
- Cilostazol is supplied as 50 mg and 100 mg tablets. The 50 mg tablets are white, round, debossed with B167 on one side and 50 on the other, and are provided in bottles of 60 tablets (NDC #51991-167-06) and 1000 tablets (NDC #51991-167-10).
- The 100 mg tablets are white, round, debossed with B168 on one side and 100 on the other, and provided in bottles of 60 tablets (NDC #51991-168-06) and 1000 tablets (NDC #51991-168-10).
- Store Cilostazol tablets at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)
## Storage
There is limited information regarding Cilostazol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- What is Cilostazol for?
- Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.
- What is intermittent claudication?
- Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.
- What treatments are available for intermittent claudication?
- The three main treatments available for intermittent claudication are:
- Exercise. Your doctor may advise an exercise program.
- Medication. Your doctor may prescribe a medication such as Cilostazol.
- Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.
- How does Cilostazol work?
- The exact way that many drugs work is not well understood. Although how Cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.
- Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.
- Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from Cilostazol after 12 weeks you and your doctor may wish to discuss other forms of treatment.
- Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.
- Who should not take Cilostazol?
- Patients who have congestive heart failure (CHF) must not take Cilostazol. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.
- How should Cilostazol be taken?
- Follow your doctor's advice about how to take Cilostazol.
- You should take Cilostazol twice a day, at least one half-hour before or two hours after breakfast and dinner. Take Cilostazol at about the same times each day.
- Do not share Cilostazol with anyone else. It was prescribed only for you.
- Keep Cilostazol and all drugs out of the reach of children.
- Can Cilostazol be taken with other drugs?
- Certain drugs and foods can increase the amount of Cilostazol in the blood. Because of this, your doctor may adjust your dose of Cilostazol or even stop it if you are taking or are going to take one of the following medications.
# Precautions with Alcohol
- Alcohol-Cilostazol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Pletal®[3]
# Look-Alike Drug Names
- N/A[4]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cilostazol | |
507796bc30724f14038f08f74d45025cc20653df | wikidoc | Cinacalcet | Cinacalcet
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# Overview
Cinacalcet is a calcium-sensing receptor agonist that is FDA approved for the {{{indicationType}}} of secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis, hypercalcemia in patients with parathyroid carcinoma, severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy. Common adverse reactions include nausea, vomiting, and diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting oral dose of Sensipar is 30 mg once daily. Serum calcium and serum phosphorus should be measured within 1 week and intact parathyroid hormone (iPTH) should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar. Sensipar should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily to target iPTH levels of 150 to 300 pg/mL. Serum iPTH levels should be assessed no earlier than 12 hours after dosing with Sensipar.
- Sensipar can be used alone or in combination with vitamin D sterols and/or phosphate binders.
- During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with Sensipar
- Dosing Information
- The recommended starting oral dose of Sensipar is 30 mg twice daily.
- The dose of Sensipar should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily, and 90 mg 3 or 4 times daily as necessary to normalize serum calcium levels.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cinacalcet in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cinacalcet in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cinacalcet in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cinacalcet in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cinacalcet in pediatric patients.
# Contraindications
- Hypocalcemia
- Sensipar treatment should not be initiated if serum calcium is less than the lower limit of the normal range.
# Warnings
### Precautions
- Hypocalcemia
- Sensipar lowers serum calcium and, therefore, patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesias, myalgias, muscle cramping, tetany, and convulsions.
- Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar. Once the maintenance dose has been established, serum calcium should be measured approximately monthly.
- If serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of Sensipar until serum calcium levels reach 8.0 mg/dL and/or symptoms of hypocalcemia have resolved. Treatment should be reinitiated using the next lowest dose of Sensipar.
- In 26-week studies of patients with CKD on dialysis, 66% of patients receiving Sensipar compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.
- Sensipar is not indicated for patients with CKD not on dialysis. In patients with secondary HPT and CKD not on dialysis, the long term safety and efficacy of Sensipar have not been established. Clinical studies indicate that Sensipar-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with Sensipar-treated patients with CKD on dialysis, which may be due to lower baseline calcium levels. In a phase 3 study of 32 weeks duration and including 404 patients with CKD not on dialysis (302 cinacalcet, 102 placebo), in which the median dose for cinacalcet was 60 mg per day at the completion of the study, 80% of Sensipar-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo.
- Seizures
- In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of Sensipar-treated patients and 0.7% (5/687) of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving Sensipar, particularly in patients with a history of a seizure disorder.
- Hypotension and/or Worsening Heart Failure
- In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function, in which a causal relationship to Sensipar could not be completely excluded and which may be mediated by reductions in serum calcium levels.
- Adynamic Bone Disease
- Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL. One clinical study evaluated bone histomorphometry in patients treated with Sensipar for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar. Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In three 6-month, phase 3 studies conducted in patients with CKD on dialysis, 11% of patients treated with Sensipar had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below 150 pg/mL in patients treated with Sensipar, the dose of Sensipar and/or vitamin D sterols should be reduced or therapy discontinued.
- Hepatic Impairment
- Cinacalcet exposure, as defined by the Area Under the Curve (AUC0-inf), is increased by 2.4 and 4.2 fold in patients with moderate and severe hepatic impairment, respectively. These patients should be monitored throughout treatment with Sensipar.
- Laboratory Tests
- Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis
- Serum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar. Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and iPTH every 1 to 3 months. Measurements of PTH during the Sensipar studies were obtained using the Nichols iPTH immunoradiometric assay (IRMA).
- In patients with end-stage renal disease, testosterone levels are often below the normal range. In a placebo-controlled study in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following 6 months of treatment with Sensipar. Levels of total testosterone decreased by a median of 15.8% in the Sensipar-treated patients and by 0.6% in the placebo-treated patients. Levels of free testosterone decreased by a median of 31.3% in the Sensipar-treated patients and by 16.3% in the placebo-treated patients. The clinical significance of these reductions in serum testosterone is unknown.
- Patients with Parathyroid Carcinoma or Primary Hyperparathyroidism
- Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar. Once maintenance dose levels have been established, serum calcium should be measured every 2 months.
# 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis
- In three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 Sensipar, 470 placebo) for up to 6 months. The most frequently reported adverse reactions (incidence of at least 5% in the Sensipar group and greater than placebo) are provided in Table 1. The most frequently reported adverse reactions in the Sensipar group were nausea, vomiting, and diarrhea.
- Seizures were observed in 1.4% (13/910) of cinacalcet-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo controlled trials.
- The incidence of serious adverse reactions was similar in the Sensipar and placebo groups (29% vs. 31%, respectively).
- 12-Month Experience with Sensipar in Secondary Hyperparathyroidism
- Two hundred sixty-six patients from two of the phase 3 studies in patients with CKD on dialysis continued to receive Sensipar or placebo treatment in a 6-month, double-blind extension study (12-month total treatment duration). The incidence and nature of adverse reactions in this long term extension study were comparable to those observed in the original phase 3 studies.
- Parathyroid Carcinoma and Primary Hyperparathyroidism
- The safety profile of Sensipar in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with cinacalcet in a single arm study, 29 with Parathyroid Carcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverse events. The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms.
- Eight patients died while on study, 7 with Parathyroid Carcinoma (24%) and 1 (6%) with intractable pHPT. Causes of death were cardiovascular (5 patients), multi-organ failure (1 patient), gastrointestinal hemorrhage (1 patient) and metastatic carcinoma (1 patient). Adverse events of hypocalcemia were reported in three patients (7%).
- Seizures were observed in 0.7% (1/140) of cinacalcet-treated patients and 0.0% (0/46) of placebo-treated patients in all clinical studies.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Sensipar. 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.
- Rash, hypersensitivity reactions (including angioedema and urticaria), diarrhea, and myalgia have been identified as adverse reactions during postapproval use of Sensipar. Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in Sensipar-treated patients with impaired cardiac function in postmarketing safety surveillance.
# Drug Interactions
- Strong CYP3A4 Inhibitors
- Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of Sensipar may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients.
- CYP2D6 Substrates
- Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e.g., desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e.g., flecainide and most tricyclic antidepressants).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on Area Under the Curve comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).
- In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day. Sensipar has been shown to cross the placental barrier in rabbits.
- In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain.
- There are no adequate and well-controlled studies of Sensipar in pregnant women. Sensipar should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Women who become pregnant during Sensipar treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cinacalcet in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cinacalcet during labor and delivery.
### Nursing Mothers
- Studies in rats have shown that Sensipar is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats, and because many drugs are excreted in human milk and there is a potential for clinically significant adverse reactions in infants who ingest Sensipar, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.
### Pediatric Use
There is no FDA guidance on the use of Cinacalcet with respect to pediatric patients.
### Geriatic Use
- Of the 1136 patients enrolled in the Sensipar phase 3 clinical program in patients with CKD on dialysis, 26% were ≥ 65 years old, and 9% were ≥ 75 years old. No differences in the safety and efficacy of Sensipar were observed in patients greater or less than 65 years of age. No dosage adjustment is required for geriatric patients.
### Gender
There is no FDA guidance on the use of Cinacalcet with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cinacalcet with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is necessary for renal impairment.
### Hepatic Impairment
- Patients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with Sensipar because cinacalcet exposure (AUC0-inf) is increased by 2.4 and 4.2 fold, respectively, in these patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cinacalcet in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cinacalcet in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms.
# IV Compatibility
There is limited information regarding IV Compatibility of Cinacalcet in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of Sensipar may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels.
### Management
- Since Sensipar is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cinacalcet in the drug label.
# Pharmacology
## Mechanism of Action
- Secondary HPT in patients with CKD is a progressive disease, associated with increases in PTH levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary HPT are to lower the levels of PTH, calcium, and phosphorus in the blood in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. Reductions in PTH are associated with a decrease in bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT.
- The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion. Sensipar directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. Measurements of PTH during the Sensipar studies were obtained using the Nichols IRMA.
## Structure
- Sensipar (cinacalcet) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Sensipar tablets contain the hydrochloride salt of cinacalcet. Its empirical formula is C22H22F3N·HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.
- The hydrochloride salt of cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.
- Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).
- The hydrochloride salt of cinacalcet is described chemically as N--3--1-aminopropane hydrochloride and has the following structural formula:
## Pharmacodynamics
- Reduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (Cmax) of cinacalcet. After steady-state cinacalcet concentrations are reached (which occurs within 7 days of dose change), serum calcium concentrations remain constant over the dosing interval in patients with CKD.
## Pharmacokinetics
- Absorption and Distribution
- After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Cinacalcet Cmax and AUC(0-inf) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers. The Cmax and AUC(0-inf) of cinacalcet were increased by 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting.
- After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once daily dosing of 30 to 180 mg. The volume of distribution is approximately 1000 L, indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.
- Metabolism and Excretion
- Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via β-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug forming dihydrodiols, which are further conjugated with glucuronic acid. The plasma concentrations of the major circulating metabolites, including the cinnamic acid derivatives and glucuronidated dihydrodiols, markedly exceed the parent drug concentrations. The hydrocinnamic acid metabolite and glucuronide conjugates have minimal or no calcimimetic activity. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.
- Drug Interactions
- In vitro studies indicate that cinacalcet is a strong inhibitor of CYP2D6, but not an inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that cinacalcet is not an inducer of CYP450 enzymes. Tables 3 and 4 list the findings from in vivo drug-drug interaction studies.
- Hepatic Impairment
- The disposition of a 50 mg Sensipar single dose was compared between patients with hepatic impairment and patients with normal hepatic function. Cinacalcet exposure (AUC(0-inf) ) was comparable between healthy volunteers and patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures (AUC(0-inf)) were 2.4 and 4.2 fold higher, respectively, than that in healthy volunteers. The mean half-life of cinacalcet increased from 49 hours in healthy volunteers to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function.
- Renal Impairment
- The pharmacokinetic profile of a 75 mg Sensipar single dose in patients with mild, moderate, and severe renal impairment, and those on hemodialysis or peritoneal dialysis is comparable with that in healthy volunteers.
- Geriatric Patients
- The pharmacokinetic profile of cinacalcet in geriatric patients (age ≥ 65 years, n = 12) is similar to that for patients who are < 65 years of age (n = 268).
- Pediatric Patients
- The pharmacokinetics of cinacalcet has not been studied in patients < 18 years of age.
## Nonclinical Toxicology
- Carcinogenicity
- Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given cinacalcet at dietary doses of 15, 50, and 125 mg/kg/day in males and 30, 70, and 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, and 35 mg/kg/day in males and 5, 20, and 35 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet.
- Mutagenicity
- Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay, nor in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation, nor in the in vivo mouse micronucleus assay.
- Impairment of Fertility
- Female rats were given oral gavage doses of 5, 25, and 75 mg/kg/day cinacalcet beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks postmating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females.
# Clinical Studies
- Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in patients with CKD on dialysis. A total of 665 patients were randomized to Sensipar and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% were Caucasian. The average baseline iPTH level by the Nichols IRMA was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P ion product was 61 mg2/dL2. The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% on peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of ≤ 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH ≤ 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of patients in the Sensipar arm and 80% of the patients in the placebo arm completed the 6-month studies. In the primary efficacy analysis, 40% of the patients on Sensipar and 5% of placebo-treated patients achieved an iPTH ≤ 250 pg/mL (p < 0.001) (Table 5, Figure 1). These studies showed that Sensipar reduced iPTH while lowering Ca x P, calcium, and phosphorus levels (Table 5, Figure 2). The median dose of Sensipar at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.
- Similar results were observed when either the iPTH or biointact PTH (biPTH) assay was used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did not alter the relationship between iPTH and biPTH.
- Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).
- Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).
- Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.
- Sensipar decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH ≥ 300 to ≤ 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of ≤ 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.
- Twenty-nine patients with Parathyroid Carcinoma were enrolled in a single-arm, open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg four times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was ≤ 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.
- Twenty-nine patients entered the study. The median exposure to cinacalcet was 229 days (range: 1 to 1051). At baseline the mean (SE) serum calcium was 14.1 (0.4) mg/dL. At the end of the titration phase, the mean (SE) serum calcium was 12.4 (0.5) mg/dL, which is a mean reduction of 1.7 (0.6) mg/dL from baseline. Figure 3 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice daily to 90 mg four times daily.
- n = Number of patients with non-missing values at the timepoint.
- End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.
- Seventeen patients with severe hypercalcemia due to primary HPT, who had failed or had contraindications to parathyroidectomy, participated in an open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. In this trial severe hypercalcemia was defined as a screening serum calcium level of > 12.5 mg/dL. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg 4 times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was ≤ 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.
- Seventeen patients entered the study. The median exposure to cinacalcet was 270 days (range: 32 to 1,105). At baseline the mean (SE) serum calcium was 12.7 (0.2) mg/dL. At the end of the titration phase the mean (SE) serum calcium was 10.4 (0.3) mg/dL, which is a mean reduction of 2.3 (0.3) mg/dL from baseline. Figure 4 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice a day to 90 mg four times a day.
- n = Number of patients with non-missing values at the timepoint.
- End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.
# How Supplied
- Sensipar 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “30” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-073-30)
- Sensipar 60 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “60” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-074-30)
- Sensipar 90 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “90” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-075-30)
- Storage
- Store at 25ºC (77ºF); excursions permitted from 15°C to 30ºC (59°F to 86ºF).
## Storage
There is limited information regarding Cinacalcet Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Take with food: Patients should be advised to take Sensipar with food or shortly after a meal. Tablets should be taken whole and should not be divided.
- Laboratory monitoring: Patients should be informed of the importance of regular blood tests, in order to monitor the safety and efficacy of Sensipar therapy.
- Side-Effects of Treatment: Patients should be advised to report nausea, vomiting, and potential symptoms of hypocalcemia, including tingling/numbness of the skin, muscle pain, and muscle cramping.
- Seizures: Patients should be queried if they are taking medication to prevent seizures or have had seizures in the past and be advised to report any seizure episodes while on Sensipar therapy.
# Precautions with Alcohol
- Alcohol-Cinacalcet interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sensipar®
# Look-Alike Drug Names
There is limited information regarding Cinacalcet Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cinacalcet
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
Cinacalcet is a calcium-sensing receptor agonist that is FDA approved for the {{{indicationType}}} of secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis, hypercalcemia in patients with parathyroid carcinoma, severe hypercalcemia in patients with primary HPT who are unable to undergo parathyroidectomy. Common adverse reactions include nausea, vomiting, and diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting oral dose of Sensipar is 30 mg once daily. Serum calcium and serum phosphorus should be measured within 1 week and intact parathyroid hormone (iPTH) should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar. Sensipar should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily to target iPTH levels of 150 to 300 pg/mL. Serum iPTH levels should be assessed no earlier than 12 hours after dosing with Sensipar.
- Sensipar can be used alone or in combination with vitamin D sterols and/or phosphate binders.
- During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with Sensipar
- Dosing Information
- The recommended starting oral dose of Sensipar is 30 mg twice daily.
- The dose of Sensipar should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily, and 90 mg 3 or 4 times daily as necessary to normalize serum calcium levels.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cinacalcet in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cinacalcet in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Cinacalcet in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cinacalcet in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cinacalcet in pediatric patients.
# Contraindications
- Hypocalcemia
- Sensipar treatment should not be initiated if serum calcium is less than the lower limit of the normal range.
# Warnings
### Precautions
- Hypocalcemia
- Sensipar lowers serum calcium and, therefore, patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesias, myalgias, muscle cramping, tetany, and convulsions.
- Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar. Once the maintenance dose has been established, serum calcium should be measured approximately monthly.
- If serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of Sensipar until serum calcium levels reach 8.0 mg/dL and/or symptoms of hypocalcemia have resolved. Treatment should be reinitiated using the next lowest dose of Sensipar.
- In 26-week studies of patients with CKD on dialysis, 66% of patients receiving Sensipar compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.
- Sensipar is not indicated for patients with CKD not on dialysis. In patients with secondary HPT and CKD not on dialysis, the long term safety and efficacy of Sensipar have not been established. Clinical studies indicate that Sensipar-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with Sensipar-treated patients with CKD on dialysis, which may be due to lower baseline calcium levels. In a phase 3 study of 32 weeks duration and including 404 patients with CKD not on dialysis (302 cinacalcet, 102 placebo), in which the median dose for cinacalcet was 60 mg per day at the completion of the study, 80% of Sensipar-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo.
- Seizures
- In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of Sensipar-treated patients and 0.7% (5/687) of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving Sensipar, particularly in patients with a history of a seizure disorder.
- Hypotension and/or Worsening Heart Failure
- In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function, in which a causal relationship to Sensipar could not be completely excluded and which may be mediated by reductions in serum calcium levels.
- Adynamic Bone Disease
- Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL. One clinical study evaluated bone histomorphometry in patients treated with Sensipar for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar. Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In three 6-month, phase 3 studies conducted in patients with CKD on dialysis, 11% of patients treated with Sensipar had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below 150 pg/mL in patients treated with Sensipar, the dose of Sensipar and/or vitamin D sterols should be reduced or therapy discontinued.
- Hepatic Impairment
- Cinacalcet exposure, as defined by the Area Under the Curve (AUC0-inf), is increased by 2.4 and 4.2 fold in patients with moderate and severe hepatic impairment, respectively. These patients should be monitored throughout treatment with Sensipar.
- Laboratory Tests
- Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis
- Serum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar. Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and iPTH every 1 to 3 months. Measurements of PTH during the Sensipar studies were obtained using the Nichols iPTH immunoradiometric assay (IRMA).
- In patients with end-stage renal disease, testosterone levels are often below the normal range. In a placebo-controlled study in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following 6 months of treatment with Sensipar. Levels of total testosterone decreased by a median of 15.8% in the Sensipar-treated patients and by 0.6% in the placebo-treated patients. Levels of free testosterone decreased by a median of 31.3% in the Sensipar-treated patients and by 16.3% in the placebo-treated patients. The clinical significance of these reductions in serum testosterone is unknown.
- Patients with Parathyroid Carcinoma or Primary Hyperparathyroidism
- Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar. Once maintenance dose levels have been established, serum calcium should be measured every 2 months.
# 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis
- In three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 Sensipar, 470 placebo) for up to 6 months. The most frequently reported adverse reactions (incidence of at least 5% in the Sensipar group and greater than placebo) are provided in Table 1. The most frequently reported adverse reactions in the Sensipar group were nausea, vomiting, and diarrhea.
- Seizures were observed in 1.4% (13/910) of cinacalcet-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo controlled trials.
- The incidence of serious adverse reactions was similar in the Sensipar and placebo groups (29% vs. 31%, respectively).
- 12-Month Experience with Sensipar in Secondary Hyperparathyroidism
- Two hundred sixty-six patients from two of the phase 3 studies in patients with CKD on dialysis continued to receive Sensipar or placebo treatment in a 6-month, double-blind extension study (12-month total treatment duration). The incidence and nature of adverse reactions in this long term extension study were comparable to those observed in the original phase 3 studies.
- Parathyroid Carcinoma and Primary Hyperparathyroidism
- The safety profile of Sensipar in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with cinacalcet in a single arm study, 29 with Parathyroid Carcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverse events. The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms.
- Eight patients died while on study, 7 with Parathyroid Carcinoma (24%) and 1 (6%) with intractable pHPT. Causes of death were cardiovascular (5 patients), multi-organ failure (1 patient), gastrointestinal hemorrhage (1 patient) and metastatic carcinoma (1 patient). Adverse events of hypocalcemia were reported in three patients (7%).
- Seizures were observed in 0.7% (1/140) of cinacalcet-treated patients and 0.0% (0/46) of placebo-treated patients in all clinical studies.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Sensipar. 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.
- Rash, hypersensitivity reactions (including angioedema and urticaria), diarrhea, and myalgia have been identified as adverse reactions during postapproval use of Sensipar. Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in Sensipar-treated patients with impaired cardiac function in postmarketing safety surveillance.
# Drug Interactions
- Strong CYP3A4 Inhibitors
- Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of Sensipar may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients.
- CYP2D6 Substrates
- Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e.g., desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e.g., flecainide and most tricyclic antidepressants).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet during gestation, no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on Area Under the Curve [AUC] comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).
- In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day cinacalcet during gestation, no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day. Sensipar has been shown to cross the placental barrier in rabbits.
- In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet during gestation through lactation, no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day cinacalcet (exposures 2 to 3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain.
- There are no adequate and well-controlled studies of Sensipar in pregnant women. Sensipar should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Women who become pregnant during Sensipar treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cinacalcet in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cinacalcet during labor and delivery.
### Nursing Mothers
- Studies in rats have shown that Sensipar is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats, and because many drugs are excreted in human milk and there is a potential for clinically significant adverse reactions in infants who ingest Sensipar, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.
### Pediatric Use
There is no FDA guidance on the use of Cinacalcet with respect to pediatric patients.
### Geriatic Use
- Of the 1136 patients enrolled in the Sensipar phase 3 clinical program in patients with CKD on dialysis, 26% were ≥ 65 years old, and 9% were ≥ 75 years old. No differences in the safety and efficacy of Sensipar were observed in patients greater or less than 65 years of age. No dosage adjustment is required for geriatric patients.
### Gender
There is no FDA guidance on the use of Cinacalcet with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cinacalcet with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is necessary for renal impairment.
### Hepatic Impairment
- Patients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with Sensipar because cinacalcet exposure (AUC0-inf) is increased by 2.4 and 4.2 fold, respectively, in these patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cinacalcet in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cinacalcet in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms.
# IV Compatibility
There is limited information regarding IV Compatibility of Cinacalcet in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of Sensipar may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels.
### Management
- Since Sensipar is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Cinacalcet in the drug label.
# Pharmacology
## Mechanism of Action
- Secondary HPT in patients with CKD is a progressive disease, associated with increases in PTH levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary HPT are to lower the levels of PTH, calcium, and phosphorus in the blood in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. Reductions in PTH are associated with a decrease in bone turnover and bone fibrosis in patients with CKD on dialysis and uncontrolled secondary HPT.
- The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion. Sensipar directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. Measurements of PTH during the Sensipar studies were obtained using the Nichols IRMA.
## Structure
- Sensipar (cinacalcet) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Sensipar tablets contain the hydrochloride salt of cinacalcet. Its empirical formula is C22H22F3N·HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.
- The hydrochloride salt of cinacalcet is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.
- Sensipar tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).
- The hydrochloride salt of cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula:
## Pharmacodynamics
- Reduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (Cmax) of cinacalcet. After steady-state cinacalcet concentrations are reached (which occurs within 7 days of dose change), serum calcium concentrations remain constant over the dosing interval in patients with CKD.
## Pharmacokinetics
- Absorption and Distribution
- After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Cinacalcet Cmax and AUC(0-inf) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers. The Cmax and AUC(0-inf) of cinacalcet were increased by 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting.
- After absorption, cinacalcet concentrations decline in a biphasic fashion with a terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and Cmax of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once daily dosing of 30 to 180 mg. The volume of distribution is approximately 1000 L, indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL.
- Metabolism and Excretion
- Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via β-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug forming dihydrodiols, which are further conjugated with glucuronic acid. The plasma concentrations of the major circulating metabolites, including the cinnamic acid derivatives and glucuronidated dihydrodiols, markedly exceed the parent drug concentrations. The hydrocinnamic acid metabolite and glucuronide conjugates have minimal or no calcimimetic activity. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces.
- Drug Interactions
- In vitro studies indicate that cinacalcet is a strong inhibitor of CYP2D6, but not an inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that cinacalcet is not an inducer of CYP450 enzymes. Tables 3 and 4 list the findings from in vivo drug-drug interaction studies.
- Hepatic Impairment
- The disposition of a 50 mg Sensipar single dose was compared between patients with hepatic impairment and patients with normal hepatic function. Cinacalcet exposure (AUC(0-inf) ) was comparable between healthy volunteers and patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures (AUC(0-inf)) were 2.4 and 4.2 fold higher, respectively, than that in healthy volunteers. The mean half-life of cinacalcet increased from 49 hours in healthy volunteers to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function.
- Renal Impairment
- The pharmacokinetic profile of a 75 mg Sensipar single dose in patients with mild, moderate, and severe renal impairment, and those on hemodialysis or peritoneal dialysis is comparable with that in healthy volunteers.
- Geriatric Patients
- The pharmacokinetic profile of cinacalcet in geriatric patients (age ≥ 65 years, n = 12) is similar to that for patients who are < 65 years of age (n = 268).
- Pediatric Patients
- The pharmacokinetics of cinacalcet has not been studied in patients < 18 years of age.
## Nonclinical Toxicology
- Carcinogenicity
- Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given cinacalcet at dietary doses of 15, 50, and 125 mg/kg/day in males and 30, 70, and 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, and 35 mg/kg/day in males and 5, 20, and 35 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet.
- Mutagenicity
- Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay, nor in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation, nor in the in vivo mouse micronucleus assay.
- Impairment of Fertility
- Female rats were given oral gavage doses of 5, 25, and 75 mg/kg/day cinacalcet beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks postmating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females.
# Clinical Studies
- Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in patients with CKD on dialysis. A total of 665 patients were randomized to Sensipar and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% were Caucasian. The average baseline iPTH level by the Nichols IRMA was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P ion product was 61 mg2/dL2. The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% on peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of ≤ 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH ≤ 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of patients in the Sensipar arm and 80% of the patients in the placebo arm completed the 6-month studies. In the primary efficacy analysis, 40% of the patients on Sensipar and 5% of placebo-treated patients achieved an iPTH ≤ 250 pg/mL (p < 0.001) (Table 5, Figure 1). These studies showed that Sensipar reduced iPTH while lowering Ca x P, calcium, and phosphorus levels (Table 5, Figure 2). The median dose of Sensipar at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.
- Similar results were observed when either the iPTH or biointact PTH (biPTH) assay was used to measure PTH levels in CKD patients on dialysis; treatment with cinacalcet did not alter the relationship between iPTH and biPTH.
- Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).
- Data are presented for patients who completed the studies; Placebo (n = 342), Sensipar (n = 439).
- Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.
- Sensipar decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH ≥ 300 to ≤ 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of ≤ 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.
- Twenty-nine patients with Parathyroid Carcinoma were enrolled in a single-arm, open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg four times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was ≤ 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.
- Twenty-nine patients entered the study. The median exposure to cinacalcet was 229 days (range: 1 to 1051). At baseline the mean (SE) serum calcium was 14.1 (0.4) mg/dL. At the end of the titration phase, the mean (SE) serum calcium was 12.4 (0.5) mg/dL, which is a mean reduction of 1.7 (0.6) mg/dL from baseline. Figure 3 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice daily to 90 mg four times daily.
- n = Number of patients with non-missing values at the timepoint.
- End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.
- Seventeen patients with severe hypercalcemia due to primary HPT, who had failed or had contraindications to parathyroidectomy, participated in an open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. In this trial severe hypercalcemia was defined as a screening serum calcium level of > 12.5 mg/dL. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg 4 times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was ≤ 10 mg/dL (2.5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases.
- Seventeen patients entered the study. The median exposure to cinacalcet was 270 days (range: 32 to 1,105). At baseline the mean (SE) serum calcium was 12.7 (0.2) mg/dL. At the end of the titration phase the mean (SE) serum calcium was 10.4 (0.3) mg/dL, which is a mean reduction of 2.3 (0.3) mg/dL from baseline. Figure 4 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice a day to 90 mg four times a day.
- n = Number of patients with non-missing values at the timepoint.
- End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration.
# How Supplied
- Sensipar 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “30” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-073-30)
- Sensipar 60 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “60” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-074-30)
- Sensipar 90 mg tablets are formulated as light-green, film-coated, oval-shaped tablets marked with “AMG” on one side and “90” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-075-30)
- Storage
- Store at 25ºC (77ºF); excursions permitted from 15°C to 30ºC (59°F to 86ºF).
## Storage
There is limited information regarding Cinacalcet Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Take with food: Patients should be advised to take Sensipar with food or shortly after a meal. Tablets should be taken whole and should not be divided.
- Laboratory monitoring: Patients should be informed of the importance of regular blood tests, in order to monitor the safety and efficacy of Sensipar therapy.
- Side-Effects of Treatment: Patients should be advised to report nausea, vomiting, and potential symptoms of hypocalcemia, including tingling/numbness of the skin, muscle pain, and muscle cramping.
- Seizures: Patients should be queried if they are taking medication to prevent seizures or have had seizures in the past and be advised to report any seizure episodes while on Sensipar therapy.
# Precautions with Alcohol
- Alcohol-Cinacalcet interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sensipar®[1]
# Look-Alike Drug Names
There is limited information regarding Cinacalcet Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cinacalcet | |
9a9079ac2d955a2a99f6f4f78b669811fcf774cf | wikidoc | Cinchonism | Cinchonism
Cinchonism or quinism is a pathological condition in humans caused by an overdose of quinine or its natural source, cinchona bark. Quinine is used to treat resistant malaria, nocturnal muscle cramps and can also act as an abortifacient. In much smaller amounts, quinine is an ingredient of tonic drinks, acting as a bittering agent. Cinchonism can occur from therapeutic doses of quinine, either from one or several large doses, or from small doses over a longer period of time, not from the amounts used in tonic drinks, but possibly from ingestion of tonic water as a beverage over a lengthy period of time. Quinidine (Class 1A anti-arrhythmic) can also cause cinchonism.
# Signs and Symptoms
Symptoms of mild cinchonism (which may occur from standard therapeutic doses of quinine) include flushed and sweaty skin, ringing of the ears (tinnitus), blurred vision, impaired hearing, confusion, reversible high-frequency hearing loss, headache, abdominal pain, rashes, lichenoid photosensitivity , vertigo, dizziness, dysphoria (feeling uneasy), nausea and vomiting, and diarrhea.
Large doses of quinine may lead to severe symptoms of cinchonism: skin rashes, deafness, somnolence, diminished visual acuity or blindness, anaphylactic shock, and disturbances in cardiac rhythm or conduction, death from cardiotoxicity. Quinine overdose can also result in a rare form of hypersensitivity reaction termed blackwater fever that results in massive hemolysis, hemoglobinemia, hemoglobinuria, and renal failure.
Patients treated with quinine may also suffer from hypoglycemia (especially if administered intravenously) and hypotension (low blood pressure). In very high doses (higher than those used to treat malaria) during the first trimester of pregnancy quinine may act as an abortifacient, or cause birth defects, especially deafness.
Most symptoms of cinchonism (except in severe cases) are reversible and disappear once quinine is withdrawn. | Cinchonism
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Cinchonism or quinism is a pathological condition in humans caused by an overdose of quinine or its natural source, cinchona bark. Quinine is used to treat resistant malaria, nocturnal muscle cramps and can also act as an abortifacient. In much smaller amounts, quinine is an ingredient of tonic drinks, acting as a bittering agent. Cinchonism can occur from therapeutic doses of quinine, either from one or several large doses, or from small doses over a longer period of time, not from the amounts used in tonic drinks, but possibly from ingestion of tonic water as a beverage over a lengthy period of time. Quinidine (Class 1A anti-arrhythmic) can also cause cinchonism.
# Signs and Symptoms
Symptoms of mild cinchonism (which may occur from standard therapeutic doses of quinine) include flushed and sweaty skin, ringing of the ears (tinnitus), blurred vision, impaired hearing, confusion, reversible high-frequency hearing loss, headache, abdominal pain, rashes, lichenoid photosensitivity [2], vertigo, dizziness, dysphoria (feeling uneasy), nausea and vomiting, and diarrhea.
Large doses of quinine may lead to severe symptoms of cinchonism: skin rashes, deafness, somnolence, diminished visual acuity or blindness, anaphylactic shock, and disturbances in cardiac rhythm or conduction, death from cardiotoxicity. Quinine overdose can also result in a rare form of hypersensitivity reaction termed blackwater fever that results in massive hemolysis, hemoglobinemia, hemoglobinuria, and renal failure.
Patients treated with quinine may also suffer from hypoglycemia (especially if administered intravenously) and hypotension (low blood pressure). In very high doses (higher than those used to treat malaria) during the first trimester of pregnancy quinine may act as an abortifacient, or cause birth defects, especially deafness.
Most symptoms of cinchonism (except in severe cases) are reversible and disappear once quinine is withdrawn.
# External links
- IPCS INTOX databank entry for quinine
- Side effect of quinine for nocturnal cramps - letter printed in the British Medical Journal with a photograph of hands affected by lichenoid photosensitivity
- Effects of Quinine on the Excitability and Voltage-Dependent Currents of Isolated Spiral Ganglion Neurons in Culture
Template:Diseases of the ear and mastoid process
Template:Poisoning and toxicity
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Cinchonism | |
f8262f32bece1ea6333048a2b919cbdccaeb19c0 | wikidoc | Cis-acting | Cis-acting
In the field of molecular biology, cis-acting generally means "acting from the same molecule". It may be considered the opposite of trans-acting which generally means "acting from a different molecule".
In the context of transcription regulation, cis-acting elements are usually considered to be DNA sequences that, via transcription factors or other trans-acting elements or factors, regulate the expression of genes on the same chromosome.
The "operator" in the lac operon is an example of a cis-acting regulatory sequence. This DNA sequence is bound by the lac repressor which in turn prevents transcription of the adjacent genes on the same DNA molecule. The lac operator is thus considered to "act in cis" on the regulation of the nearby genes. The operator itself doesn't code for any protein or RNA. | Cis-acting
In the field of molecular biology, cis-acting generally means "acting from the same molecule". It may be considered the opposite of trans-acting which generally means "acting from a different molecule".
In the context of transcription regulation, cis-acting elements are usually considered to be DNA sequences that, via transcription factors or other trans-acting elements or factors, regulate the expression of genes on the same chromosome.[1]
The "operator" in the lac operon is an example of a cis-acting regulatory sequence. This DNA sequence is bound by the lac repressor which in turn prevents transcription of the adjacent genes on the same DNA molecule. The lac operator is thus considered to "act in cis" on the regulation of the nearby genes. The operator itself doesn't code for any protein or RNA. | https://www.wikidoc.org/index.php/Cis-acting | |
0dfef9c64d31fb04d88336fdc5a9b33f49f265e5 | wikidoc | Prilocaine | Prilocaine
# Overview
Prilocaine /ˈpraɪlkeɪn/ is a local anesthetic of the amino amide type first prepared by Claes Tegner and Nils Löfgren. In its injectable form (trade name Citanest), it is often used in dentistry. It is also often combined with lidocaine as a preparation for dermal anesthesia (lidocaine/prilocaine or EMLA), for treatment of conditions like paresthesia. As it has low cardiac toxicity, it is commonly used for intravenous regional anaesthesia (IVRA).
In some patients, ortho-toluidine, a metabolite of prilocaine may cause methemoglobinemia, which may be treated with methylene blue.
Maximum dosage for dental use: 8.0 mg/kg (2.7 mg/lb), with a maximum dose of 500 mg.
It is given as a combination with the vasoconstrictor epinephrine under the trade name Citanest Forte.
# Synthesis
Prilocaine can be synthesized from o-toluidine, 2-bromopropionyl bromide, and n-butylamine.
# Compendial status
- United States Pharmacopeia 31
# Notes
- ↑ Template:Cite doi
- ↑ The United States Pharmacopeial Convention. "Revision Bulletin: Lidocaine and Prilocaine Cream–Revision to Related Compounds Test". Retrieved 10 July 2009..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} | Prilocaine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Prilocaine /ˈpraɪl[invalid input: 'ɵ']keɪn/ is a local anesthetic of the amino amide type first prepared by Claes Tegner and Nils Löfgren. In its injectable form (trade name Citanest), it is often used in dentistry. It is also often combined with lidocaine as a preparation for dermal anesthesia (lidocaine/prilocaine or EMLA), for treatment of conditions like paresthesia. As it has low cardiac toxicity, it is commonly used for intravenous regional anaesthesia (IVRA).
In some patients, ortho-toluidine, a metabolite of prilocaine may cause methemoglobinemia, which may be treated with methylene blue.
Maximum dosage for dental use: 8.0 mg/kg (2.7 mg/lb), with a maximum dose of 500 mg.
It is given as a combination with the vasoconstrictor epinephrine under the trade name Citanest Forte.
# Synthesis
Prilocaine can be synthesized from o-toluidine, 2-bromopropionyl bromide, and n-butylamine.[1]
# Compendial status
- United States Pharmacopeia 31 [2]
# Notes
- ↑ Template:Cite doi
- ↑ The United States Pharmacopeial Convention. "Revision Bulletin: Lidocaine and Prilocaine Cream–Revision to Related Compounds Test". Retrieved 10 July 2009..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} | https://www.wikidoc.org/index.php/Citanest_HCl_Plain | |
ac1bac7229c955df9adeace3ed602ae8316c4702 | wikidoc | Citrulline | Citrulline
# Overview
The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelo], from which it was first isolated in 1930.
It has the idealized formula H2NC(O)NH(CH2)3CH(NH2)CO2H. It is a key intermediate in the urea cycle, the pathway by which mammals excrete ammonia. Citrulline is a substituted urea.
# Biosynthesis
Citrulline is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a by-product of the reaction catalyzed by NOS family (NOS; EC 1.14.13.39). Arginine is first oxidized into N-hydroxyl-arginine, which is then further oxidized to citrulline concomitant with release of nitric oxide. When starved for arginine, organisms will convert ornithine to citrulline, which in turn gives arginine.
# Function
Although citrulline is not coded for by DNA directly, several proteins are known to contain citrulline as a result of a posttranslational modification. These citrulline residues are generated by a family of enzymes called peptidylarginine deiminases (PADs), which convert arginine into citrulline in a process called citrullination or deimination. Proteins that normally contain citrulline residues include myelin basic protein (MBP), filaggrin, and several histone proteins, whereas other proteins, such as fibrin and vimentin are susceptible to citrullination during cell death and tissue inflammation.
Patients with rheumatoid arthritis often (at least 80% of them) develop an immune response against proteins containing citrulline. Although the origin of this immune response is not known, detection of antibodies reactive with citrulline containing proteins or peptides is now becoming an important help in the diagnosis of rheumatoid arthritis.
# Dietary supplement
Citrulline in the form of citrulline malate is sold as a performance-enhancing athletic dietary supplement which is said to reduce muscle fatigue. | Citrulline
Template:OrganicBox small
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelo], from which it was first isolated in 1930.[1]
It has the idealized formula H2NC(O)NH(CH2)3CH(NH2)CO2H. It is a key intermediate in the urea cycle, the pathway by which mammals excrete ammonia. Citrulline is a substituted urea.
# Biosynthesis
Citrulline is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a by-product of the reaction catalyzed by NOS family (NOS; EC 1.14.13.39).[2] Arginine is first oxidized into N-hydroxyl-arginine, which is then further oxidized to citrulline concomitant with release of nitric oxide. When starved for arginine, organisms will convert ornithine to citrulline, which in turn gives arginine.
# Function
Although citrulline is not coded for by DNA directly, several proteins are known to contain citrulline as a result of a posttranslational modification. These citrulline residues are generated by a family of enzymes called peptidylarginine deiminases (PADs), which convert arginine into citrulline in a process called citrullination or deimination. Proteins that normally contain citrulline residues include myelin basic protein (MBP), filaggrin, and several histone proteins, whereas other proteins, such as fibrin and vimentin are susceptible to citrullination during cell death and tissue inflammation.
Patients with rheumatoid arthritis often (at least 80% of them) develop an immune response against proteins containing citrulline. Although the origin of this immune response is not known, detection of antibodies reactive with citrulline containing proteins or peptides is now becoming an important help in the diagnosis of rheumatoid arthritis.
# Dietary supplement
Citrulline in the form of citrulline malate is sold as a performance-enhancing athletic dietary supplement which is said to reduce muscle fatigue. [2] | https://www.wikidoc.org/index.php/Citrulline | |
9a0983d6b79be93519acacd68db4177bed4caed6 | wikidoc | Cladistics | Cladistics
Cladistics is a philosophy of classification that arranges organisms only by their order of branching in an evolutionary tree and not by their morphological similarity, in the words of Luria et al. (1981). A major contributor to this school of thought was the German entomologist Willi Hennig, who referred to it as phylogenetic systematics (Hennig, 1966). The word cladistics is derived from the ancient Greek Template:Polytonic, klados, or "branch."
As the end result of a cladistic analysis, tree-like relationship-diagrams called "cladograms" are drawn up to show hypothesized relationships.
A cladistic analysis can be based on as much or as little information as the researcher selects. Modern systematic research is likely to be based on a wide variety of information, including DNA-sequences (so-called "molecular data"), biochemical data and morphological data.
In a cladogram, all organisms lie at the leaves, and each inner node is ideally binary (two-way). The two taxa on either side of a split are called sister taxa or sister groups. Each subtree, whether it contains one item or a hundred thousand items, is called a clade. A natural group has all the organisms contained in any one clade that share a unique ancestor (one which they do not share with any other organisms on the diagram) for that clade. Each clade is distinguished by a set of characteristics that appear in its members, but not in the other forms from which it diverged. These identifying characteristics of a clade are called synapomorphies (shared, derived characters). For instance, hardened front wings (elytra) are a synapomorphy of beetles, while circinate vernation, or the unrolling of new fronds, is a synapomorphy of ferns.
# Definitions
A character state (see below) that is present in both the outgroups (see below) and in the ancestors is called a plesiomorphy (meaning "close form", also called an ancestral state). A character state that occurs only in later descendants is called an apomorphy (meaning "separate form", also called a "derived" state) for that group. The adjectives plesiomorphic and apomorphic are used instead of "primitive" and "advanced" to avoid placing value-judgments on the evolution of the character states, since both may be advantageous in different circumstances. It is not uncommon to refer informally to a collective set of plesiomorphies as a ground plan for the clade or clades they refer to.
Several more terms are defined for the description of cladograms and the positions of items within them. A species or clade is basal to another clade if it holds more plesiomorphic characters than that other clade. Usually a basal group is very species-poor as compared to a more derived group. It is not a requirement that a basal group be extant. For example, when considering birds and mammals together, neither is basal to the other: both have many derived characters.
A clade or species located within another clade can be described as nested within that clade.
# Cladistics as a break with the past
The school of thought now known as cladistics took inspiration from the work of Willi Hennig. But Hennig's major book, even the 1979 version, does not contain the term 'cladistics' in the index. He referred to his own approach as phylogenetic systematics, implied by the book's title (Hennig, 1979). A review paper by Dupuis (1984) observes that the term 'clade' was introduced in 1958 by Julian Huxley, 'cladistic' by Cain and Harrison in 1960 and 'cladist' (for an adherent of Hennig's school) by Mayr in 1965. Some of the debates that the cladists engaged in had been running since the 19th century, but they entered these debates with a new fervor, as can be learned from the Foreword to Hennig (1979) in which Rosen, Nelson and Patterson wrote the following:
Encumbered with vague and slippery ideas about adaptation, fitness, biological species and natural selection, neo-Darwinism (summed up in the "evolutionary" systematics of Mayr and Simpson) not only lacked a definable investigatory method, but came to depend, both for evolutionary interpretation and classification, on consensus or authority. (Foreword, page ix).
# Cladistic methods
A cladistic analysis is applied to a certain set of information. To organize this information a distinction is made between characters, and character states. Consider the color of feathers, this may be blue in one species but red in another. Thus, "red feathers" and "blue feathers" are two character states of the character "feather-color."
The researcher decides which character states were present before the last common ancestor of the species group (plesiomorphies) and which were present in the last common ancestor (synapomorphies) by considering one or more outgroups. An outgroup is an organism that is considered not to be part of the group in question, but is closely related to the group. This makes the choice of an outgroup an important task, since this choice can profoundly change the topology of a tree. Note that only synapomorphies are of use in characterising clades.
Next, different possible cladograms are drawn up and evaluated. Clades ideally have many "agreeing" synapomorphies. Ideally there is a sufficient number of true synapomorphies to overwhelm homoplasies caused by convergent evolution (i.e. characters that resemble each other because of environmental conditions or function, not because of common ancestry). A well-known example of homoplasy due to convergent evolution would be a character "presence of wings". Though the wings of birds and insects serve the same function, each evolved independently, as can be seen by their anatomy. If a bird and a winged insect were scored for the character "presence of wings", a homoplasy would be introduced into the dataset, and this confounds the analysis, possibly resulting in a false picture of evolution.
Homoplasies can often be avoided outright in morphological datasets by defining characters more precisely and increasing their number: in the example above, e.g. utilizing "wings supported by bony endoskeleton" and "wings supported by chitinous exoskeleton" as characters would avoid the homoplasy. When analyzing "supertrees" (datasets incorporating as many taxa of a suspected clade as possible), it may become unavoidable to introduce character definitions that are unprecise, as otherwise the characters might not apply at all to a large number of taxa. The "wings" example would be hardly useful if attempting a phylogeny of all Metazoa as most of these don't have wings at all. Cautious choice and definition of characters thus is another important element in cladistic analyses. With a faulty outgroup and/or character set, no method of evaluation is likely to produce a phylogeny representing the evolutionary reality.
Many cladograms are possible for any given set of taxa, but one is chosen based on the principle of parsimony: the most compact arrangement, that is, with the fewest character state changes (synapomorphies), is the hypothesis of relationship accept here (see Occam's razor for a discussion of the principle of parsimony and possible complications). Though at one time this analysis was done by hand, computers are now used to evaluate much larger data sets. Sophisticated software packages such as PAUP- allow the statistical evaluation of the confidence we can put in the veracity of the nodes of a cladogram.
It is important to note that the nodes of cladograms do not usually represent divergences of evolutionary lineages, but divergences of character states that are found between such lineages. DNA sequence characters can only diverge after gene flow between (sub)populations has been reduced below some threshold, whereas comprehensive morphological alterations, usually being epistatic (the product of interactions of several genes), usually occur only after lineages have already evolved separately for quite some time: Biological subspecies can usually be distinguished genetically but not for example by internal anatomy
As DNA sequencing has become cheaper and easier, molecular systematics has become a more and more popular way to reconstruct phylogenies. Using a parsimony criterion is only one of several methods to infer a phylogeny from molecular data; maximum likelihood and Bayesian inference, which incorporate explicit models of sequence evolution, are non-Hennigian ways to evaluate sequence data. Another powerful method of reconstructing phylogenies is the use of genomic retrotransposon markers, which are thought to be less prone to the problem of reversion that plagues sequence data. They are also generally assumed to have a low incidence of homoplasies because it was once thought that their integration into the genome was entirely random; this seems at least sometimes not to be the case however.
Ideally, morphological, molecular and possibly other (behavioral etc.) phylogenies should be combined into an analysis of total evidence: all have different intrinsic sources of error. For example, character convergence (homoplasy) is much more common in morphological data than in molecular sequence data, but character reversions that cannot be noticed as such are more common in the latter (see long branch attraction). Morphological homoplasies can usually be recognized as such if character states are defined with enough attention to detail.
Cladistics does not assume any particular theory of evolution, only the background knowledge of descent with modification. Thus, cladistic methods can be, and recently have been, usefully applied to non-biological systems, including determining language families in historical linguistics and the filiation of manuscripts in textual criticism.
# Classification using cladistics
A recent trend in biology since the 1960s, called phylogenetic nomenclature, attempts to use cladistic trees as the basis for scientific classification, requiring taxa to be clades. In other words, cladists argue that the classification system should be reformed to eliminate all non-clades. In contrast, other taxonomists insist that groups reflect phylogenies and often make use of cladistic techniques, but allow both monophyletic and paraphyletic groups as taxa. In effect, already since the early 20th century at latest, it was generally attempted to make genus- and lower-level taxa monophyletic (even though the word might not have been used). Class- and higher-level taxa proved to be more difficult.
A monophyletic group is a clade, comprising an ancestral form and all of its descendants, and so forming one (and only one) evolutionary group. A paraphyletic group is similar, but excludes some of the descendants that have undergone significant changes. For instance, the traditional class Reptilia excludes birds even though they evolved from the ancestral reptile. Similarly, the traditional Invertebrates are paraphyletic because Vertebrates are excluded, although the latter evolved from an Invertebrate.
A group with members from separate evolutionary lines is called polyphyletic. For instance, the once-recognized Pachydermata was found to be polyphyletic because elephants and rhinoceroses arose from non-pachyderms separately. Evolutionary taxonomists consider polyphyletic groups to be errors in classification, often occurring because convergence or other homoplasy was misinterpreted as homology.
Following Hennig, cladists argue that paraphyly is as harmful as polyphyly. The idea is that monophyletic groups can be defined objectively, in terms of common ancestors or the presence of synapomorphies. In contrast, paraphyletic and polyphyletic groups are both defined based on key characters, and the decision of which characters are of taxonomic import is inherently subjective. Many argue that they lead to "gradistic" thinking, where groups advance from "lowly" grades to "advanced" grades, which can in turn lead to teleology. In evolutionary studies, teleology is usually avoided because it implies a plan that cannot be empirically demonstrated.
Going further, some cladists argue that ranks for groups above species are too subjective to present any meaningful information, and so argue that they should be abandoned. Thus they have moved away from Linnaean taxonomy towards a simple hierarchy of clades. The validity of this argument hinges crucially on how often in evolution gradualist near-equilibria are punctuated. A quasi-stable state will result in phylogenies, which may be all but unmappable onto the Linnaean hierarchy, whereas a punctuation event that balances a taxon out of its ecological equilibrium is likely to lead to a split between clades that occurs in comparatively short time and thus lends itself readily for classification according to the Linnaean system.
Other evolutionary systematists argue that all taxa are inherently subjective, even when they reflect evolutionary relationships, since living things form an essentially continuous tree. Any dividing line is artificial, and creates both a monophyletic section above and a paraphyletic section below. Paraphyletic taxa are necessary for classifying earlier sections of the tree – for instance, the early vertebrates that would someday evolve into the family Hominidae cannot be placed in any other monophyletic family. They also argue that paraphyletic taxa provide information about significant changes in organisms' morphology, ecology, or life history – in short, that both taxa and clades are valuable but distinct notions, with separate purposes. Many use the term monophyly in its older sense, where it includes paraphyly, and use the alternate term holophyly to describe clades (monophyly in Hennig's sense). As an unscientific rule of thumb, if a distinct lineage that renders the containing clade paraphyletic has undergone marked adaptive radiation and collected many synapomorphies - especially ones that are radical and/or unprecedented -, the paraphyly is usually not considered a sufficient argument to prevent recognition of the lineage as distinct under the Linnaean system (but it is by definition sufficient in phylogenetic nomenclature). For example, as touched upon briefly above, the Sauropsida ("reptiles") and the Aves (birds) are both ranked as a Linnaean class, although the latter are a highly derived offshoot of some forms of the former which themselves were already quite advanced.
A formal code of phylogenetic nomenclature, the PhyloCode, is currently under development for cladistic taxonomy. It is intended for use by both those who would like to abandon Linnaean taxonomy and those who would like to use taxa and clades side by side. In several instances (see for example Hesperornithes) it has been employed to clarify uncertainties in Linnaean systematics so that in combination they yield a taxonomy that is unambiguously placing the group in the evolutionary tree in a way that is consistent with current knowledge.
# Footnotes
- ↑ See, for example, pp. 45, 78 and 555 of Joel Cracraft and Michael J. Donaghue, eds. (2004). Assembling the Tree of Life. Oxford, England: Oxford University Press. | Cladistics
Cladistics is a philosophy of classification that arranges organisms only by their order of branching in an evolutionary tree and not by their morphological similarity, in the words of Luria et al. (1981). A major contributor to this school of thought was the German entomologist Willi Hennig, who referred to it as phylogenetic systematics (Hennig, 1966). The word cladistics is derived from the ancient Greek Template:Polytonic, klados, or "branch."
As the end result of a cladistic analysis, tree-like relationship-diagrams called "cladograms" are drawn up to show hypothesized relationships.
[1]
A cladistic analysis can be based on as much or as little information as the researcher selects. Modern systematic research is likely to be based on a wide variety of information, including DNA-sequences (so-called "molecular data"), biochemical data and morphological data.
In a cladogram, all organisms lie at the leaves, and each inner node is ideally binary (two-way). The two taxa on either side of a split are called sister taxa or sister groups. Each subtree, whether it contains one item or a hundred thousand items, is called a clade. A natural group has all the organisms contained in any one clade that share a unique ancestor (one which they do not share with any other organisms on the diagram) for that clade. Each clade is distinguished by a set of characteristics that appear in its members, but not in the other forms from which it diverged. These identifying characteristics of a clade are called synapomorphies (shared, derived characters). For instance, hardened front wings (elytra) are a synapomorphy of beetles, while circinate vernation, or the unrolling of new fronds, is a synapomorphy of ferns.
# Definitions
A character state (see below) that is present in both the outgroups (see below) and in the ancestors is called a plesiomorphy (meaning "close form", also called an ancestral state). A character state that occurs only in later descendants is called an apomorphy (meaning "separate form", also called a "derived" state) for that group. The adjectives plesiomorphic and apomorphic are used instead of "primitive" and "advanced" to avoid placing value-judgments on the evolution of the character states, since both may be advantageous in different circumstances. It is not uncommon to refer informally to a collective set of plesiomorphies as a ground plan for the clade or clades they refer to.
Several more terms are defined for the description of cladograms and the positions of items within them. A species or clade is basal to another clade if it holds more plesiomorphic characters than that other clade. Usually a basal group is very species-poor as compared to a more derived group. It is not a requirement that a basal group be extant. For example, when considering birds and mammals together, neither is basal to the other: both have many derived characters.
A clade or species located within another clade can be described as nested within that clade.
# Cladistics as a break with the past
The school of thought now known as cladistics took inspiration from the work of Willi Hennig. But Hennig's major book, even the 1979 version, does not contain the term 'cladistics' in the index. He referred to his own approach as phylogenetic systematics, implied by the book's title (Hennig, 1979). A review paper by Dupuis (1984) observes that the term 'clade' was introduced in 1958 by Julian Huxley, 'cladistic' by Cain and Harrison in 1960 and 'cladist' (for an adherent of Hennig's school) by Mayr in 1965. Some of the debates that the cladists engaged in had been running since the 19th century, but they entered these debates with a new fervor, as can be learned from the Foreword to Hennig (1979) in which Rosen, Nelson and Patterson wrote the following:
Encumbered with vague and slippery ideas about adaptation, fitness, biological species and natural selection, neo-Darwinism (summed up in the "evolutionary" systematics of Mayr and Simpson) not only lacked a definable investigatory method, but came to depend, both for evolutionary interpretation and classification, on consensus or authority. (Foreword, page ix).
# Cladistic methods
A cladistic analysis is applied to a certain set of information. To organize this information a distinction is made between characters, and character states. Consider the color of feathers, this may be blue in one species but red in another. Thus, "red feathers" and "blue feathers" are two character states of the character "feather-color."
The researcher decides which character states were present before the last common ancestor of the species group (plesiomorphies) and which were present in the last common ancestor (synapomorphies) by considering one or more outgroups. An outgroup is an organism that is considered not to be part of the group in question, but is closely related to the group. This makes the choice of an outgroup an important task, since this choice can profoundly change the topology of a tree. Note that only synapomorphies are of use in characterising clades.
Next, different possible cladograms are drawn up and evaluated. Clades ideally have many "agreeing" synapomorphies. Ideally there is a sufficient number of true synapomorphies to overwhelm homoplasies caused by convergent evolution (i.e. characters that resemble each other because of environmental conditions or function, not because of common ancestry). A well-known example of homoplasy due to convergent evolution would be a character "presence of wings". Though the wings of birds and insects serve the same function, each evolved independently, as can be seen by their anatomy. If a bird and a winged insect were scored for the character "presence of wings", a homoplasy would be introduced into the dataset, and this confounds the analysis, possibly resulting in a false picture of evolution.
Homoplasies can often be avoided outright in morphological datasets by defining characters more precisely and increasing their number: in the example above, e.g. utilizing "wings supported by bony endoskeleton" and "wings supported by chitinous exoskeleton" as characters would avoid the homoplasy. When analyzing "supertrees" (datasets incorporating as many taxa of a suspected clade as possible), it may become unavoidable to introduce character definitions that are unprecise, as otherwise the characters might not apply at all to a large number of taxa. The "wings" example would be hardly useful if attempting a phylogeny of all Metazoa as most of these don't have wings at all. Cautious choice and definition of characters thus is another important element in cladistic analyses. With a faulty outgroup and/or character set, no method of evaluation is likely to produce a phylogeny representing the evolutionary reality.
Many cladograms are possible for any given set of taxa, but one is chosen based on the principle of parsimony: the most compact arrangement, that is, with the fewest character state changes (synapomorphies), is the hypothesis of relationship accept here (see Occam's razor for a discussion of the principle of parsimony and possible complications). Though at one time this analysis was done by hand, computers are now used to evaluate much larger data sets. Sophisticated software packages such as PAUP* allow the statistical evaluation of the confidence we can put in the veracity of the nodes of a cladogram.
It is important to note that the nodes of cladograms do not usually represent divergences of evolutionary lineages, but divergences of character states that are found between such lineages. DNA sequence characters can only diverge after gene flow between (sub)populations has been reduced below some threshold, whereas comprehensive morphological alterations, usually being epistatic (the product of interactions of several genes), usually occur only after lineages have already evolved separately for quite some time: Biological subspecies can usually be distinguished genetically but not for example by internal anatomy
As DNA sequencing has become cheaper and easier, molecular systematics has become a more and more popular way to reconstruct phylogenies. Using a parsimony criterion is only one of several methods to infer a phylogeny from molecular data; maximum likelihood and Bayesian inference, which incorporate explicit models of sequence evolution, are non-Hennigian ways to evaluate sequence data. Another powerful method of reconstructing phylogenies is the use of genomic retrotransposon markers, which are thought to be less prone to the problem of reversion that plagues sequence data. They are also generally assumed to have a low incidence of homoplasies because it was once thought that their integration into the genome was entirely random; this seems at least sometimes not to be the case however.
Ideally, morphological, molecular and possibly other (behavioral etc.) phylogenies should be combined into an analysis of total evidence: all have different intrinsic sources of error. For example, character convergence (homoplasy) is much more common in morphological data than in molecular sequence data, but character reversions that cannot be noticed as such are more common in the latter (see long branch attraction). Morphological homoplasies can usually be recognized as such if character states are defined with enough attention to detail.
Cladistics does not assume any particular theory of evolution, only the background knowledge of descent with modification. Thus, cladistic methods can be, and recently have been, usefully applied to non-biological systems, including determining language families in historical linguistics and the filiation of manuscripts in textual criticism.
# Classification using cladistics
A recent trend in biology since the 1960s, called phylogenetic nomenclature, attempts to use cladistic trees as the basis for scientific classification, requiring taxa to be clades. In other words, cladists argue that the classification system should be reformed to eliminate all non-clades. In contrast, other taxonomists insist that groups reflect phylogenies and often make use of cladistic techniques, but allow both monophyletic and paraphyletic groups as taxa. In effect, already since the early 20th century at latest, it was generally attempted to make genus- and lower-level taxa monophyletic (even though the word might not have been used). Class- and higher-level taxa proved to be more difficult.
A monophyletic group is a clade, comprising an ancestral form and all of its descendants, and so forming one (and only one) evolutionary group. A paraphyletic group is similar, but excludes some of the descendants that have undergone significant changes. For instance, the traditional class Reptilia excludes birds even though they evolved from the ancestral reptile. Similarly, the traditional Invertebrates are paraphyletic because Vertebrates are excluded, although the latter evolved from an Invertebrate.
A group with members from separate evolutionary lines is called polyphyletic. For instance, the once-recognized Pachydermata was found to be polyphyletic because elephants and rhinoceroses arose from non-pachyderms separately. Evolutionary taxonomists consider polyphyletic groups to be errors in classification, often occurring because convergence or other homoplasy was misinterpreted as homology.
Following Hennig, cladists argue that paraphyly is as harmful as polyphyly. The idea is that monophyletic groups can be defined objectively, in terms of common ancestors or the presence of synapomorphies. In contrast, paraphyletic and polyphyletic groups are both defined based on key characters, and the decision of which characters are of taxonomic import is inherently subjective. Many argue that they lead to "gradistic" thinking, where groups advance from "lowly" grades to "advanced" grades, which can in turn lead to teleology. In evolutionary studies, teleology is usually avoided because it implies a plan that cannot be empirically demonstrated.
Going further, some cladists argue that ranks for groups above species are too subjective to present any meaningful information, and so argue that they should be abandoned. Thus they have moved away from Linnaean taxonomy towards a simple hierarchy of clades. The validity of this argument hinges crucially on how often in evolution gradualist near-equilibria are punctuated. A quasi-stable state will result in phylogenies, which may be all but unmappable onto the Linnaean hierarchy, whereas a punctuation event that balances a taxon out of its ecological equilibrium is likely to lead to a split between clades that occurs in comparatively short time and thus lends itself readily for classification according to the Linnaean system.
Other evolutionary systematists argue that all taxa are inherently subjective, even when they reflect evolutionary relationships, since living things form an essentially continuous tree. Any dividing line is artificial, and creates both a monophyletic section above and a paraphyletic section below. Paraphyletic taxa are necessary for classifying earlier sections of the tree – for instance, the early vertebrates that would someday evolve into the family Hominidae cannot be placed in any other monophyletic family. They also argue that paraphyletic taxa provide information about significant changes in organisms' morphology, ecology, or life history – in short, that both taxa and clades are valuable but distinct notions, with separate purposes. Many use the term monophyly in its older sense, where it includes paraphyly, and use the alternate term holophyly to describe clades (monophyly in Hennig's sense). As an unscientific rule of thumb, if a distinct lineage that renders the containing clade paraphyletic has undergone marked adaptive radiation and collected many synapomorphies - especially ones that are radical and/or unprecedented -, the paraphyly is usually not considered a sufficient argument to prevent recognition of the lineage as distinct under the Linnaean system (but it is by definition sufficient in phylogenetic nomenclature). For example, as touched upon briefly above, the Sauropsida ("reptiles") and the Aves (birds) are both ranked as a Linnaean class, although the latter are a highly derived offshoot of some forms of the former which themselves were already quite advanced.
A formal code of phylogenetic nomenclature, the PhyloCode, is currently under development for cladistic taxonomy. It is intended for use by both those who would like to abandon Linnaean taxonomy and those who would like to use taxa and clades side by side. In several instances (see for example Hesperornithes) it has been employed to clarify uncertainties in Linnaean systematics so that in combination they yield a taxonomy that is unambiguously placing the group in the evolutionary tree in a way that is consistent with current knowledge.
# Footnotes
- ↑ See, for example, pp. 45, 78 and 555 of Joel Cracraft and Michael J. Donaghue, eds. (2004). Assembling the Tree of Life. Oxford, England: Oxford University Press. | https://www.wikidoc.org/index.php/Cladistics | |
13b9009fa555d1f6cd4130c9cf893cf5b9272d7f | wikidoc | Cladribine | Cladribine
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# Black Box Warning
# Overview
Cladribine is an antineoplastic agent that is FDA approved for the treatment of active hairy Cell Leukemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include neutropenia, fever, infections, fatigue, nausea and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Active Hairy Cell Leukemia
- Defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms
- Dosage: single course given by continuous infusion for 7 consecutive days at a dose of 0.09 mg/kg/day.
- If the patient does not respond to the initial course of Cladribine Injection for hairy Cell Leukemia, it is unlikely that they will benefit from additional courses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cladribine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cladribine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Cladribine 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 Cladribine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cladribine in pediatric patients.
# Contraindications
- Cladribine Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components.
# Warnings
- Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with Cladribine, especially at high doses.
- At initiation of treatment, most patients in the clinical studies had hematologic impairment as a manifestation of active hairy Cell Leukemia.
- Following treatment with Cladribine, further hematologic impairment occurred before recovery of peripheral blood counts began.
- During the first two weeks after treatment initiation, mean platelet count, ANC, and hemoglobin concentration declined and subsequently increased with normalization of mean counts by Day 12, Week 5 and Week 8, respectively.
- The myelosuppressive effects of Cladribine were most notable during the first month following treatment.
- Forty-four percent (44%) of patients received transfusions with RBCs and 14% received transfusions with platelets during Month 1.
- Careful hematologic monitoring, especially during the first 4 to 8 weeks after treatment with Cladribine Injection, is recommended.
- Fever (T ≥ 100°F) was associated with the use of Cladribine in approximately two-thirds of patients (131/196) in the first month of therapy.
- Virtually all of these patients were treated empirically with parenteral antibiotics. Overall, 47% (93/196) of all patients had fever in the setting of neutropenia (ANC ≤ 1000), including 62 patients (32%) with severe neutropenia (i.e., ANC ≤ 500).
- In a Phase I investigational study using Cladribine in high doses (4 to 9 times the recommended dose for hairy Cell Leukemia) as part of a bone marrow transplant conditioning regimen, which also included high dose cyclophosphamide and total body irradiation, acute nephrotoxicity and delayed onset neurotoxicity were observed.
- Thirty one (31) poor-risk patients with drug-resistant acute leukemia in relapse (29 cases) or non-Hodgkins Lymphoma (2 cases) received Cladribine for 7 to 14 days prior to bone marrow transplantation.
- During infusion, 8 patients experienced gastrointestinal symptoms.
- While the bone marrow was initially cleared of all hematopoietic elements, including tumor cells, leukemia eventually recurred in all treated patients. Within 7 to 13 days after starting treatment with Cladribine, 6 patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine, etc.) and 5 required dialysis.
- Several of these patients were also being treated with other medications having known nephrotoxic potential.
- Renal dysfunction was reversible in 2 of these patients. In the 4 patients whose renal function had not recovered at the time of death, autopsies were performed; in 2 of these, evidence of tubular damage was noted.
- Eleven (11) patients (35%) experienced delayed onset neurologic toxicity.
- In the majority, this was characterized by progressive irreversible motor weakness (paraparesis/quadriparesis) of the upper and/or lower extremities, first noted 35 to 84 days after starting high dose therapy with Cladribine.
- Non-invasive testing (electromyography and nerve conduction studies) was consistent with demyelinating disease. Severe neurologic toxicity has also been noted with high doses of another drug in this class.
Axonal peripheral polyneuropathy was observed in a dose escalation study at the highest dose levels (approximately 4 times the recommended dose for Hairy Cell Leukemia) in patients not receiving cyclophosphamide or total body irradiation.
- Severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens.
In patients with Hairy Cell Leukemia treated with the recommended treatment regimen (0.09 mg/kg/day for 7 consecutive days), there have been no reports of nephrologic toxicities.
- Of the 196 Hairy Cell Leukemia patients entered in the two trials, there were 8 deaths following treatment. Of these, 6 were of infectious etiology, including 3 pneumonias, and 2 occurred in the first month following Cladribine therapy. Of the 8 deaths, 6 occurred in previously treated patients who were refractory to alpha interferon.
- Benzyl alcohol is a constituent of the recommended diluent for the 7-day infusion solution. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.
# Adverse Reactions
## Clinical Trials Experience
Safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same two centers after the original enrollment cutoff.
- In Month 1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Other adverse experiences reported frequently during the first 14 days after initiating treatment included: fatigue (45%), nausea (28%), rash (27%), headache (22%) and injection site reactions (19%). Most non-hematologic adverse experiences were mild to moderate in severity.
Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC < 500 x 106/L) was noted in 70% of patients, compared with 26% in whom it was present initially. Severe anemia (Hemoglobin < 8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 x 109/L) developed in 12% of patients, compared to 4% in whom it was noted initially. During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection.
Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease.
During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding Cladribine therapy. During the first month, 11% of patients experienced severe fever (i.e., ≥104°F). Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics.
Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/μL. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/μL. Fifteen (15) months after treatment, mean CD4 counts remained below 500/μL. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear.
Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts.
The vast majority of rashes were mild and occurred in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause rash.
Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.
Adverse reactions reported during the first 2 weeks following treatment initiation (regardless of relationship to drug) by > 5% of patients included:
### Body as a Whole
- Fever (69%)
- Fatigue (45%),
- Chills (9%)
- Asthenia (9%)
- Diaphoresis (9%)
- Malaise (7%)
- Trunk pain (6%)
### Gastrointestinal
- Nausea (28%)
- Decreased appetite (17%)
- Vomiting (13%)
- Diarrhea (10%)
- Constipation (9%)
- Abdominal pain (6%)
### Hemic/Lymphatic
- Purpura (10%)
- Petechiae (8%)
- Epistaxis (5%)
### Nervous System
- Headache (22%)
- Dizziness (9%)
- Insomnia (7%)
### Cardiovascular System
- Edema (6%)
- Tachycardia (6%)
### Respiratory System
- Abnormal breath sounds (11%)
- Cough (10%)
- Abnormal chest sounds (9%)
- Shortness of breath (7%)
### Skin/Subcutaneous Tissue
- Rash (27%)
- Injection site reactions (19%)
- Pruritis (6%)
- Pain (6%)
- Erythema (6%)
### Musculoskeletal System
- Myalgia (7%)
- Arthralgia (5%)
### Adverse experiences related to intravenous administration included
- Injection site reactions (9%) (i.e., redness, swelling, pain),
- Thrombosis (2%)
- Phlebitis (2%)
- Broken catheter (1%).
These appear to be related to the infusion procedure and/or indwelling catheter, rather than the medication or the vehicle.
From Day 15 to the last follow-up visit, the only events reported by > 5% of patients were: fatigue (11%), rash (10%), headache (7%), cough (7%), and malaise (5%).
For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients.
## Postmarketing Experience
The following additional adverse events have been reported since the drug became commercially available. These adverse events have been reported primarily in patients who received multiple courses of Cladribine Injection:
### Hematologic
- Bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia, which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported.
### Hepatic
- Reversible, generally mild increases in bilirubin and transaminases.
### Nervous System
- Neurological toxicity; however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens.
### Respiratory System
- Pulmonary interstitial infiltrates; in most cases, an infectious etiology was identified.
### Skin/Subcutaneous
- Urticaria
- Hypereosinophilia
- In isolated cases Stevens-Johnson and toxic epidermal necrolysis have been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes.
Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by Cladribine Injection.
# Drug Interactions
There are no known drug interactions with Cladribine Injection. Caution should be exercised if Cladribine Injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Cladribine Injection should not be given during pregnancy.
- Cladribine is teratogenic in mice and rabbits and consequently has the potential to cause fetal harm when administered to a pregnant woman.
- A significant increase in fetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m2) and increased resorptions, reduced litter size and increased fetal malformations were observed when mice received 3.0 mg/kg/day (9 mg/m2). Fetal death and malformations were observed in rabbits that received 3.0 mg/kg/day (33.0 mg/m2).
- No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m2) or in rabbits at 1.0 mg/kg/day (11.0 mg/m2).
- Although there is no evidence of teratogenicity in humans due to Cladribine, other drugs which inhibit DNA synthesis (e.g., methotrexate and aminopterin) have been reported to be teratogenic in humans.
- Cladribine has been shown to be embryotoxic in mice when given at doses equivalent to the recommended dose.
- There are no adequate and well controlled studies in pregnant women. If Cladribine 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. Women of childbearing age should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cladribine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cladribine 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 and because of the potential for serious adverse reactions in nursing infants from cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
- In a Phase I study involving patients 1-21 years old with relapsed acute leukemia, Cladribine was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m2/day for 5 days (one-half to twice the dose recommended in Hairy Cell Leukemia).
- In this study, the dose-limiting toxicity was severe myelosuppression with profound neutropenia and thrombocytopenia.
- At the highest dose (10.7 mg/m2/day), 3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study
### Geriatic Use
- Clinical studies of Cladribine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- In general, 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 in elderly patients.
### Gender
There is no FDA guidance on the use of Cladribine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cladribine with respect to specific racial populations.
### Renal Impairment
- There are inadequate data on dosing of patients with renal insufficiency.
- Development of acute renal insufficiency in some patients receiving high doses of Cladribine has been described.
### Hepatic Impairment
- There are inadequate data on dosing of patients with hepatic insufficiency.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cladribine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cladribine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous Infusion
### Monitoring
- Periodic assessment of peripheral blood counts, particularly during the first 4 to 8 weeks post-treatment, is recommended to detect the development of anemia, neutropenia and thrombocytopenia and for early detection of any potential sequelae (e.g., infection or bleeding). *As with other potent chemotherapeutic agents, monitoring of renal and hepatic function is also recommended, especially in patients with underlying kidney or liver dysfunction.
- Fever was a frequently observed side effect during the first month on study. Since the majority of fevers occurred in neutropenic patients, patients should be closely monitored during the first month of treatment and empiric antibiotics should be initiated as clinically indicated.
# IV Compatibility
Preparation and Administration of Intravenous Solutions:
- Cladribine Injection must be diluted with the designated diluent prior to administration.
- Since the drug product does not contain any anti-microbial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of Cladribine Injection solutions.
To prepare a single daily dose:
- Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of Cladribine Injection to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP.
- Infuse continuously over 24 hours.
- Repeat daily for a total of 7 consecutive days.
- The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine.
- Admixtures of Cladribine Injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in PVC infusion containers.
- Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.
To prepare a 7-day infusion:
- The 7-day infusion solution should only be prepared with Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved).
- In order to minimize the risk of microbial contamination, both Cladribine Injection and the diluent should be passed through a sterile 0.22μ disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir.
- First add the calculated dose of Cladribine Injection (7 days x 0.09 mg/kg or mL/kg) to the infusion reservoir through the sterile filter.
- Then add a calculated amount of Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved) also through the filter to bring the total volume of the solution to 100 mL.
- After completing solution preparation, clamp off the line, disconnect and discard the filter. *Aseptically aspirate air bubbles from the reservoir as necessary using the syringe and a dry second sterile filter or a sterile vent filter assembly.
- Reclamp the line and discard the syringe and filter assembly.
- Infuse continuously over 7 days.
- Solutions prepared with Bacteriostatic Sodium Chloride Injection for individuals weighing more than 85 kg may have reduced preservative effectiveness due to greater dilution of the benzyl alcohol preservative.
- Admixtures for the 7-day infusion have demonstrated acceptable chemical and physical stability for at least 7 days in the MEDICATION CASSETTE Reservoir.
- Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.
- Solutions containing Cladribine Injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed.
- Preparations containing benzyl alcohol should not be used in neonates.
- Care must be taken to assure the sterility of prepared solutions.
- Once diluted, solutions of Cladribine Injection should be administered promptly or stored in the refrigerator (2° to 8° C) for no more than 8 hours prior to start of administration.
- Vials of Cladribine Injection are for single-use only. Any unused portion should be discarded in an appropriate manner
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- A precipitate may occur during the exposure of Cladribine Injection to low temperatures; it may be resolubilized by allowing the solution to warm naturally to room temperature and by shaking vigorously.
- DO NOT HEAT OR MICROWAVE.
Chemical Stability of Vials:
- When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) protected from light, unopened vials of Cladribine Injection are stable until the expiration date indicated on the package.
- Freezing does not adversely affect the solution.
- If freezing occurs, thaw naturally to room temperature.
- DO NOT heat or microwave.
- Once thawed, the vial of Cladribine Injection is stable until expiry if refrigerated.
- DO NOT refreeze.
- Once diluted, solutions containing Cladribine Injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to administration.
Handling and Disposal:
- The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering Cladribine Injection. *The use of disposable gloves and protective garments is recommended.
- If Cladribine Injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water.
- Several guidelines on this subject have been published.(2-8) There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Refer to your Institution's guidelines and all applicable state/local regulations for disposal of cytotoxic waste.
# Overdosage
High doses of Cladribine have been associated with:
- Irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.
- There is no known specific antidote to overdosage.
- Treatment of overdosage consists of discontinuation of Cladribine, careful observation and appropriate supportive measures.
- It is not known whether the drug can be removed from the circulation by dialysis or hemofiltration.
# Pharmacology
## Mechanism of Action
- The selective toxicity of 2-chloro-2΄-deoxy-β-D-adenosine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase and deoxynucleotidase.
- Cladribine passively crosses the cell membrane.
- In cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2΄-deoxy- β -D-adenosine monophosphate (2-CdAMP). *Since 2-chloro-2΄-deoxy- β -D-adenosine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into the active triphosphate deoxynucleotide, 2-chloro-2΄-deoxy- β -D-adenosine triphosphate (2-CdATP).
- It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by 2-chloro-2΄-deoxy- β -D-adenosine as toxic deoxynucleotides accumulate intracellularly.
- Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. The broken ends of DNA activate the enzyme poly (ADP-ribose) polymerase resulting in NAD and ATP depletion and disruption of cellular metabolism.
- There is evidence, also, that 2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment of DNA synthesis.
- Thus, 2-chloro-2΄-deoxy- β -D-adenosine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.
## Structure
Cladribine Injection (also commonly known as 2-chloro-2΄-deoxy- β -D-adenosine) is a synthetic antineoplastic agent for continuous intravenous infusion. It is a clear, colorless, sterile, preservative-free, isotonic solution. Cladribine Injection is available in single-use vials containing 10 mg (1 mg/mL) of cladribine, a chlorinated purine nucleoside analog. Each milliliter of Cladribine Injection contains 1 mg of the active ingredient and 9 mg (0.15 mEq) of sodium chloride as an inactive ingredient. The solution has a pH range of 5.5 to 8.0. Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the pH to 6.3±0.3.
The chemical name for cladribine is 2-chloro-6-amino-9-(2-deoxy-β-D-erythropento-furanosyl) purine and the structure is represented below:
## Pharmacodynamics
There is limited information regarding Cladribine Pharmacodynamics in the drug label.
## Pharmacokinetics
In a clinical investigation, 17 patients with Hairy Cell Leukemia and normal renal function were treated for 7 days with the recommended treatment regimen of Cladribine Injection (0.09 mg/kg/day) by continuous intravenous infusion. The mean steady-state serum concentration was estimated to be 5.7 ng/mL with an estimated systemic clearance of 663.5 mL/h/kg when Cladribine was given by continuous infusion over 7 days. In Hairy Cell Leukemia patients, there does not appear to be a relationship between serum concentrations and ultimate clinical outcome.
In another study, 8 patients with hematologic malignancies received a two (2) hour infusion of Cladribine Injection (0.12 mg/kg). The mean end-of-infusion plasma Cladribine concentration was 48±19 ng/mL. For 5 of these patients, the disappearance of Cladribine could be described by either a biphasic or triphasic decline. For these patients with normal renal function, the mean terminal half-life was 5.4 hours. Mean values for clearance and steady-state volume of distribution were 978±422 mL/h/kg and 4.5±2.8 L/kg, respectively.
Cladribine plasma concentration after intravenous administration declines multi-exponentially with an average half-life of 6.7 +/- 2.5 hours. In general, the apparent volume of distribution of cladribine is approximately 9 L/kg, indicating an extensive distribution in body tissues.
Cladribine penetrates into cerebrospinal fluid. One report indicates that concentrations are approximately 25% of those in plasma.
Cladribine is bound approximately 20% to plasma proteins.
Except for some understanding of the mechanism of cellular toxicity, no other information is available on the metabolism of Cladribine in humans. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumors during a 5-day continuous intravenous infusion of 3.5-8.1 mg/m2/day of Cladribine. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.
## Nonclinical Toxicology
### Carcinogenesis
No animal carcinogenicity studies have been conducted with cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of cladribine.
### Mutagenesis
As expected for compounds in this class, the actions of cladribine yield DNA damage. In mammalian cells in culture, cladribine caused the accumulation of DNA strand breaks. Cladribine was also incorporated into DNA of human lymphoblastic leukemia cells. Cladribine was not mutagenic in vitro (Ames and Chinese hamster ovary cell gene mutation tests) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However, cladribine was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test).
### Impairment of Fertility
When administered intravenously to Cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells. The effect on human fertility is unknown.
# Clinical Studies
Two single-center open label studies of Cladribine have been conducted in patients with Hairy Cell Leukemia with evidence of active disease requiring therapy. In the study conducted at the Scripps Clinic and Research Foundation (Study A), 89 patients were treated with a single course of Cladribine Injection given by continuous intravenous infusion for 7 days at a dose of 0.09 mg/kg/day. In the study conducted at the M.D. Anderson Cancer Center (Study B), 35 patients were treated with a 7-day continuous intravenous infusion of Cladribine Injection at a comparable dose of 3.6 mg/m2/day. A complete response (CR) required clearing of the peripheral blood and bone marrow of hairy cells and recovery of the hemoglobin to 12 g/dL, platelet count to 100 x 109/L, and absolute neutrophil count to 1500 x 106/L. A good partial response (GPR) required the same hematologic parameters as a complete response, and that fewer than 5% hairy cells remain in the bone marrow. A partial response (PR) required that hairy cells in the bone marrow be decreased by at least 50% from baseline and the same response for hematologic parameters as for complete response. A pathologic relapse was defined as an increase in bone marrow hairy cells to 25% of pretreatment levels. A clinical relapse was defined as the recurrence of cytopenias, specifically, decreases in hemoglobin ≥ 2 g/dL, ANC ≥ 25% or platelet counts ≥ 50,000. Patients who met the criteria for a complete response but subsequently were found to have evidence of bone marrow hairy cells (< 25% of pretreatment levels) were reclassified as partial responses and were not considered to be complete responses with relapse.
Among patients evaluable for efficacy (N=106), using the hematologic and bone marrow response criteria described above, the complete response rates in patients treated with Cladribine Injection were 65% and 68% for Study A and Study B, respectively, yielding a combined complete response rate of 66%. Overall response rates (i.e., Complete plus Good Partial plus Partial Responses) were 89% and 86% in Study A and Study B, respectively, for a combined overall response rate of 88% in evaluable patients treated with Cladribine Injection.
Using an intent-to-treat analysis (N=123) and further requiring no evidence of splenomegaly as a criterion for CR (i.e., no palpable spleen on physical examination and≤ 13 cm on CT scan), the complete response rates for Study A and Study B were 54% and 53%, respectively, giving a combined CR rate of 54%. The overall response rates (CR + GPR + PR) were 90% and 85%, for Studies A and B, respectively, yielding a combined overall response rate of 89%.
In these studies, 60% of the patients had not received prior chemotherapy for Hairy Cell Leukemia or had undergone splenectomy as the only prior treatment and were receiving Cladribine as a first-line treatment. The remaining 40% of the patients received Cladribine as a second-line treatment, having been treated previously with other agents, including α-interferon and/or deoxycoformycin. The overall response rate for patients without prior chemotherapy was 92%, compared with 84% for previously treated patients. Cladribine is active in previously treated patients; however, retrospective analysis suggests that the overall response rate is decreased in patients previously treated with splenectomy or deoxycoformycin and in patients refractory to α-interferon.
After a reversible decline, normalization of peripheral blood counts (Hemoglobin >12.0 g/dL, Platelets >100 x 109/L, Absolute Neutrophil Count (ANC) >1500 x 106/L) was achieved by 92% of evaluable patients. The median time to normalization of peripheral counts was 9 weeks from the start of treatment (Range: 2 to 72). The median time to normalization of Platelet Count was 2 weeks, the median time to normalization of ANC was 5 weeks and the median time to normalization of Hemoglobin was 8 weeks. With normalization of Platelet Count and Hemoglobin, requirements for platelet and RBC transfusions were abolished after Months 1 and 2, respectively, in those patients with complete response. Platelet recovery may be delayed in a minority of patients with severe baseline thrombocytopenia. Corresponding to normalization of ANC, a trend toward a reduced incidence of infection was seen after the third month, when compared to the months immediately preceding Cladribine therapy.
For patients achieving a complete response, the median time to response (i.e., absence of hairy cells in bone marrow and peripheral blood together with normalization of peripheral blood parameters), measured from treatment start, was approximately 4 months. Since bone marrow aspiration and biopsy were frequently not performed at the time of peripheral blood normalization, the median time to complete response may actually be shorter than that which was recorded. At the time of data cut-off, the median duration of complete response was greater than 8 months and ranged to 25+ months. Among 93 responding patients, seven had shown evidence of disease progression at the time of the data cut-off. In four of these patients, disease was limited to the bone marrow without peripheral blood abnormalities (pathologic progression), while in three patients there were also peripheral blood abnormalities (clinical progression). Seven patients who did not respond to a first course of Cladribine received a second course of therapy. In the five patients who had adequate follow-up, additional courses did not appear to improve their overall response.
# How Supplied
- Cladribine Injection is supplied as a sterile, preservative-free, isotonic solution containing 10 mg (1 mg/mL) of Cladribine as 10 mL filled into a single-use clear flint glass vial, individually boxed. NDC 67457-450-10.
## Storage
- Store in refrigerator at 2° to 8°C (36° to 46°F). Protect from light during storage.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cladribine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Cladribine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Leustatin
# Look-Alike Drug Names
There is limited information regarding Cladribine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cladribine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [2]; Sree Teja Yelamanchili, MBBS [3]
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# Black Box Warning
# Overview
Cladribine is an antineoplastic agent that is FDA approved for the treatment of active hairy Cell Leukemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include neutropenia, fever, infections, fatigue, nausea and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Active Hairy Cell Leukemia
- Defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms
- Dosage: single course given by continuous infusion for 7 consecutive days at a dose of 0.09 mg/kg/day.
- If the patient does not respond to the initial course of Cladribine Injection for hairy Cell Leukemia, it is unlikely that they will benefit from additional courses.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cladribine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cladribine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Cladribine 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 Cladribine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cladribine in pediatric patients.
# Contraindications
- Cladribine Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components.
# Warnings
- Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with Cladribine, especially at high doses.
- At initiation of treatment, most patients in the clinical studies had hematologic impairment as a manifestation of active hairy Cell Leukemia.
- Following treatment with Cladribine, further hematologic impairment occurred before recovery of peripheral blood counts began.
- During the first two weeks after treatment initiation, mean platelet count, ANC, and hemoglobin concentration declined and subsequently increased with normalization of mean counts by Day 12, Week 5 and Week 8, respectively.
- The myelosuppressive effects of Cladribine were most notable during the first month following treatment.
- Forty-four percent (44%) of patients received transfusions with RBCs and 14% received transfusions with platelets during Month 1.
- Careful hematologic monitoring, especially during the first 4 to 8 weeks after treatment with Cladribine Injection, is recommended.
- Fever (T ≥ 100°F) was associated with the use of Cladribine in approximately two-thirds of patients (131/196) in the first month of therapy.
- Virtually all of these patients were treated empirically with parenteral antibiotics. Overall, 47% (93/196) of all patients had fever in the setting of neutropenia (ANC ≤ 1000), including 62 patients (32%) with severe neutropenia (i.e., ANC ≤ 500).
- In a Phase I investigational study using Cladribine in high doses (4 to 9 times the recommended dose for hairy Cell Leukemia) as part of a bone marrow transplant conditioning regimen, which also included high dose cyclophosphamide and total body irradiation, acute nephrotoxicity and delayed onset neurotoxicity were observed.
- Thirty one (31) poor-risk patients with drug-resistant acute leukemia in relapse (29 cases) or non-Hodgkins Lymphoma (2 cases) received Cladribine for 7 to 14 days prior to bone marrow transplantation.
- During infusion, 8 patients experienced gastrointestinal symptoms.
- While the bone marrow was initially cleared of all hematopoietic elements, including tumor cells, leukemia eventually recurred in all treated patients. Within 7 to 13 days after starting treatment with Cladribine, 6 patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine, etc.) and 5 required dialysis.
- Several of these patients were also being treated with other medications having known nephrotoxic potential.
- Renal dysfunction was reversible in 2 of these patients. In the 4 patients whose renal function had not recovered at the time of death, autopsies were performed; in 2 of these, evidence of tubular damage was noted.
- Eleven (11) patients (35%) experienced delayed onset neurologic toxicity.
- In the majority, this was characterized by progressive irreversible motor weakness (paraparesis/quadriparesis) of the upper and/or lower extremities, first noted 35 to 84 days after starting high dose therapy with Cladribine.
- Non-invasive testing (electromyography and nerve conduction studies) was consistent with demyelinating disease. Severe neurologic toxicity has also been noted with high doses of another drug in this class.
Axonal peripheral polyneuropathy was observed in a dose escalation study at the highest dose levels (approximately 4 times the recommended dose for Hairy Cell Leukemia) in patients not receiving cyclophosphamide or total body irradiation.
- Severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens.
In patients with Hairy Cell Leukemia treated with the recommended treatment regimen (0.09 mg/kg/day for 7 consecutive days), there have been no reports of nephrologic toxicities.
- Of the 196 Hairy Cell Leukemia patients entered in the two trials, there were 8 deaths following treatment. Of these, 6 were of infectious etiology, including 3 pneumonias, and 2 occurred in the first month following Cladribine therapy. Of the 8 deaths, 6 occurred in previously treated patients who were refractory to alpha interferon.
- Benzyl alcohol is a constituent of the recommended diluent for the 7-day infusion solution. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants.
# Adverse Reactions
## Clinical Trials Experience
Safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same two centers after the original enrollment cutoff.
- In Month 1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Other adverse experiences reported frequently during the first 14 days after initiating treatment included: fatigue (45%), nausea (28%), rash (27%), headache (22%) and injection site reactions (19%). Most non-hematologic adverse experiences were mild to moderate in severity.
Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC < 500 x 106/L) was noted in 70% of patients, compared with 26% in whom it was present initially. Severe anemia (Hemoglobin < 8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 x 109/L) developed in 12% of patients, compared to 4% in whom it was noted initially. During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection.
Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease.
During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding Cladribine therapy. During the first month, 11% of patients experienced severe fever (i.e., ≥104°F). Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics.
Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/μL. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/μL. Fifteen (15) months after treatment, mean CD4 counts remained below 500/μL. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear.
Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts.
The vast majority of rashes were mild and occurred in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause rash.
Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.
Adverse reactions reported during the first 2 weeks following treatment initiation (regardless of relationship to drug) by > 5% of patients included:
### Body as a Whole
- Fever (69%)
- Fatigue (45%),
- Chills (9%)
- Asthenia (9%)
- Diaphoresis (9%)
- Malaise (7%)
- Trunk pain (6%)
### Gastrointestinal
- Nausea (28%)
- Decreased appetite (17%)
- Vomiting (13%)
- Diarrhea (10%)
- Constipation (9%)
- Abdominal pain (6%)
### Hemic/Lymphatic
- Purpura (10%)
- Petechiae (8%)
- Epistaxis (5%)
### Nervous System
- Headache (22%)
- Dizziness (9%)
- Insomnia (7%)
### Cardiovascular System
- Edema (6%)
- Tachycardia (6%)
### Respiratory System
- Abnormal breath sounds (11%)
- Cough (10%)
- Abnormal chest sounds (9%)
- Shortness of breath (7%)
### Skin/Subcutaneous Tissue
- Rash (27%)
- Injection site reactions (19%)
- Pruritis (6%)
- Pain (6%)
- Erythema (6%)
### Musculoskeletal System
- Myalgia (7%)
- Arthralgia (5%)
### Adverse experiences related to intravenous administration included
- Injection site reactions (9%) (i.e., redness, swelling, pain),
- Thrombosis (2%)
- Phlebitis (2%)
- Broken catheter (1%).
These appear to be related to the infusion procedure and/or indwelling catheter, rather than the medication or the vehicle.
From Day 15 to the last follow-up visit, the only events reported by > 5% of patients were: fatigue (11%), rash (10%), headache (7%), cough (7%), and malaise (5%).
For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients.
## Postmarketing Experience
The following additional adverse events have been reported since the drug became commercially available. These adverse events have been reported primarily in patients who received multiple courses of Cladribine Injection:
### Hematologic
- Bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia, which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported.
### Hepatic
- Reversible, generally mild increases in bilirubin and transaminases.
### Nervous System
- Neurological toxicity; however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens.
### Respiratory System
- Pulmonary interstitial infiltrates; in most cases, an infectious etiology was identified.
### Skin/Subcutaneous
- Urticaria
- Hypereosinophilia
- In isolated cases Stevens-Johnson and toxic epidermal necrolysis have been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes.
Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by Cladribine Injection.
# Drug Interactions
There are no known drug interactions with Cladribine Injection. Caution should be exercised if Cladribine Injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Cladribine Injection should not be given during pregnancy.
- Cladribine is teratogenic in mice and rabbits and consequently has the potential to cause fetal harm when administered to a pregnant woman.
- A significant increase in fetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m2) and increased resorptions, reduced litter size and increased fetal malformations were observed when mice received 3.0 mg/kg/day (9 mg/m2). Fetal death and malformations were observed in rabbits that received 3.0 mg/kg/day (33.0 mg/m2).
- No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m2) or in rabbits at 1.0 mg/kg/day (11.0 mg/m2).
- Although there is no evidence of teratogenicity in humans due to Cladribine, other drugs which inhibit DNA synthesis (e.g., methotrexate and aminopterin) have been reported to be teratogenic in humans.
- Cladribine has been shown to be embryotoxic in mice when given at doses equivalent to the recommended dose.
- There are no adequate and well controlled studies in pregnant women. If Cladribine 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. Women of childbearing age should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cladribine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cladribine 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 and because of the potential for serious adverse reactions in nursing infants from cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
- In a Phase I study involving patients 1-21 years old with relapsed acute leukemia, Cladribine was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m2/day for 5 days (one-half to twice the dose recommended in Hairy Cell Leukemia).
- In this study, the dose-limiting toxicity was severe myelosuppression with profound neutropenia and thrombocytopenia.
- At the highest dose (10.7 mg/m2/day), 3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study
### Geriatic Use
- Clinical studies of Cladribine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- In general, 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 in elderly patients.
### Gender
There is no FDA guidance on the use of Cladribine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Cladribine with respect to specific racial populations.
### Renal Impairment
- There are inadequate data on dosing of patients with renal insufficiency.
- Development of acute renal insufficiency in some patients receiving high doses of Cladribine has been described.
### Hepatic Impairment
- There are inadequate data on dosing of patients with hepatic insufficiency.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cladribine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Cladribine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous Infusion
### Monitoring
- Periodic assessment of peripheral blood counts, particularly during the first 4 to 8 weeks post-treatment, is recommended to detect the development of anemia, neutropenia and thrombocytopenia and for early detection of any potential sequelae (e.g., infection or bleeding). *As with other potent chemotherapeutic agents, monitoring of renal and hepatic function is also recommended, especially in patients with underlying kidney or liver dysfunction.
- Fever was a frequently observed side effect during the first month on study. Since the majority of fevers occurred in neutropenic patients, patients should be closely monitored during the first month of treatment and empiric antibiotics should be initiated as clinically indicated.
# IV Compatibility
Preparation and Administration of Intravenous Solutions:
- Cladribine Injection must be diluted with the designated diluent prior to administration.
- Since the drug product does not contain any anti-microbial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of Cladribine Injection solutions.
To prepare a single daily dose:
- Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of Cladribine Injection to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP.
- Infuse continuously over 24 hours.
- Repeat daily for a total of 7 consecutive days.
- The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine.
- Admixtures of Cladribine Injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in PVC infusion containers.
- Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.
To prepare a 7-day infusion:
- The 7-day infusion solution should only be prepared with Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved).
- In order to minimize the risk of microbial contamination, both Cladribine Injection and the diluent should be passed through a sterile 0.22μ disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir.
- First add the calculated dose of Cladribine Injection (7 days x 0.09 mg/kg or mL/kg) to the infusion reservoir through the sterile filter.
- Then add a calculated amount of Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved) also through the filter to bring the total volume of the solution to 100 mL.
- After completing solution preparation, clamp off the line, disconnect and discard the filter. *Aseptically aspirate air bubbles from the reservoir as necessary using the syringe and a dry second sterile filter or a sterile vent filter assembly.
- Reclamp the line and discard the syringe and filter assembly.
- Infuse continuously over 7 days.
- Solutions prepared with Bacteriostatic Sodium Chloride Injection for individuals weighing more than 85 kg may have reduced preservative effectiveness due to greater dilution of the benzyl alcohol preservative.
- Admixtures for the 7-day infusion have demonstrated acceptable chemical and physical stability for at least 7 days in the MEDICATION CASSETTE Reservoir.
- Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.
- Solutions containing Cladribine Injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed.
- Preparations containing benzyl alcohol should not be used in neonates.
- Care must be taken to assure the sterility of prepared solutions.
- Once diluted, solutions of Cladribine Injection should be administered promptly or stored in the refrigerator (2° to 8° C) for no more than 8 hours prior to start of administration.
- Vials of Cladribine Injection are for single-use only. Any unused portion should be discarded in an appropriate manner
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- A precipitate may occur during the exposure of Cladribine Injection to low temperatures; it may be resolubilized by allowing the solution to warm naturally to room temperature and by shaking vigorously.
- DO NOT HEAT OR MICROWAVE.
Chemical Stability of Vials:
- When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) protected from light, unopened vials of Cladribine Injection are stable until the expiration date indicated on the package.
- Freezing does not adversely affect the solution.
- If freezing occurs, thaw naturally to room temperature.
- DO NOT heat or microwave.
- Once thawed, the vial of Cladribine Injection is stable until expiry if refrigerated.
- DO NOT refreeze.
- Once diluted, solutions containing Cladribine Injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to administration.
Handling and Disposal:
- The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering Cladribine Injection. *The use of disposable gloves and protective garments is recommended.
- If Cladribine Injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water.
- Several guidelines on this subject have been published.(2-8) There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Refer to your Institution's guidelines and all applicable state/local regulations for disposal of cytotoxic waste.
# Overdosage
High doses of Cladribine have been associated with:
- Irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.
- There is no known specific antidote to overdosage.
- Treatment of overdosage consists of discontinuation of Cladribine, careful observation and appropriate supportive measures.
- It is not known whether the drug can be removed from the circulation by dialysis or hemofiltration.
# Pharmacology
## Mechanism of Action
- The selective toxicity of 2-chloro-2΄-deoxy-β-D-adenosine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase and deoxynucleotidase.
- Cladribine passively crosses the cell membrane.
- In cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2΄-deoxy- β -D-adenosine monophosphate (2-CdAMP). *Since 2-chloro-2΄-deoxy- β -D-adenosine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into the active triphosphate deoxynucleotide, 2-chloro-2΄-deoxy- β -D-adenosine triphosphate (2-CdATP).
- It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by 2-chloro-2΄-deoxy- β -D-adenosine as toxic deoxynucleotides accumulate intracellularly.
- Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. The broken ends of DNA activate the enzyme poly (ADP-ribose) polymerase resulting in NAD and ATP depletion and disruption of cellular metabolism.
- There is evidence, also, that 2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment of DNA synthesis.
- Thus, 2-chloro-2΄-deoxy- β -D-adenosine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.
## Structure
Cladribine Injection (also commonly known as 2-chloro-2΄-deoxy- β -D-adenosine) is a synthetic antineoplastic agent for continuous intravenous infusion. It is a clear, colorless, sterile, preservative-free, isotonic solution. Cladribine Injection is available in single-use vials containing 10 mg (1 mg/mL) of cladribine, a chlorinated purine nucleoside analog. Each milliliter of Cladribine Injection contains 1 mg of the active ingredient and 9 mg (0.15 mEq) of sodium chloride as an inactive ingredient. The solution has a pH range of 5.5 to 8.0. Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the pH to 6.3±0.3.
The chemical name for cladribine is 2-chloro-6-amino-9-(2-deoxy-β-D-erythropento-furanosyl) purine and the structure is represented below:
## Pharmacodynamics
There is limited information regarding Cladribine Pharmacodynamics in the drug label.
## Pharmacokinetics
In a clinical investigation, 17 patients with Hairy Cell Leukemia and normal renal function were treated for 7 days with the recommended treatment regimen of Cladribine Injection (0.09 mg/kg/day) by continuous intravenous infusion. The mean steady-state serum concentration was estimated to be 5.7 ng/mL with an estimated systemic clearance of 663.5 mL/h/kg when Cladribine was given by continuous infusion over 7 days. In Hairy Cell Leukemia patients, there does not appear to be a relationship between serum concentrations and ultimate clinical outcome.
In another study, 8 patients with hematologic malignancies received a two (2) hour infusion of Cladribine Injection (0.12 mg/kg). The mean end-of-infusion plasma Cladribine concentration was 48±19 ng/mL. For 5 of these patients, the disappearance of Cladribine could be described by either a biphasic or triphasic decline. For these patients with normal renal function, the mean terminal half-life was 5.4 hours. Mean values for clearance and steady-state volume of distribution were 978±422 mL/h/kg and 4.5±2.8 L/kg, respectively.
Cladribine plasma concentration after intravenous administration declines multi-exponentially with an average half-life of 6.7 +/- 2.5 hours. In general, the apparent volume of distribution of cladribine is approximately 9 L/kg, indicating an extensive distribution in body tissues.
Cladribine penetrates into cerebrospinal fluid. One report indicates that concentrations are approximately 25% of those in plasma.
Cladribine is bound approximately 20% to plasma proteins.
Except for some understanding of the mechanism of cellular toxicity, no other information is available on the metabolism of Cladribine in humans. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumors during a 5-day continuous intravenous infusion of 3.5-8.1 mg/m2/day of Cladribine. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.
## Nonclinical Toxicology
### Carcinogenesis
No animal carcinogenicity studies have been conducted with cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of cladribine.
### Mutagenesis
As expected for compounds in this class, the actions of cladribine yield DNA damage. In mammalian cells in culture, cladribine caused the accumulation of DNA strand breaks. Cladribine was also incorporated into DNA of human lymphoblastic leukemia cells. Cladribine was not mutagenic in vitro (Ames and Chinese hamster ovary cell gene mutation tests) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However, cladribine was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test).
### Impairment of Fertility
When administered intravenously to Cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells. The effect on human fertility is unknown.
# Clinical Studies
Two single-center open label studies of Cladribine have been conducted in patients with Hairy Cell Leukemia with evidence of active disease requiring therapy. In the study conducted at the Scripps Clinic and Research Foundation (Study A), 89 patients were treated with a single course of Cladribine Injection given by continuous intravenous infusion for 7 days at a dose of 0.09 mg/kg/day. In the study conducted at the M.D. Anderson Cancer Center (Study B), 35 patients were treated with a 7-day continuous intravenous infusion of Cladribine Injection at a comparable dose of 3.6 mg/m2/day. A complete response (CR) required clearing of the peripheral blood and bone marrow of hairy cells and recovery of the hemoglobin to 12 g/dL, platelet count to 100 x 109/L, and absolute neutrophil count to 1500 x 106/L. A good partial response (GPR) required the same hematologic parameters as a complete response, and that fewer than 5% hairy cells remain in the bone marrow. A partial response (PR) required that hairy cells in the bone marrow be decreased by at least 50% from baseline and the same response for hematologic parameters as for complete response. A pathologic relapse was defined as an increase in bone marrow hairy cells to 25% of pretreatment levels. A clinical relapse was defined as the recurrence of cytopenias, specifically, decreases in hemoglobin ≥ 2 g/dL, ANC ≥ 25% or platelet counts ≥ 50,000. Patients who met the criteria for a complete response but subsequently were found to have evidence of bone marrow hairy cells (< 25% of pretreatment levels) were reclassified as partial responses and were not considered to be complete responses with relapse.
Among patients evaluable for efficacy (N=106), using the hematologic and bone marrow response criteria described above, the complete response rates in patients treated with Cladribine Injection were 65% and 68% for Study A and Study B, respectively, yielding a combined complete response rate of 66%. Overall response rates (i.e., Complete plus Good Partial plus Partial Responses) were 89% and 86% in Study A and Study B, respectively, for a combined overall response rate of 88% in evaluable patients treated with Cladribine Injection.
Using an intent-to-treat analysis (N=123) and further requiring no evidence of splenomegaly as a criterion for CR (i.e., no palpable spleen on physical examination and≤ 13 cm on CT scan), the complete response rates for Study A and Study B were 54% and 53%, respectively, giving a combined CR rate of 54%. The overall response rates (CR + GPR + PR) were 90% and 85%, for Studies A and B, respectively, yielding a combined overall response rate of 89%.
In these studies, 60% of the patients had not received prior chemotherapy for Hairy Cell Leukemia or had undergone splenectomy as the only prior treatment and were receiving Cladribine as a first-line treatment. The remaining 40% of the patients received Cladribine as a second-line treatment, having been treated previously with other agents, including α-interferon and/or deoxycoformycin. The overall response rate for patients without prior chemotherapy was 92%, compared with 84% for previously treated patients. Cladribine is active in previously treated patients; however, retrospective analysis suggests that the overall response rate is decreased in patients previously treated with splenectomy or deoxycoformycin and in patients refractory to α-interferon.
After a reversible decline, normalization of peripheral blood counts (Hemoglobin >12.0 g/dL, Platelets >100 x 109/L, Absolute Neutrophil Count (ANC) >1500 x 106/L) was achieved by 92% of evaluable patients. The median time to normalization of peripheral counts was 9 weeks from the start of treatment (Range: 2 to 72). The median time to normalization of Platelet Count was 2 weeks, the median time to normalization of ANC was 5 weeks and the median time to normalization of Hemoglobin was 8 weeks. With normalization of Platelet Count and Hemoglobin, requirements for platelet and RBC transfusions were abolished after Months 1 and 2, respectively, in those patients with complete response. Platelet recovery may be delayed in a minority of patients with severe baseline thrombocytopenia. Corresponding to normalization of ANC, a trend toward a reduced incidence of infection was seen after the third month, when compared to the months immediately preceding Cladribine therapy.
For patients achieving a complete response, the median time to response (i.e., absence of hairy cells in bone marrow and peripheral blood together with normalization of peripheral blood parameters), measured from treatment start, was approximately 4 months. Since bone marrow aspiration and biopsy were frequently not performed at the time of peripheral blood normalization, the median time to complete response may actually be shorter than that which was recorded. At the time of data cut-off, the median duration of complete response was greater than 8 months and ranged to 25+ months. Among 93 responding patients, seven had shown evidence of disease progression at the time of the data cut-off. In four of these patients, disease was limited to the bone marrow without peripheral blood abnormalities (pathologic progression), while in three patients there were also peripheral blood abnormalities (clinical progression). Seven patients who did not respond to a first course of Cladribine received a second course of therapy. In the five patients who had adequate follow-up, additional courses did not appear to improve their overall response.
# How Supplied
- Cladribine Injection is supplied as a sterile, preservative-free, isotonic solution containing 10 mg (1 mg/mL) of Cladribine as 10 mL filled into a single-use clear flint glass vial, individually boxed. NDC 67457-450-10.
## Storage
- Store in refrigerator at 2° to 8°C (36° to 46°F). Protect from light during storage.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Cladribine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Cladribine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Leustatin[2]
# Look-Alike Drug Names
There is limited information regarding Cladribine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cladribine | |
4861155d0801326d28c70affd300cd8603a8df25 | wikidoc | Clara cell | Clara cell
Clara cells are non-mucous and non-ciliated secretory cells found in the primary bronchioles of the lungs.
Clara cells are dome-shaped and have short microvilli. One of the main functions of Clara cells is to protect the bronchiolar epithelium. They do this by secreting a small variety of products, including Clara cell secretory protein (CCSP) and a component of the lung surfactant. They are also responsible for detoxifying harmful substances inhaled into the lungs. Clara cells accomplish this with cytochrome P450 enzymes found in their smooth endoplasmic reticulum. Clara cells also multiply and differentiate into ciliated cells to regenerate the bronchiolar epithelium.
Clara cells were originally described by their namesake, Max Clara in 1937.
The respiratory bronchioles represent the transition from the conducting portion to the respiratory portion of the respiratory system. The narrow channels are usually less than 2 mm in diameter and they are lined by a simple cuboidal epithelium, consisting of ciliated cells and non-ciliated Clara cells, which are unique to bronchioles. In addition to being structurally diverse, Clara cells are also functionally variable. One major function they carry out is the synthesis and secretion of the material lining the bronchiolar lumen. This material includes glycosaminoglycans, and proteins such as antibodies and lysosymes. These play an important defensive role, and they also contribute to the degradation of the mucus produced by the upper airways. The heterogeneous nature of the dense granules within the Clara cell's cytoplasm suggests that they may not all have a secretory function. Some of them may contain lysosomal enzymes, which carry out a digestive role, either in defense: Clara cells engulf airborne toxins and break them down via their cytochrome P-450 enzymes present in their smooth endoplasmic reticulum; or in the recycling of secretory products. Clara cells are mitotically active cells. They divide and differentiate to form both ciliated and non-ciliated epithelial cells. | Clara cell
Clara cells are non-mucous and non-ciliated secretory cells found in the primary bronchioles of the lungs.
Clara cells are dome-shaped and have short microvilli. One of the main functions of Clara cells is to protect the bronchiolar epithelium. They do this by secreting a small variety of products, including Clara cell secretory protein (CCSP) and a component of the lung surfactant. They are also responsible for detoxifying harmful substances inhaled into the lungs. Clara cells accomplish this with cytochrome P450 enzymes found in their smooth endoplasmic reticulum. Clara cells also multiply and differentiate into ciliated cells to regenerate the bronchiolar epithelium.
Clara cells were originally described by their namesake, Max Clara in 1937.
The respiratory bronchioles represent the transition from the conducting portion to the respiratory portion of the respiratory system. The narrow channels are usually less than 2 mm in diameter and they are lined by a simple cuboidal epithelium, consisting of ciliated cells and non-ciliated Clara cells, which are unique to bronchioles. In addition to being structurally diverse, Clara cells are also functionally variable. One major function they carry out is the synthesis and secretion of the material lining the bronchiolar lumen. This material includes glycosaminoglycans, and proteins such as antibodies and lysosymes. These play an important defensive role, and they also contribute to the degradation of the mucus produced by the upper airways. The heterogeneous nature of the dense granules within the Clara cell's cytoplasm suggests that they may not all have a secretory function. Some of them may contain lysosomal enzymes, which carry out a digestive role, either in defense: Clara cells engulf airborne toxins and break them down via their cytochrome P-450 enzymes present in their smooth endoplasmic reticulum; or in the recycling of secretory products. Clara cells are mitotically active cells. They divide and differentiate to form both ciliated and non-ciliated epithelial cells. | https://www.wikidoc.org/index.php/Clara_cell | |
2728444a4b17e9414a8d877138b96eff3321860b | wikidoc | Clear cell | Clear cell
# Overview
Clear cell tumors are part of the surface epithelial-stromal tumor group of Ovarian cancers, accounting for 6% of these neoplastic cases. Clear cell tumors are also associated with the pancreas and salivary glands.
Benign and borderline variants of this neoplasm are rare, and most cases are malignant.
Typically, they are cystic neoplasms with polypoid masses that protrude into the cyst.
On microscopic pathological examination, they are composed of cells with clear cytoplasm (that contains glycogen) and hob nail cells (from which the glycogen has been secreted).
The pattern may be glandular, papillary or solid. | Clear cell
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Clear cell tumors are part of the surface epithelial-stromal tumor group of Ovarian cancers, accounting for 6% of these neoplastic cases. Clear cell tumors are also associated with the pancreas and salivary glands.
Benign and borderline variants of this neoplasm are rare, and most cases are malignant.
Typically, they are cystic neoplasms with polypoid masses that protrude into the cyst.
On microscopic pathological examination, they are composed of cells with clear cytoplasm (that contains glycogen) and hob nail cells (from which the glycogen has been secreted).
The pattern may be glandular, papillary or solid. | https://www.wikidoc.org/index.php/Clear_cell | |
ff03129108bc8eceb3d159a63e93df204c16a007 | wikidoc | Clemastine | Clemastine
# 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
Clemastine is a antihistamine that is FDA approved for the treatment of allergic rhinitis, urticaria and angioedema. Common adverse reactions include drowsiness, urinary retention.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Clemastine fumarate tablets are indicated for the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus, and lacrimation.
- Clemastine fumarate tablets are also indicated for the relief of mild, uncomplicated allergic skin manifestations of urticaria and angioedema.
- It should be noted that clemastine is indicated for the dermatologic indications at the 2.68 mg dosage level only.
### Dosage
- DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND RESPONSE OF THE PATIENT.
- The recommended starting dose is 1.34 mg (1/2 tablet) twice daily. Dosage may be increased as required. Clemastine fumarate tablets are recommended for the dermatologic indications at the 2.68 mg dosage level only.
- The maximum recommended dosage is 2.68 mg three times daily. Many patients respond favorably to a single dose which may be repeated as required, but not to exceed three tablets daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clemastine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clemastine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy of clemastine fumarate have not been established in children under the age of 12 years.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clemastine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clemastine in pediatric patients.
# Contraindications
- Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, antihistamine therapy is contraindicated in nursing mothers.
- Antihistamines should not be used to treat lower respiratory tract symptoms including asthma.
- Antihistamines are also contraindicated in the following conditions:
- Hypersensitivity to clemastine fumarate or other antihistamines of similar chemical structure.
- Monoamine oxidase inhibitor therapy
# Warnings
- Antihistamines should be used with considerable caution in patients with: narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, and bladder neck obstruction.
- Clemastine has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc.)
- Patients should be warned about engaging in activities requiring mental alertness such as driving a car or operating appliances, machinery, etc.
### Precautions
- Clemastine fumarate should be used with caution in patients with: history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, and hypertension.
# Adverse Reactions
## Clinical Trials Experience
- Transient drowsiness, the most common adverse reaction associated with clemastine fumarate, occurs relatively frequently and may require discontinuation of therapy in some instances.
- It should be noted that the following reactions have occurred with one or more antihistamines and, therefore, should be kept in mind when prescribing drugs belonging to this class, including clemastine fumarate.
- The most frequent adverse reactions are underlined.
- General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, dryness of mouth, nose, and throat.
- Cardiovascular System: Hypotension, headache, palpitations, tachycardia, extrasystoles.
- Hematologic System: Hemolytic anemia, thrombocytopenia, agranulocytosis.
- Nervous System: Sedation, sleepiness, dizziness, disturbed coordination, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesias, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, hysteria, neuritis, convulsions.
- GI System: Epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation.
- GU System: Urinary frequency, difficult urination, urinary retention, early menses.
- Respiratory System: Thickening of bronchial secretions, tightness of chest and wheezing, nasal stuffiness.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Clemastine in the drug label.
# Drug Interactions
- MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Experience with this drug in pregnant women is inadequate to determine whether there exists a potential for harm to the developing fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clemastine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Clemastine during labor and delivery.
### Nursing Mothers
- Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, antihistamine therapy is contraindicated in nursing mothers.
### Pediatric Use
- Safety and efficacy of clemastine fumarate have not been established in children under the age of 12 years.
### Geriatic Use
- Antihistamines are more likely to cause dizziness, sedation, and hypotension in elderly patients.
### Gender
There is no FDA guidance on the use of Clemastine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Clemastine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Clemastine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Clemastine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clemastine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Clemastine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Clemastine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Clemastine in the drug label.
# Overdosage
- Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. Stimulation is particularly likely in children. Atropine-like signs and symptoms: dry mouth; fixed, dilated pupils; flushing; and gastrointestinal symptoms may also occur.
- If vomiting has not occured spontaneously the conscious patient should be induced to vomit. This is best done by having him drink a glass of water or milk after which he should be made to gag. Precautions against aspiration must be taken, especially in infants and children.
- If vomiting is unsuccessful gastric lavage is indicated within 3 hours after ingestion and even later if large amounts of milk or cream were given beforehand. Isotonic and 1/2 isotonic saline is the lavage solution of choice.
- Saline cathartics, such as milk of magnesia, by osmosis draw water into the bowel and therefore, are valuable for their action in rapid dilution of bowel content.
- Stimulants should not be used.
- Vasopressors may be used to treat hypotension.
# Pharmacology
## Mechanism of Action
- Clemastine fumarate is an antihistamine with anticholinergic (drying) and sedative side effects. Antihistamines appear to compete with histamine for cell receptor sites on effector cells.
## Structure
- Clemastine fumarate belongs to the benzhydryl ether group of antihistaminic compounds. The chemical name is (+)-2- ethyl]-1-methylpyrrolidine hydrogen fumarate. It has the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Clemastine in the drug label.
## Pharmacokinetics
- The inherently long duration of antihistaminic effects of clemastine has been demonstrated in wheal and flare studies. In normal human subjects who received histamine injections over a 24-hour period, the antihistaminic activity of clemastine reached a peak at 5 to 7 hours, persisted for 10 to 12 hours and, in some cases, for as long as 24 hours. Pharmacokinetic studies in man utilizing 3H and 14C labeled compound demonstrates that: clemastine is rapidly and nearly completely absorbed from the gastrointestinal tract, peak plasma concentrations are attained in 2 to 4 hours, and urinary excretion is the major mode of elimination.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Clemastine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Clemastine in the drug label.
# How Supplied
- Clemastine fumarate tablets, USP are available as:
2.68 mg: Round, white tablets, scored, debossed GG 160 on one side and plain on the reverse side and supplied as:
NDC 0781-1359-01 bottles of 100
NDC 0781-1359-05 bottles of 500
NDC 0781-1359-10 bottles of 1000
## Storage
- Store below 25°C. Dispense in a tight, light-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
### 2.68 MG LABEL
Clemastine
Fumarate
Tablets, USP
2.68 mg
Rx only
100 Tablets
SANDOZ
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Clemastine in the drug label.
# Precautions with Alcohol
- Alcohol-Clemastine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tavist®
# Look-Alike Drug Names
There is limited information regarding Clemastine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Clemastine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [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
Clemastine is a antihistamine that is FDA approved for the treatment of allergic rhinitis, urticaria and angioedema. Common adverse reactions include drowsiness, urinary retention.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Clemastine fumarate tablets are indicated for the relief of symptoms associated with allergic rhinitis such as sneezing, rhinorrhea, pruritus, and lacrimation.
- Clemastine fumarate tablets are also indicated for the relief of mild, uncomplicated allergic skin manifestations of urticaria and angioedema.
- It should be noted that clemastine is indicated for the dermatologic indications at the 2.68 mg dosage level only.
### Dosage
- DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND RESPONSE OF THE PATIENT.
- The recommended starting dose is 1.34 mg (1/2 tablet) twice daily. Dosage may be increased as required. Clemastine fumarate tablets are recommended for the dermatologic indications at the 2.68 mg dosage level only.
- The maximum recommended dosage is 2.68 mg three times daily. Many patients respond favorably to a single dose which may be repeated as required, but not to exceed three tablets daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clemastine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clemastine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy of clemastine fumarate have not been established in children under the age of 12 years.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Clemastine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Clemastine in pediatric patients.
# Contraindications
- Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, antihistamine therapy is contraindicated in nursing mothers.
- Antihistamines should not be used to treat lower respiratory tract symptoms including asthma.
- Antihistamines are also contraindicated in the following conditions:
- Hypersensitivity to clemastine fumarate or other antihistamines of similar chemical structure.
- Monoamine oxidase inhibitor therapy
# Warnings
- Antihistamines should be used with considerable caution in patients with: narrow angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy, and bladder neck obstruction.
- Clemastine has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc.)
- Patients should be warned about engaging in activities requiring mental alertness such as driving a car or operating appliances, machinery, etc.
### Precautions
- Clemastine fumarate should be used with caution in patients with: history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, and hypertension.
# Adverse Reactions
## Clinical Trials Experience
- Transient drowsiness, the most common adverse reaction associated with clemastine fumarate, occurs relatively frequently and may require discontinuation of therapy in some instances.
- It should be noted that the following reactions have occurred with one or more antihistamines and, therefore, should be kept in mind when prescribing drugs belonging to this class, including clemastine fumarate.
- The most frequent adverse reactions are underlined.
- General: Urticaria, drug rash, anaphylactic shock, photosensitivity, excessive perspiration, chills, dryness of mouth, nose, and throat.
- Cardiovascular System: Hypotension, headache, palpitations, tachycardia, extrasystoles.
- Hematologic System: Hemolytic anemia, thrombocytopenia, agranulocytosis.
- Nervous System: Sedation, sleepiness, dizziness, disturbed coordination, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesias, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, hysteria, neuritis, convulsions.
- GI System: Epigastric distress, anorexia, nausea, vomiting, diarrhea, constipation.
- GU System: Urinary frequency, difficult urination, urinary retention, early menses.
- Respiratory System: Thickening of bronchial secretions, tightness of chest and wheezing, nasal stuffiness.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Clemastine in the drug label.
<--Drug Interactions-->
# Drug Interactions
- MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Experience with this drug in pregnant women is inadequate to determine whether there exists a potential for harm to the developing fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clemastine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Clemastine during labor and delivery.
### Nursing Mothers
- Because of the higher risk of antihistamines for infants generally and for newborns and prematures in particular, antihistamine therapy is contraindicated in nursing mothers.
### Pediatric Use
- Safety and efficacy of clemastine fumarate have not been established in children under the age of 12 years.
### Geriatic Use
- Antihistamines are more likely to cause dizziness, sedation, and hypotension in elderly patients.
### Gender
There is no FDA guidance on the use of Clemastine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Clemastine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Clemastine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Clemastine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Clemastine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Clemastine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Clemastine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Clemastine in the drug label.
# Overdosage
- Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. Stimulation is particularly likely in children. Atropine-like signs and symptoms: dry mouth; fixed, dilated pupils; flushing; and gastrointestinal symptoms may also occur.
- If vomiting has not occured spontaneously the conscious patient should be induced to vomit. This is best done by having him drink a glass of water or milk after which he should be made to gag. Precautions against aspiration must be taken, especially in infants and children.
- If vomiting is unsuccessful gastric lavage is indicated within 3 hours after ingestion and even later if large amounts of milk or cream were given beforehand. Isotonic and 1/2 isotonic saline is the lavage solution of choice.
- Saline cathartics, such as milk of magnesia, by osmosis draw water into the bowel and therefore, are valuable for their action in rapid dilution of bowel content.
- Stimulants should not be used.
- Vasopressors may be used to treat hypotension.
# Pharmacology
## Mechanism of Action
- Clemastine fumarate is an antihistamine with anticholinergic (drying) and sedative side effects. Antihistamines appear to compete with histamine for cell receptor sites on effector cells.
## Structure
- Clemastine fumarate belongs to the benzhydryl ether group of antihistaminic compounds. The chemical name is (+)-2-[-2- [(p-chloro-α-methyl-α-phenylbenzyl) oxy] ethyl]-1-methylpyrrolidine hydrogen fumarate. It has the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Clemastine in the drug label.
## Pharmacokinetics
- The inherently long duration of antihistaminic effects of clemastine has been demonstrated in wheal and flare studies. In normal human subjects who received histamine injections over a 24-hour period, the antihistaminic activity of clemastine reached a peak at 5 to 7 hours, persisted for 10 to 12 hours and, in some cases, for as long as 24 hours. Pharmacokinetic studies in man utilizing 3H and 14C labeled compound demonstrates that: clemastine is rapidly and nearly completely absorbed from the gastrointestinal tract, peak plasma concentrations are attained in 2 to 4 hours, and urinary excretion is the major mode of elimination.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Clemastine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Clemastine in the drug label.
# How Supplied
- Clemastine fumarate tablets, USP are available as:
2.68 mg: Round, white tablets, scored, debossed GG 160 on one side and plain on the reverse side and supplied as:
NDC 0781-1359-01 bottles of 100
NDC 0781-1359-05 bottles of 500
NDC 0781-1359-10 bottles of 1000
## Storage
- Store below 25°C. Dispense in a tight, light-resistant container.
# Images
## Drug Images
## Package and Label Display Panel
### 2.68 MG LABEL
Clemastine
Fumarate
Tablets, USP
2.68 mg
Rx only
100 Tablets
SANDOZ
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Clemastine in the drug label.
# Precautions with Alcohol
- Alcohol-Clemastine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tavist®[1]
# Look-Alike Drug Names
There is limited information regarding Clemastine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Clemastine | |
9f34bd1d3809e4d02f4d5432a0edd8c09fd98d2e | wikidoc | Enoxaparin | Enoxaparin
# Disclaimer
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# Black Box Warning
# Overview
Enoxaparin is an anticoagulant that is FDA approved for the treatment of acute deep vein thrombosis, acute ST-segment elevation myocardial infarction and prophylaxis of deep vein thrombosis and ischemic complications of unstable angina and non-Q-wave myocardial infarction. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, anemia, major bleeding, thrombocytopenia, increased liver function test, and fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Prophylaxis of Deep Vein Thrombosis
- Dosing information
- Recommended dose: 40 mg SC q24h (with the initial dose given 2 hours prior to surgery)
- Duration of administration: 7 to 10 days (maximum: 12 days)
- Dosing information
- Recommended dose: 30 mg SC q12h (with the initial dose given 12 to 24 hours after surgery)
- Duration of administration: 7 to 10 days (maximum: 14 days)
- Alternative dosage for hip replacement surgery
- Recommended dose: 40 mg SC q24h (with the initial dose given 12±3 hours prior to surgery)
- Duration of administration: 3 weeks
- Dosing information
- Recommended dose: 40 mg SC q24h
- Duration of administration: 6 to 11 days (maximum: 14 days)
### Treatment of Acute Deep Vein Thrombosis (With or Without Pulmonary Embolism)
- Dosing information
- Recommended dose:
- For outpatient: 1 mg/kg SC q12h
- For inpatient: 1 mg/kg SC q12h or 1.5 mg/kg SC q24h
- Warfarin therapy should be initiated when appropriate (usually within 72 hours of enoxaparin injection).
- Duration of administration: 7 days (maximum: 17 days)
- Enoxaparin should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (INR 2.0–3.0).
### Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave Myocardial Infarction
- Dosing information
- Recommended dose: 1 mg/kg SC q12h (in conjunction with aspirin 100–325 mg PO qd)
- Duration of administration: 2 to 8 days (maximum: 12.5 days)
### Treatment of Acute ST-Segment Elevation Myocardial Infarction
- Dosing information
- Recommended dose (<75 years of age): 30 mg IV bolus PLUS 1 mg/kg SC for one dose FOLLOWED BY 1 mg/kg SC q12h
- Recommended dose (≥75 years of age): 0.75 mg/kg SC q12h
- All STEMI patients should receive aspirin 75–325 mg PO qd unless contraindicated.
## Renal Impairment
- Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.
- The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
Patients with solid tumor and low bleeding risk
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Class II
- Strength of Evidence: Level B
- Dosing Information
- Not applicable
### Vitamin K Antagonists
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Outpatient Cancer Patients
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level B
- Dosing Information
- Not applicable
### Thoracic Surgery
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level B
- Dosing Information
- Not applicable
### Spinal Surgery
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Major Trauma
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Management of HIT
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 1
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Management of Acute HIT or Subacute HIT
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Management in Patients with a Past History of HIT
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Atrial Fibrillation Undergoing Cardioversion (≥48 h)
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 1
- Strength of Evidence: Level B
- Dosing Information
- Not applicable
### Atrial Fibrillation Undergoing Cardioversion (<48 h)
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Endocarditis
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Mechanical Prosthetic Heart Valves
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### VTE Prevention in Intracranial hemorrhage
### Non–Guideline-Supported Use
### Adjunction treatment of Cardiopulmonary bypass operation
- Dosing information
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information about the FDA-labeled indications and dosage information for children.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
### Homozygous Protein C deficiency
### Non–Guideline-Supported Use
- There is limited information about Off-Label Non–Guideline-Supported Use of Enoxaparin in pediatric patients.
# Contraindications
- Active major bleeding
- Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium
- Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/anaphylactoid reactions).
- Known hypersensitivity to heparin or pork products
- Known hypersensitivity to benzyl alcohol (which is in only the multi-dose formulation of Lovenox)
# Warnings
- Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of Lovenox and epidural or spinal anesthesia/analgesia or spinal puncture procedures, resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are also discussed in other sections of the labeling:
- Spinal/epidural hematoma
- Thrombocytopenia
- 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 clinical practice.
- During clinical development for the approved indications, 15,918 patients were exposed to enoxaparin sodium. These included 1,228 for prophylaxis of deep vein thrombosisfollowing abdominal surgery in patients at risk for thromboembolic complications, 1,368 for prophylaxis of deep vein thrombosisfollowing hip or knee replacement surgery, 711 for prophylaxis of deep vein thrombosisin medical patients with severely restricted mobility during acute illness, 1,578 for prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, 10,176 for treatment of acute ST-elevation myocardial infarction, and 857 for treatment of deep vein thrombosiswith or without pulmonary embolism. Enoxaparin sodium doses in the clinical trials for prophylaxis of deep vein thrombosisfollowing abdominal or hip or knee replacement surgery or in medical patients with severely restricted mobility during acute illness ranged from 40 mg SC once daily to 30 mg SC twice daily. In the clinical studies for prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction doses were 1 mg/kg every 12 hours and in the clinical studies for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium doses were a 30 mg IV bolus followed by 1 mg/kg every 12 hours SC.
### Hemorrhage
- The incidence of major hemorrhagic complications during Lovenox treatment has been low.
- The following rates of major bleeding events have been reported during clinical trials with Lovenox .
- NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours post-operative hip replacement surgery prophylactic regimens compared in clinical trials.
- Injection site hematomas during the extended prophylaxis period after hip replacement surgery occurred in 9% of the Lovenox patients versus 1.8% of the placebo patients.
### Elevations of Serum Aminotransferases
- Asymptomatic increases in aspartate (AST ) and alanine (ALT ) aminotransferase levels greater than three times the upper limit of normal of the laboratory reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during treatment with Lovenox. Similar significant increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are fully reversible and are rarely associated with increases in bilirubin.
- Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like Lovenox should be interpreted with caution.
### Local Reactions
- Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of Lovenox.
- Other adverse reactions that were thought to be possibly or probably related to treatment with Lovenox, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at least 2% in the Lovenox group, are provided below .
- Non-hemorrhagic clinical events reported to be related to Lovenox therapy occurred at an incidence of ≤1%.
- Non-major hemorrhagic events, primarily injection site ecchymoses and hematomas, were more frequently reported in patients treated with SC Lovenox than in patients treated with IV heparin.
- Serious adverse events with Lovenox or heparin in a clinical trial in patients with unstable angina or non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox group are provided below .
- In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only adverse reaction that occurred at a rate of at least 0.5% in the Lovenox group was thrombocytopenia (1.5%).
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Lovenox. 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.
- There have been reports of epidural or spinal hematoma formation with concurrent use of Lovenox and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post-operative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis.
- Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic reactions (e.g. pruritus, urticaria, anaphylactic/anaphylactoid reactions including shock), vesiculobullous rash, rare cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with thrombosis have been reported.
- Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues). Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined.
- Cases of headache, hemorrhagic anemia, eosinophilia, alopecia, hepatocellular and cholestatic liver injury have been reported.
- Osteoporosis has also been reported following long-term therapy.
# Drug Interactions
- Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of Lovenox therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of Lovenox to increase the risk of developmental abnormalities above the background risk.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enoxaparin in women who are pregnant.
### Labor and Delivery
- Lovenox does not cross the placenta, and is not expected to result in fetal exposure to the drug. Human data from a retrospective cohort study, which included 693 live births, suggest that Lovenox does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities
### Nursing Mothers
- It is not known whether Lovenox is 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 Lovenox, a decision should be made whether to discontinue nursing or discontinue Lovenox, taking into account the importance of Lovenox to the mother and the known benefits of nursing.
### Pediatric Use
- Safety and effectiveness of Lovenox in pediatric patients have not been established.
### Geriatic Use
### Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave Myocardial Infarction
- Over 2800 patients, 65 years and older, have received Lovenox in pivotal clinical trials. The efficacy of Lovenox in the geriatric (≥65 years) was similar to that seen in younger patients (<65 years). The incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when Lovenox was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of Lovenox-associated bleeding increased with age. Serious adverse events increased with age for patients receiving Lovenox. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of Lovenox between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Lovenox should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered.
### Treatment of Acute ST-Segment Elevation Myocardial Infarction
- In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age (n=9015). Patients ≥75 years of age did not receive a 30 mg IV bolus prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours. The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).
### Gender
There is no FDA guidance on the use of Enoxaparin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Enoxaparin with respect to specific racial populations.
### Renal Impairment
- In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment. In patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia .
### Hepatic Impairment
- The impact of hepatic impairment on enoxaparin's exposure and antithrombotic effect has not been investigated. Caution should be exercised when administering enoxaparin to patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enoxaparin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enoxaparin in patients who are immunocompromised.
### Low-Weight Patients
- An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such patients should be observed carefully for signs and symptoms of bleeding.
# Administration and Monitoring
### Administration
- Lovenox is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.
- The use of a tuberculin syringe or equivalent is recommended when using Lovenox multiple-dose vials to assure withdrawal of the appropriate volume of drug.
- Lovenox must not be administered by intramuscular injection. Lovenox is intended for use under the guidance of a physician.
- For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided.
Subcutaneous Injection Technique:
- Patients should be lying down and Lovenox administered by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not expel the air bubble from the syringe before the injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.
- Lovenox prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection.
- Remove the prefilled syringe from the blister packaging by peeling at the arrow as directed on the blister. Do not remove by pulling on the plunger as this may damage the syringe.
1.Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient.
Figure A
- Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B).
Figure B
Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C).
Figure C
- Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation (see Figure D).
Figure D
- Immediately dispose of the syringe in the nearest sharps container (see Figure E).
Figure E
NOTE:
- The safety system can only be activated once the syringe has been emptied.
- Activation of the safety system must be done only after removing the needle from the patient's skin.
- Do not replace the needle shield after injection.
- The safety system should not be sterilized.
- Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate the system while orienting it downwards away from yourself and others.
Intravenous (Bolus) Injection Technique:
- For intravenous injection, the multiple-dose vial should be used. Lovenox should be administered through an intravenous line. Lovenox should not be mixed or co-administered with other medications. To avoid the possible mixture of Lovenox with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of Lovenox to clear the port of drug. Lovenox may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.
### Monitoring
- All patients should be evaluated for a bleeding disorder before administration of Enoxaparin Sodium Injection, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring Enoxaparin Sodium Injection activity, routine monitoring of coagulation parameters is not required
- Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, enoxaparin sodium injection should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death
- Women with mechanical prosthetic heart valves may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore, frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be needed
- Anti-Factor Xa may be used to monitor the anticoagulant effect of enoxaparin sodium injection in patients with significant renal impairment. If during enoxaparin sodium injection therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin sodium injection
- Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium injection therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring
- Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered
# IV Compatibility
There is limited information regarding the compatibility of Enoxaparin and IV administrations.
# Overdosage
- Accidental overdosage following administration of Lovenox may lead to hemorrhagic complications. Injected Lovenox may be largely neutralized by the slow IV injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of Lovenox injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg of Lovenox may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged.
- If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information consult the labeling of protamine sulfate injection products.
# Pharmacology
## Mechanism of Action
- Enoxaparin is a low molecular weight heparin which has antithrombotic properties.
## Structure
- Lovenox is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight heparin. The pH of the injection is 5.5 to 7.5.
- Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight distribution is:
- <2000 daltons ≤20%
- 2000 to 8000 daltons ≥68%
- >8000 daltons ≤18%
- STRUCTURAL FORMULA
- Lovenox 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1000 IU ) per 0.1 mL Water for Injection.
- Lovenox 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1500 IU ) per 0.1 mL Water for Injection.
- The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative
## Pharmacodynamics
- In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ± SD, 14.0 ± 3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin (mean±SD, 1.22 ± 0.13). Increases of up to 1.8 times the control values were seen in the thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1 mg/kg dose (100 mg/mL concentration), administered SC every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n = 1607). A 30 mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16% higher than on Day 4.
## Pharmacokinetics
There is limited information regarding Enoxaparin Pharmacokinetics in the drug label.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin. Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test. Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day or 141 mg/m2/day. The maximum human dose in clinical trials was 2.0 mg/kg/day or 78 mg/m2/day (for an average body weight of 70 kg, height of 170 cm, and body surface area of 1.8 m2).
- Animal Toxicology and/or Pharmacology
- A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity were ataxia, decreased motility, dyspnea, cyanosis, and coma.
- Reproductive and Developmental Toxicology
- Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day corresponding to 211 mg/m2/day and 410 mg/m2/day in rats and rabbits respectively. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
# Clinical Studies
## Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications
- Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE).
- In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4% Asian and 0.4% others. Lovenox 40 mg SC, administered once a day, beginning 2 hours prior to surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours SC in reducing the risk of DVT. The efficacy data are provided below .
- In a second double-blind, parallel group study, Lovenox 40 mg SC once a day was compared to heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hours prior to surgery and continued for approximately 7 to 10 days after surgery. The efficacy data are provided below .
## Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
- Lovenox has been shown to reduce the risk of post-operative deep vein thrombosis (DVT) following hip or knee replacement surgery.
- In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients with hip replacement. A total of 100 patients were randomized in the study and all patients were treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and 55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below .
- A double-blind, multicenter study compared three dosing regimens of Lovenox in patients with hip replacement. A total of 572 patients were randomized in the study and 568 patients were treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and 37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy data are provided below .
- There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens. In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the study and 131 patients were treated, of which 99 had total knee replacement and 32 had either unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT after surgery was significantly lower for Lovenox compared to placebo. The efficacy data are provided below .
- Additionally, in an open-label, parallel group, randomized clinical study, Lovenox 30 mg every 12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was significantly lower for Lovenox compared to heparin.
- Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery for the prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic disease were randomized to a post-discharge regimen of either Lovenox 40 mg (n = 90) once a day SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were randomized in the double-blind phase of the study and all patients were treated. Patients ranged in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this population of patients, the incidence of DVT during extended prophylaxis was significantly lower for Lovenox compared to placebo. The efficacy data are provided below .
- In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease were randomized to a post-discharge regimen of either Lovenox 40 mg (n = 131) once a day SC or to placebo (n = 131) for 3 weeks. A total of 262 patients were randomized in the study double-blind phase and all patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended prophylaxis was significantly lower for Lovenox compared to placebo, with a statistically significant difference in both total DVT (Lovenox 21 versus placebo 45 ; p = 0.001) and proximal DVT (Lovenox 8 versus placebo 28 ; p = <0.001).
## Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness
- In a double blind multicenter, parallel group study, Lovenox 20 mg or 40 mg once a day SC was compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection (excluding septic shock); or acute rheumatic disorder . A total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women. Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose of 40 mg once a day SC, Lovenox significantly reduced the incidence of DVT as compared to placebo. The efficacy data are provided below .
- At approximately 3 months following enrollment, the incidence of venous thromboembolism remained significantly lower in the Lovenox 40 mg treatment group versus the placebo treatment group.
## Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism
- In a multicenter, parallel group study, 900 patients with acute lower extremity deep vein thrombosis (DVT) with or without pulmonary embolism (PE) were randomized to an inpatient (hospital) treatment of either (i) Lovenox 1.5 mg/kg once a day SC, (ii) Lovenox 1 mg/kg every 12 hours SC, or (iii) heparin IV bolus (5000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted according to PT to achieve an International Normalization Ratio of 2.0 to 3.0), commencing within 72 hours of initiation of Lovenox or standard heparin therapy, and continuing for 90 days. Lovenox or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both Lovenox regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided below .
- Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to Lovenox or heparin. Patients who could not receive outpatient therapy were excluded from entering the study. Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated co-morbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients were randomized to either Lovenox 1 mg/kg every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. Lovenox or standard heparin therapy was administered for a minimum of 5 days. Lovenox was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are provided below .
## Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
- In a multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non-Q-wave myocardial infarction were randomized to either Lovenox 1 mg/kg every 12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25–94 years (median age 64 years), with 33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent angina was lower for Lovenox compared with heparin therapy at 14 days after initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an analysis of both all-randomized and all-treated patients. The efficacy data are provided below .
- The combined incidence of death or myocardial infarction at all time points was lower for Lovenox compared to standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below .
- In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence of death, myocardial infarction, or recurrent angina remained lower for Lovenox versus heparin (32.0% vs 35.7%).
- Urgent revascularization procedures were performed less frequently in the Lovenox group as compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
## Treatment of Acute ST-Segment Elevation Myocardial Infarction
- In a multicenter, double-blind, double-dummy, parallel group study, patients with acute ST-segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive either Lovenox or unfractionated heparin.
- Study medication was initiated between 15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60 U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted according to the patient's age and renal function. For patients younger than 75 years of age, enoxaparin was given as a single 30 mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first). The mean treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated heparin was 54 hours.
- When percutaneous coronary intervention was performed during study medication period, patients received antithrombotic support with blinded study drug. For patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies, i.e. no additional dosing, if the last SC administration was less than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin if the last SC administration was more than 8 hours before balloon inflation.
- All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20% received streptokinase.
- Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male. Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56%, and both in 1%.
- The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first 30 days after randomization. Total follow-up was one year.
- The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative risk, (P=0.000003) .
- The beneficial effect of enoxaparin on the primary end point was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1); however, it is necessary to interpret such subgroup analyses with caution.
- The beneficial effect of enoxaparin on the primary end point observed during the first 30 days was maintained over a 12 month follow-up period (see Figure 2).
- There is a trend in favor of enoxaparin during the first 48 hours, but most of the treatment difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen inFigure 2), an effect that is more striking when comparing the event rates just prior to and just subsequent to actual times of discontinuation. These results provide evidence that UFH was effective and that it would be better if used longer than 48 hours. There is a similar increase in endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued too soon in this study.
- The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30 days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group. The rates of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin group (10.1%) as compared to the heparin group (12.2%).
# How Supplied
- Lovenox is available in two concentrations :
## Storage
- Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F).
- Do not store the multiple-dose vials for more than 28 days after the first use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, they should be informed to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately.
- Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Their use should be discontinued prior to enoxaparin therapy whenever possible; if co-administration is essential, the patient's clinical and laboratory status should be closely monitored.
- Patients should also be informed:
- of the instructions for injecting Lovenox if their therapy is to continue after discharge from the hospitals.
- it may take them longer than usual to stop bleeding.
- they may bruise and/or bleed more easily when they are treated with Lovenox.
- they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician.
- to tell their physicians and dentists they are taking Lovenox and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug istaken.
- to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs .
# Precautions with Alcohol
- Alcohol-Enoxaparin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ENOXAPARIN SODIUM
# Look-Alike Drug Names
There is limited information regarding Enoxaparin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Enoxaparin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Black Box Warning
# Overview
Enoxaparin is an anticoagulant that is FDA approved for the treatment of acute deep vein thrombosis, acute ST-segment elevation myocardial infarction and prophylaxis of deep vein thrombosis and ischemic complications of unstable angina and non-Q-wave myocardial infarction. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, anemia, major bleeding, thrombocytopenia, increased liver function test, and fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Prophylaxis of Deep Vein Thrombosis
- Dosing information
- Recommended dose: 40 mg SC q24h (with the initial dose given 2 hours prior to surgery)
- Duration of administration: 7 to 10 days (maximum: 12 days)
- Dosing information
- Recommended dose: 30 mg SC q12h (with the initial dose given 12 to 24 hours after surgery)
- Duration of administration: 7 to 10 days (maximum: 14 days)
- Alternative dosage for hip replacement surgery
- Recommended dose: 40 mg SC q24h (with the initial dose given 12±3 hours prior to surgery)
- Duration of administration: 3 weeks
- Dosing information
- Recommended dose: 40 mg SC q24h
- Duration of administration: 6 to 11 days (maximum: 14 days)
### Treatment of Acute Deep Vein Thrombosis (With or Without Pulmonary Embolism)
- Dosing information
- Recommended dose:
- For outpatient: 1 mg/kg SC q12h
- For inpatient: 1 mg/kg SC q12h or 1.5 mg/kg SC q24h
- Warfarin therapy should be initiated when appropriate (usually within 72 hours of enoxaparin injection).
- Duration of administration: 7 days (maximum: 17 days)
- Enoxaparin should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (INR 2.0–3.0).
### Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave Myocardial Infarction
- Dosing information
- Recommended dose: 1 mg/kg SC q12h (in conjunction with aspirin 100–325 mg PO qd)
- Duration of administration: 2 to 8 days (maximum: 12.5 days)
### Treatment of Acute ST-Segment Elevation Myocardial Infarction
- Dosing information
- Recommended dose (<75 years of age): 30 mg IV bolus PLUS 1 mg/kg SC for one dose FOLLOWED BY 1 mg/kg SC q12h
- Recommended dose (≥75 years of age): 0.75 mg/kg SC q12h
- All STEMI patients should receive aspirin 75–325 mg PO qd unless contraindicated.
## Renal Impairment
- Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.
- The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
Patients with solid tumor and low bleeding risk
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Class II
- Strength of Evidence: Level B
- Dosing Information
- Not applicable
### Vitamin K Antagonists
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Outpatient Cancer Patients
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level B
- Dosing Information
- Not applicable
### Thoracic Surgery
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level B
- Dosing Information
- Not applicable
### Spinal Surgery
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Major Trauma
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Management of HIT
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 1
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Management of Acute HIT or Subacute HIT
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Management in Patients with a Past History of HIT
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Atrial Fibrillation Undergoing Cardioversion (≥48 h)
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 1
- Strength of Evidence: Level B
- Dosing Information
- Not applicable
### Atrial Fibrillation Undergoing Cardioversion (<48 h)
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Endocarditis
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### Mechanical Prosthetic Heart Valves
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Grade 2
- Strength of Evidence: Level C
- Dosing Information
- Not applicable
### VTE Prevention in Intracranial hemorrhage
### Non–Guideline-Supported Use
### Adjunction treatment of Cardiopulmonary bypass operation
- Dosing information
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information about the FDA-labeled indications and dosage information for children.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
### Homozygous Protein C deficiency
### Non–Guideline-Supported Use
- There is limited information about Off-Label Non–Guideline-Supported Use of Enoxaparin in pediatric patients.
# Contraindications
- Active major bleeding
- Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium
- Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/anaphylactoid reactions).
- Known hypersensitivity to heparin or pork products
- Known hypersensitivity to benzyl alcohol (which is in only the multi-dose formulation of Lovenox)
# Warnings
- Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of Lovenox and epidural or spinal anesthesia/analgesia or spinal puncture procedures, resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are also discussed in other sections of the labeling:
- Spinal/epidural hematoma
- Thrombocytopenia
- 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 clinical practice.
- During clinical development for the approved indications, 15,918 patients were exposed to enoxaparin sodium. These included 1,228 for prophylaxis of deep vein thrombosisfollowing abdominal surgery in patients at risk for thromboembolic complications, 1,368 for prophylaxis of deep vein thrombosisfollowing hip or knee replacement surgery, 711 for prophylaxis of deep vein thrombosisin medical patients with severely restricted mobility during acute illness, 1,578 for prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, 10,176 for treatment of acute ST-elevation myocardial infarction, and 857 for treatment of deep vein thrombosiswith or without pulmonary embolism. Enoxaparin sodium doses in the clinical trials for prophylaxis of deep vein thrombosisfollowing abdominal or hip or knee replacement surgery or in medical patients with severely restricted mobility during acute illness ranged from 40 mg SC once daily to 30 mg SC twice daily. In the clinical studies for prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction doses were 1 mg/kg every 12 hours and in the clinical studies for treatment of acute ST-segment elevation myocardial infarction enoxaparin sodium doses were a 30 mg IV bolus followed by 1 mg/kg every 12 hours SC.
### Hemorrhage
- The incidence of major hemorrhagic complications during Lovenox treatment has been low.
- The following rates of major bleeding events have been reported during clinical trials with Lovenox [see Tables 2 to 7].
- NOTE: At no time point were the 40 mg once a day pre-operative and the 30 mg every 12 hours post-operative hip replacement surgery prophylactic regimens compared in clinical trials.
- Injection site hematomas during the extended prophylaxis period after hip replacement surgery occurred in 9% of the Lovenox patients versus 1.8% of the placebo patients.
### Elevations of Serum Aminotransferases
- Asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than three times the upper limit of normal of the laboratory reference range have been reported in up to 6.1% and 5.9% of patients, respectively, during treatment with Lovenox. Similar significant increases in aminotransferase levels have also been observed in patients and healthy volunteers treated with heparin and other low molecular weight heparins. Such elevations are fully reversible and are rarely associated with increases in bilirubin.
- Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like Lovenox should be interpreted with caution.
### Local Reactions
- Mild local irritation, pain, hematoma, ecchymosis, and erythema may follow SC injection of Lovenox.
- Other adverse reactions that were thought to be possibly or probably related to treatment with Lovenox, heparin, or placebo in clinical trials with patients undergoing hip or knee replacement surgery, abdominal or colorectal surgery, or treatment for DVT and that occurred at a rate of at least 2% in the Lovenox group, are provided below [see Tables 8 to 11].
- Non-hemorrhagic clinical events reported to be related to Lovenox therapy occurred at an incidence of ≤1%.
- Non-major hemorrhagic events, primarily injection site ecchymoses and hematomas, were more frequently reported in patients treated with SC Lovenox than in patients treated with IV heparin.
- Serious adverse events with Lovenox or heparin in a clinical trial in patients with unstable angina or non-Q-wave myocardial infarction that occurred at a rate of at least 0.5% in the Lovenox group are provided below [see Table 12].
- In a clinical trial in patients with acute ST-segment elevation myocardial infarction, the only adverse reaction that occurred at a rate of at least 0.5% in the Lovenox group was thrombocytopenia (1.5%).
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of Lovenox. 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.
- There have been reports of epidural or spinal hematoma formation with concurrent use of Lovenox and spinal/epidural anesthesia or spinal puncture. The majority of patients had a post-operative indwelling epidural catheter placed for analgesia or received additional drugs affecting hemostasis such as NSAIDs. Many of the epidural or spinal hematomas caused neurologic injury, including long-term or permanent paralysis.
- Local reactions at the injection site (e.g. nodules, inflammation, oozing), systemic allergic reactions (e.g. pruritus, urticaria, anaphylactic/anaphylactoid reactions including shock), vesiculobullous rash, rare cases of hypersensitivity cutaneous vasculitis, purpura, skin necrosis (occurring at either the injection site or distant from the injection site), thrombocytosis, and thrombocytopenia with thrombosis [see Warnings and Precautions (5.5)] have been reported.
- Cases of hyperkalemia have been reported. Most of these reports occurred in patients who also had conditions that tend toward the development of hyperkalemia (e.g., renal dysfunction, concomitant potassium-sparing drugs, administration of potassium, hematoma in body tissues). Very rare cases of hyperlipidemia have also been reported, with one case of hyperlipidemia, with marked hypertriglyceridemia, reported in a diabetic pregnant woman; causality has not been determined.
- Cases of headache, hemorrhagic anemia, eosinophilia, alopecia, hepatocellular and cholestatic liver injury have been reported.
- Osteoporosis has also been reported following long-term therapy.
# Drug Interactions
- Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of Lovenox therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of Lovenox to increase the risk of developmental abnormalities above the background risk.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enoxaparin in women who are pregnant.
### Labor and Delivery
- Lovenox does not cross the placenta, and is not expected to result in fetal exposure to the drug. Human data from a retrospective cohort study, which included 693 live births, suggest that Lovenox does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities
### Nursing Mothers
- It is not known whether Lovenox is 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 Lovenox, a decision should be made whether to discontinue nursing or discontinue Lovenox, taking into account the importance of Lovenox to the mother and the known benefits of nursing.
### Pediatric Use
- Safety and effectiveness of Lovenox in pediatric patients have not been established.
### Geriatic Use
### Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave Myocardial Infarction
- Over 2800 patients, 65 years and older, have received Lovenox in pivotal clinical trials. The efficacy of Lovenox in the geriatric (≥65 years) was similar to that seen in younger patients (<65 years). The incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once a day doses of Lovenox were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when Lovenox was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of Lovenox-associated bleeding increased with age. Serious adverse events increased with age for patients receiving Lovenox. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of Lovenox between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Lovenox should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered.
### Treatment of Acute ST-Segment Elevation Myocardial Infarction
- In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age (n=9015). Patients ≥75 years of age did not receive a 30 mg IV bolus prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours. The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).
### Gender
There is no FDA guidance on the use of Enoxaparin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Enoxaparin with respect to specific racial populations.
### Renal Impairment
- In patients with renal impairment, there is an increase in exposure of enoxaparin sodium. All such patients should be observed carefully for signs and symptoms of bleeding. Because exposure of enoxaparin sodium is significantly increased in patients with severe renal impairment (creatinine clearance <30 mL/min), a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. No dosage adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment. In patients with renal failure, treatment with enoxaparin has been associated with the development of hyperkalemia .
### Hepatic Impairment
- The impact of hepatic impairment on enoxaparin's exposure and antithrombotic effect has not been investigated. Caution should be exercised when administering enoxaparin to patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Enoxaparin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Enoxaparin in patients who are immunocompromised.
### Low-Weight Patients
- An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg). All such patients should be observed carefully for signs and symptoms of bleeding.
# Administration and Monitoring
### Administration
- Lovenox is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.
- The use of a tuberculin syringe or equivalent is recommended when using Lovenox multiple-dose vials to assure withdrawal of the appropriate volume of drug.
- Lovenox must not be administered by intramuscular injection. Lovenox is intended for use under the guidance of a physician.
- For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided.
Subcutaneous Injection Technique:
- Patients should be lying down and Lovenox administered by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not expel the air bubble from the syringe before the injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.
- Lovenox prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection.
- Remove the prefilled syringe from the blister packaging by peeling at the arrow as directed on the blister. Do not remove by pulling on the plunger as this may damage the syringe.
1.Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient.
Figure A
- Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B).
Figure B
Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C).
Figure C
- Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation (see Figure D).
Figure D
- Immediately dispose of the syringe in the nearest sharps container (see Figure E).
Figure E
NOTE:
- The safety system can only be activated once the syringe has been emptied.
- Activation of the safety system must be done only after removing the needle from the patient's skin.
- Do not replace the needle shield after injection.
- The safety system should not be sterilized.
- Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate the system while orienting it downwards away from yourself and others.
Intravenous (Bolus) Injection Technique:
- For intravenous injection, the multiple-dose vial should be used. Lovenox should be administered through an intravenous line. Lovenox should not be mixed or co-administered with other medications. To avoid the possible mixture of Lovenox with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of Lovenox to clear the port of drug. Lovenox may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.
### Monitoring
- All patients should be evaluated for a bleeding disorder before administration of Enoxaparin Sodium Injection, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring Enoxaparin Sodium Injection activity, routine monitoring of coagulation parameters is not required
- Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, enoxaparin sodium injection should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death
- Women with mechanical prosthetic heart valves may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore, frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be needed
- Anti-Factor Xa may be used to monitor the anticoagulant effect of enoxaparin sodium injection in patients with significant renal impairment. If during enoxaparin sodium injection therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin sodium injection
- Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium injection therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring
- Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered
# IV Compatibility
There is limited information regarding the compatibility of Enoxaparin and IV administrations.
# Overdosage
- Accidental overdosage following administration of Lovenox may lead to hemorrhagic complications. Injected Lovenox may be largely neutralized by the slow IV injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of Lovenox injected: 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg of Lovenox may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged.
- If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information consult the labeling of protamine sulfate injection products.
# Pharmacology
## Mechanism of Action
- Enoxaparin is a low molecular weight heparin which has antithrombotic properties.
## Structure
- Lovenox is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight heparin. The pH of the injection is 5.5 to 7.5.
- Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight distribution is:
- <2000 daltons ≤20%
- 2000 to 8000 daltons ≥68%
- >8000 daltons ≤18%
- STRUCTURAL FORMULA
- Lovenox 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
- Lovenox 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection.
- The Lovenox prefilled syringes and graduated prefilled syringes are preservative-free and intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative
## Pharmacodynamics
- In humans, enoxaparin given at a dose of 1.5 mg/kg subcutaneously (SC) is characterized by a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean ± SD, 14.0 ± 3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin (mean±SD, 1.22 ± 0.13). Increases of up to 1.8 times the control values were seen in the thrombin time (TT) and the activated partial thromboplastin time (aPTT). Enoxaparin at a 1 mg/kg dose (100 mg/mL concentration), administered SC every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n = 1607). A 30 mg IV bolus immediately followed by a 1 mg/kg SC administration resulted in aPTT post-injection values of 50 seconds. The average aPTT prolongation value on Day 1 was about 16% higher than on Day 4.
## Pharmacokinetics
There is limited information regarding Enoxaparin Pharmacokinetics in the drug label.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin. Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test. Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day or 141 mg/m2/day. The maximum human dose in clinical trials was 2.0 mg/kg/day or 78 mg/m2/day (for an average body weight of 70 kg, height of 170 cm, and body surface area of 1.8 m2).
- Animal Toxicology and/or Pharmacology
- A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity were ataxia, decreased motility, dyspnea, cyanosis, and coma.
- Reproductive and Developmental Toxicology
- Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day corresponding to 211 mg/m2/day and 410 mg/m2/day in rats and rabbits respectively. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
# Clinical Studies
## Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications
- Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE).
- In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4% Asian and 0.4% others. Lovenox 40 mg SC, administered once a day, beginning 2 hours prior to surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours SC in reducing the risk of DVT. The efficacy data are provided below [see Table 14].
- In a second double-blind, parallel group study, Lovenox 40 mg SC once a day was compared to heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hours prior to surgery and continued for approximately 7 to 10 days after surgery. The efficacy data are provided below [see Table 15].
## Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
- Lovenox has been shown to reduce the risk of post-operative deep vein thrombosis (DVT) following hip or knee replacement surgery.
- In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients with hip replacement. A total of 100 patients were randomized in the study and all patients were treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and 55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below [see Table 16].
- A double-blind, multicenter study compared three dosing regimens of Lovenox in patients with hip replacement. A total of 572 patients were randomized in the study and 568 patients were treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and 37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy data are provided below [see Table 17].
- There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens. In a double-blind study, Lovenox 30 mg every 12 hours SC was compared to placebo in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the study and 131 patients were treated, of which 99 had total knee replacement and 32 had either unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT after surgery was significantly lower for Lovenox compared to placebo. The efficacy data are provided below [see Table 18].
- Additionally, in an open-label, parallel group, randomized clinical study, Lovenox 30 mg every 12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was significantly lower for Lovenox compared to heparin.
- Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery for the prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic disease were randomized to a post-discharge regimen of either Lovenox 40 mg (n = 90) once a day SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were randomized in the double-blind phase of the study and all patients were treated. Patients ranged in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this population of patients, the incidence of DVT during extended prophylaxis was significantly lower for Lovenox compared to placebo. The efficacy data are provided below [see Table 19].
- In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with Lovenox 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease were randomized to a post-discharge regimen of either Lovenox 40 mg (n = 131) once a day SC or to placebo (n = 131) for 3 weeks. A total of 262 patients were randomized in the study double-blind phase and all patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended prophylaxis was significantly lower for Lovenox compared to placebo, with a statistically significant difference in both total DVT (Lovenox 21 [16%] versus placebo 45 [34%]; p = 0.001) and proximal DVT (Lovenox 8 [6%] versus placebo 28 [21%]; p = <0.001).
## Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness
- In a double blind multicenter, parallel group study, Lovenox 20 mg or 40 mg once a day SC was compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain, vertebral compression (due to osteoporosis or tumor), acute arthritic episodes of the lower extremities]. A total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women. Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose of 40 mg once a day SC, Lovenox significantly reduced the incidence of DVT as compared to placebo. The efficacy data are provided below [see Table 20].
- At approximately 3 months following enrollment, the incidence of venous thromboembolism remained significantly lower in the Lovenox 40 mg treatment group versus the placebo treatment group.
## Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism
- In a multicenter, parallel group study, 900 patients with acute lower extremity deep vein thrombosis (DVT) with or without pulmonary embolism (PE) were randomized to an inpatient (hospital) treatment of either (i) Lovenox 1.5 mg/kg once a day SC, (ii) Lovenox 1 mg/kg every 12 hours SC, or (iii) heparin IV bolus (5000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted according to PT to achieve an International Normalization Ratio [INR] of 2.0 to 3.0), commencing within 72 hours of initiation of Lovenox or standard heparin therapy, and continuing for 90 days. Lovenox or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both Lovenox regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided below [see Table 21].
- Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to Lovenox or heparin. Patients who could not receive outpatient therapy were excluded from entering the study. Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated co-morbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients were randomized to either Lovenox 1 mg/kg every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. Lovenox or standard heparin therapy was administered for a minimum of 5 days. Lovenox was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are provided below [see Table 22].
## Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
- In a multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non-Q-wave myocardial infarction were randomized to either Lovenox 1 mg/kg every 12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25–94 years (median age 64 years), with 33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent angina was lower for Lovenox compared with heparin therapy at 14 days after initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an analysis of both all-randomized and all-treated patients. The efficacy data are provided below [see Table 23].
- The combined incidence of death or myocardial infarction at all time points was lower for Lovenox compared to standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below [see Table 24].
- In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence of death, myocardial infarction, or recurrent angina remained lower for Lovenox versus heparin (32.0% vs 35.7%).
- Urgent revascularization procedures were performed less frequently in the Lovenox group as compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047).
## Treatment of Acute ST-Segment Elevation Myocardial Infarction
- In a multicenter, double-blind, double-dummy, parallel group study, patients with acute ST-segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive either Lovenox or unfractionated heparin.
- Study medication was initiated between 15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60 U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted according to the patient's age and renal function. For patients younger than 75 years of age, enoxaparin was given as a single 30 mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first). The mean treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated heparin was 54 hours.
- When percutaneous coronary intervention was performed during study medication period, patients received antithrombotic support with blinded study drug. For patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies, i.e. no additional dosing, if the last SC administration was less than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin if the last SC administration was more than 8 hours before balloon inflation.
- All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20% received streptokinase.
- Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male. Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56%, and both in 1%.
- The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first 30 days after randomization. Total follow-up was one year.
- The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative risk, (P=0.000003) [see Table 25].
- The beneficial effect of enoxaparin on the primary end point was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1); however, it is necessary to interpret such subgroup analyses with caution.
- The beneficial effect of enoxaparin on the primary end point observed during the first 30 days was maintained over a 12 month follow-up period (see Figure 2).
- There is a trend in favor of enoxaparin during the first 48 hours, but most of the treatment difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen inFigure 2), an effect that is more striking when comparing the event rates just prior to and just subsequent to actual times of discontinuation. These results provide evidence that UFH was effective and that it would be better if used longer than 48 hours. There is a similar increase in endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued too soon in this study.
- The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30 days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group. The rates of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin group (10.1%) as compared to the heparin group (12.2%).
# How Supplied
- Lovenox is available in two concentrations [see Tables 26 and 27]:
## Storage
- Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F).
- Do not store the multiple-dose vials for more than 28 days after the first use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, they should be informed to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately.
- Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Their use should be discontinued prior to enoxaparin therapy whenever possible; if co-administration is essential, the patient's clinical and laboratory status should be closely monitored.
- Patients should also be informed:
- of the instructions for injecting Lovenox if their therapy is to continue after discharge from the hospitals.
- it may take them longer than usual to stop bleeding.
- they may bruise and/or bleed more easily when they are treated with Lovenox.
- they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician.
- to tell their physicians and dentists they are taking Lovenox and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug istaken.
- to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs .
# Precautions with Alcohol
- Alcohol-Enoxaparin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ENOXAPARIN SODIUM
# Look-Alike Drug Names
There is limited information regarding Enoxaparin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Clexane | |
b55c0f857ccc1e352fdd20754b2d22a877354a72 | wikidoc | Immunology | Immunology
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with, among other things, the physiological functioning of the immune system in states of both health and disease; malfunctions of the immune system in immunological disorders (autoimmune diseases, hypersensitivities, immune deficiency, allograft rejection); the physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ, and in vivo. Immunology has various applications in several disciplines of science, and as such is further divided.
# Histological examination of the immune system
Even before the concept of immunity (from immunis, Latin for "exempt") was developed, numerous early physicians characterised organs that would later prove to be part of the immune system. The key primary lymphoid organs of the immune system are thymus and bone marrow, and secondary lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and skin. When health conditions warrant, immune system organs including the thymus, spleen, portions of bone marrow, lymph nodes and secondary lymphatic tissues can be surgically excised for examination while patients are still alive.
Many components of the immune system are actually cellular in nature and not associated with any specific organ but rather are embedded or circulating in various tissues located throughout the body.
# Classical immunology
Classical immunology ties in with the fields of epidemiology and medicine. It studies the relationship between the body systems, pathogens, and immunity. The earliest written mention of immunity can be traced back to the plague of Athens in 430 BCE. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. Many other ancient societies have references to this phenomenon, but it was not until the 19th and 20th centuries before the concept developed into scientific theory.
The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science of immunology. The immune system has been divided into a more primitive innate immune system, and acquired or adaptive immune system of vertebrates, the latter of which is further divided into humoral and cellular components.
The humoral (antibody) response is defined as the interaction between antibodies and antigens. Antibodies are specific proteins released from a certain class of immune cells (B lymphocytes). Antigens are defined as anything that elicits generation of antibodies, hence they are Antibody Generators. Immunology itself rests on an understanding of the properties of these two biological entities. However, equally important is the cellular response, which can not only kill infected cells in its own right, but is also crucial in controlling the antibody response. Put simply, both systems are highly interdependent.
In the 21st century, immunology has broadened its horizons with much research being performed in the more specialized niches of immunology. This includes the immunological function of cells, organs and systems not normally associated with the immune system, as well as the function of the immune system outside classical models of immunity.
# Clinical immunology
Clinical immunology is the study of diseases caused by disorders of the immune system (failure, aberrant action, and malignant growth of the cellular elements of the system). It also involves diseases of other systems, where immune reactions play a part in the pathology and clinical features.
The diseases caused by disorders of the immune system fall into two broad categories: immunodeficiency, in which parts of the immune system fail to provide an adequate response (examples include chronic granulomatous disease), and autoimmunity, in which the immune system attacks its own host's body (examples include systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's disease and myasthenia gravis). Other immune system disorders include different hypersensitivities, in which the system responds inappropriately to harmless compounds (asthma and other allergies) or responds too intensely.
The most well-known disease that affects the immune system itself is AIDS, caused by HIV. AIDS is an immunodeficiency characterized by the lack of CD4+ ("helper") T cells and macrophages, which are destroyed by HIV.
Clinical immunologists also study ways to prevent transplant rejection, in which the immune system attempts to destroy allografts or xenografts.
# Immunotherapy
The use of immune system components to treat a disease or disorder is known as immunotherapy. Immunotherapy is most commonly used in the context of the treatment of cancers together with chemotherapy (drugs) and radiotherapy (radiation). However, immunotherapy is also often used in the immunosuppressed (such as HIV patients) and people suffering from other immune deficiencies or autoimmune diseases.
# Diagnostic immunology
The specificity of the bond between antibody and antigen has made it an excellent tool in the detection of substances in a variety of diagnostic techniques. Antibodies specific for a desired antigen can be conjugated with a radiolabel, fluorescent label, or color-forming enzyme and are used as a "probe" to detect it.
# Evolutionary immunology
Study of the immune system in extant and extinct species is capable of giving us a key understanding of the evolution of species and the immune system.
A development of complexity of the immune system can be seen from simple phagocytotic protection of single celled organisms, to circulating antimicrobial peptides in insects to lymphoid organs in vertebrates. Of course, like much of evolutionary observation, these physical properties are often seen from the anthropocentric aspect. It should be recognized, that every organism living today has an immune system absolutely capable of protecting it from most forms of harm; those organisms that did not adapt their immune systems to external threats are no longer around to be observed.
Insects and other arthropods, while not possessing true adaptive immunity, show highly evolved systems of innate immunity, and are additionally protected from external injury (and exposure to pathogens) by their chitinous shells. | Immunology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with, among other things, the physiological functioning of the immune system in states of both health and disease; malfunctions of the immune system in immunological disorders (autoimmune diseases, hypersensitivities, immune deficiency, allograft rejection); the physical, chemical and physiological characteristics of the components of the immune system in vitro, in situ, and in vivo. Immunology has various applications in several disciplines of science, and as such is further divided.
# Histological examination of the immune system
Even before the concept of immunity (from immunis, Latin for "exempt") was developed, numerous early physicians characterised organs that would later prove to be part of the immune system. The key primary lymphoid organs of the immune system are thymus and bone marrow, and secondary lymphatic tissues such as spleen, tonsils, lymph vessels, lymph nodes, adenoids, and skin. When health conditions warrant, immune system organs including the thymus, spleen, portions of bone marrow, lymph nodes and secondary lymphatic tissues can be surgically excised for examination while patients are still alive.
Many components of the immune system are actually cellular in nature and not associated with any specific organ but rather are embedded or circulating in various tissues located throughout the body.
# Classical immunology
Classical immunology ties in with the fields of epidemiology and medicine. It studies the relationship between the body systems, pathogens, and immunity. The earliest written mention of immunity can be traced back to the plague of Athens in 430 BCE. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. Many other ancient societies have references to this phenomenon, but it was not until the 19th and 20th centuries before the concept developed into scientific theory.
The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science of immunology. The immune system has been divided into a more primitive innate immune system, and acquired or adaptive immune system of vertebrates, the latter of which is further divided into humoral and cellular components.
The humoral (antibody) response is defined as the interaction between antibodies and antigens. Antibodies are specific proteins released from a certain class of immune cells (B lymphocytes). Antigens are defined as anything that elicits generation of antibodies, hence they are Antibody Generators. Immunology itself rests on an understanding of the properties of these two biological entities. However, equally important is the cellular response, which can not only kill infected cells in its own right, but is also crucial in controlling the antibody response. Put simply, both systems are highly interdependent.
In the 21st century, immunology has broadened its horizons with much research being performed in the more specialized niches of immunology. This includes the immunological function of cells, organs and systems not normally associated with the immune system, as well as the function of the immune system outside classical models of immunity.
# Clinical immunology
Clinical immunology is the study of diseases caused by disorders of the immune system (failure, aberrant action, and malignant growth of the cellular elements of the system). It also involves diseases of other systems, where immune reactions play a part in the pathology and clinical features.
The diseases caused by disorders of the immune system fall into two broad categories: immunodeficiency, in which parts of the immune system fail to provide an adequate response (examples include chronic granulomatous disease), and autoimmunity, in which the immune system attacks its own host's body (examples include systemic lupus erythematosus, rheumatoid arthritis, Hashimoto's disease and myasthenia gravis). Other immune system disorders include different hypersensitivities, in which the system responds inappropriately to harmless compounds (asthma and other allergies) or responds too intensely.
The most well-known disease that affects the immune system itself is AIDS, caused by HIV. AIDS is an immunodeficiency characterized by the lack of CD4+ ("helper") T cells and macrophages, which are destroyed by HIV.
Clinical immunologists also study ways to prevent transplant rejection, in which the immune system attempts to destroy allografts or xenografts.
# Immunotherapy
The use of immune system components to treat a disease or disorder is known as immunotherapy. Immunotherapy is most commonly used in the context of the treatment of cancers together with chemotherapy (drugs) and radiotherapy (radiation). However, immunotherapy is also often used in the immunosuppressed (such as HIV patients) and people suffering from other immune deficiencies or autoimmune diseases.
# Diagnostic immunology
The specificity of the bond between antibody and antigen has made it an excellent tool in the detection of substances in a variety of diagnostic techniques. Antibodies specific for a desired antigen can be conjugated with a radiolabel, fluorescent label, or color-forming enzyme and are used as a "probe" to detect it.
# Evolutionary immunology
Study of the immune system in extant and extinct species is capable of giving us a key understanding of the evolution of species and the immune system.
A development of complexity of the immune system can be seen from simple phagocytotic protection of single celled organisms, to circulating antimicrobial peptides in insects to lymphoid organs in vertebrates. Of course, like much of evolutionary observation, these physical properties are often seen from the anthropocentric aspect. It should be recognized, that every organism living today has an immune system absolutely capable of protecting it from most forms of harm; those organisms that did not adapt their immune systems to external threats are no longer around to be observed.
Insects and other arthropods, while not possessing true adaptive immunity, show highly evolved systems of innate immunity, and are additionally protected from external injury (and exposure to pathogens) by their chitinous shells. | https://www.wikidoc.org/index.php/Clinical_immunology | |
952d87c6e488a79c270a54e1fd9cff6846624915 | wikidoc | Clioquinol | Clioquinol
# Overview
Clioquinol is an antifungal drug and antiprotozoal drug. It is neurotoxic in large doses. It is a member of a family of drugs called hydroxyquinolines which inhibit certain enzymes related to DNA replication. The drugs have been found to have activity against both viral and protozoal infections.
# Antiprotozoal use
A 1964 report described the use of Clioquinol in both the treatment and prevention of shigella infection and Entamoeba histolytica infection in institutionalized individuals at Sonoma State Hospital in California. The report indicates 4000 individuals were treated over a 4-year period with few side effects.
Several recently reported journal articles describing its use as an antiprotozoal include:
- A 2005 reference to its use in treating a Dutch family for Entamoeba histolytica infection.
- A 2004 reference to its use in Denmark in the treatment of Dientamoeba fragilis infection.
- A 1979 reference to the use in Zaire in the treatment of Entamoeba histolytica infection.
# Clioquinol and SMON
Clioquinol's use as an antiprotozoal drug has been restricted or discontinued in some countries due to an event in Japan where over 10,000 people developed SMON (subacute myelo-optic neuropathy) between 1957 and 1970. The drug was used widely in many countries before and after the SMON event without similar reports. As yet, no explanation exists as to why it produced this reaction, and some researchers have questioned whether clioquinol was the causative agent in the disease, noting that the drug had been used for 20 years prior to the epidemic without incident, and that the SMON cases began to reduce in number prior to the discontinuation of the drug. Theories suggested have included improper dosing, the permitted use of the drug for extended periods of time, and dosing which did not consider the smaller average stature of Japanese. Researchers have also suggested the SMON epidemic could have been due to a viral infection with a Inoue-Melnick virus.
# Topical use
Clioquinol is used in the drug Vioform, which is a topical antifungal treatment.
# Use in neurodegenerative diseases
Recent research at UCSF indicates that clioquinol appears to block the genetic action of Huntington's disease in mice and in cell culture.
Evidence from phase 2 clinical trials suggested that clioquinol could halt cognitive decline in Alzheimer's disease, possibly owing to its ability to act as a chelator for copper and zinc ions. This led to development of analogs including PBT2 as potential therapeutic compounds for the treatment of Alzheimer's disease.
# Continued use and manufacture around the world | Clioquinol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Clioquinol is an antifungal drug and antiprotozoal drug. It is neurotoxic in large doses. It is a member of a family of drugs called hydroxyquinolines which inhibit certain enzymes related to DNA replication. The drugs have been found to have activity against both viral and protozoal infections.[1]
# Antiprotozoal use
A 1964 report described the use of Clioquinol in both the treatment and prevention of shigella infection and Entamoeba histolytica infection in institutionalized individuals at Sonoma State Hospital in California. The report indicates 4000 individuals were treated over a 4-year period with few side effects. [2]
Several recently reported journal articles describing its use as an antiprotozoal include:
- A 2005 reference to its use in treating a Dutch family for Entamoeba histolytica infection. [3]
- A 2004 reference to its use in Denmark in the treatment of Dientamoeba fragilis infection.[4]
- A 1979 reference to the use in Zaire in the treatment of Entamoeba histolytica infection. [5]
# Clioquinol and SMON
Clioquinol's use as an antiprotozoal drug has been restricted or discontinued in some countries due to an event in Japan where over 10,000 people developed SMON (subacute myelo-optic neuropathy) between 1957 and 1970. The drug was used widely in many countries before and after the SMON event without similar reports.[6] As yet, no explanation exists as to why it produced this reaction, and some researchers have questioned whether clioquinol was the causative agent in the disease, noting that the drug had been used for 20 years prior to the epidemic without incident, and that the SMON cases began to reduce in number prior to the discontinuation of the drug.[7] Theories suggested have included improper dosing, the permitted use of the drug for extended periods of time, [8] and dosing which did not consider the smaller average stature of Japanese. Researchers have also suggested the SMON epidemic could have been due to a viral infection with a Inoue-Melnick virus.[9]
# Topical use
Clioquinol is used in the drug Vioform, which is a topical antifungal treatment.
# Use in neurodegenerative diseases
Recent research at UCSF indicates that clioquinol appears to block the genetic action of Huntington's disease in mice and in cell culture.[10]
Evidence from phase 2 clinical trials suggested that clioquinol could halt cognitive decline in Alzheimer's disease, possibly owing to its ability to act as a chelator for copper and zinc ions. This led to development of analogs including PBT2 as potential therapeutic compounds for the treatment of Alzheimer's disease.
# Continued use and manufacture around the world | https://www.wikidoc.org/index.php/Clioquinol | |
8657d348511717d7a0404d23fac15c27abe98f1a | wikidoc | Clobutinol | Clobutinol
# Overview
Clobutinol is a cough suppressant distributed by Boehringer-Ingelheim, Novartis's Hexal (Sandoz), Stada and possibly other companies.
# Side effects and withdrawal
Studies in 2004 had indicated that clobutinol has the potential to prolong the QT interval.
Clobutinol was in 2007 determined to cause cardiac arrhythmia in some patients.
Boehringer Ingelheim products containing clobutinol were voluntarily withdrawn from sale in Germany, and the rest of the world, on August 31, 2007.
The approval for Germany and the EU was revoked in 2008. | Clobutinol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Clobutinol is a cough suppressant distributed by Boehringer-Ingelheim, Novartis's Hexal (Sandoz), Stada and possibly other companies.
# Side effects and withdrawal
Studies in 2004 had indicated that clobutinol has the potential to prolong the QT interval.
Clobutinol was in 2007 determined to cause cardiac arrhythmia in some patients.
Boehringer Ingelheim products containing clobutinol were voluntarily withdrawn from sale in Germany, and the rest of the world, on August 31, 2007.
The approval for Germany and the EU was revoked in 2008. | https://www.wikidoc.org/index.php/Clobutinol | |
f25ca9c7057217c1e360f19b1b5443ac512acec0 | wikidoc | Clodronate | Clodronate
# Overview
Clodronic acid (INN) or clodronate disodium (USAN) is a first generation (non-nitrogenous) bisphosphonate. It is an anti-osteoporotic drug approved for the prevention and treatment of osteoporosis in post-menopausal women and men to reduce vertebral fractures, hyperparathyroidism, hypercalcemia in malignancy, multiple myeloma and fracture related pain because of its potent anti-inflammatory and analgesic effects shown as a reduction in inflammatory markers like IL-1β, IL-6, and TNF-alfa.
An Italian study compared the analgesic effect of clodronic acid versus acetaminophen in reumatic condition related pain. Study result show a reduction in pain in favor of clodronic acid that provided more analgesia than 3 grams/day of acetaminophen. Clodronate is also used in experimental medicine to selectively deplete macrophages.
Clodronic acid is approved for human use in Canada and Australia, the United Kingdom, where it is marketed as Bonefos, Loron, Clodron and in Italy as Clasteon, Difosfonal, Osteostab and several generics. In other countries is prescribed as a bone resorption inhibitor and antihypercalcemic agent.
# Use in equine medicine
Clodronic acid is approved for use in horses under the trade name Osphos, for treatment of navicular syndrome. It is given by intramuscular injection, with the total dose divided into 3 sites on the horse. Clinical effects may not be seen for up to 2 months, and horses may need treatments repeated every 3 to 6 months.
## Adverse reactions and contraindications
Osphos has been shown to have several adverse effects. These include:
- Signs of discomfort, agitation, or colic, usually within 2 hours of treatment.
- Head shaking
- Lip licking | Clodronate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Clodronic acid (INN) or clodronate disodium (USAN) is a first generation (non-nitrogenous) bisphosphonate. It is an anti-osteoporotic drug approved for the prevention and treatment of osteoporosis in post-menopausal women and men to reduce vertebral fractures, hyperparathyroidism, hypercalcemia in malignancy, multiple myeloma and fracture related pain because of its potent anti-inflammatory and analgesic effects shown as a reduction in inflammatory markers like IL-1β, IL-6, and TNF-alfa.
An Italian study compared the analgesic effect of clodronic acid versus acetaminophen in reumatic condition related pain. Study result show a reduction in pain in favor of clodronic acid that provided more analgesia than 3 grams/day of acetaminophen. Clodronate is also used in experimental medicine to selectively deplete macrophages.
Clodronic acid is approved for human use in Canada and Australia, the United Kingdom, where it is marketed as Bonefos, Loron, Clodron and in Italy as Clasteon, Difosfonal, Osteostab and several generics. In other countries is prescribed as a bone resorption inhibitor and antihypercalcemic agent.
# Use in equine medicine
Clodronic acid is approved for use in horses under the trade name Osphos, for treatment of navicular syndrome. It is given by intramuscular injection, with the total dose divided into 3 sites on the horse. Clinical effects may not be seen for up to 2 months, and horses may need treatments repeated every 3 to 6 months.
## Adverse reactions and contraindications
Osphos has been shown to have several adverse effects. These include:
- Signs of discomfort, agitation, or colic, usually within 2 hours of treatment.
- Head shaking
- Lip licking | https://www.wikidoc.org/index.php/Clodronate | |
209ab4f09c4fc6490f903baf0da291be9a29c8e8 | wikidoc | Clomiphene | Clomiphene
# 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
Clomiphene is an endocrine metabolic agent that is FDA approved for the treatment of ovulatory dysfunction in women desiring pregnancy. Common adverse reactions include abdominal bloating, abdominal discomfort, abdominal distention, nausea, vomiting, headache, visual disturbances, pain of breast.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Clomiphene citrate is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy. Impediments to achieving pregnancy must be excluded or adequately treated before beginning clomiphene citrate therapy. Those patients most likely to achieve success with clomiphene therapy include patients with polycystic ovary syndrome: Ovarian Hyperstimulation Syndrome), amenorrhea-galactorrhea syndrome, psychogenic amenorrhea, post-oral-contraceptive amenorrhea, and certain cases of secondary amenorrhea of undetermined etiology.
- Properly timed coitus in relationship to ovulation is important. A basal body temperature graph or other appropriate tests may help the patient and her physician determine if ovulation occurred. Once ovulation has been established, each course of clomiphene citrate should be started on or about the 5th day of the cycle. Long-term cyclic therapy is not recommended beyond a total of about six cycles (including three ovulatory cycles).
- Clomiphene citrate is indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below:
- Patients who are not pregnant.
- Patients without ovarian cysts. Clomiphene citrate should not be used in patients with ovarian enlargement except those with polycystic ovary syndrome.
- Pelvic examination is necessary prior to the first and each subsequent course of clomiphene citrate treatment.
- Patients without abnormal vaginal bleeding. If abnormal vaginal bleeding is present, the patient should be carefully evaluated to ensure that neoplastic lesions are not present.
- Patients with normal liver function.
- In addition, patients selected for clomiphene citrate therapy should be evaluated in regard to the following:
- Estrogen Levels. Patients should have adequate levels of endogenous estrogen (as estimated from vaginal smears, endometrial biopsy, assay of urinary estrogen, or from bleeding in response to progesterone). Reduced estrogen levels, while less favorable, do not preclude successful therapy.
- Primary Pituitary or Ovarian Failure. Clomiphene citrate therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure.
- Endometriosis and Endometrial Carcinoma. The incidence of endometriosis and endometrial carcinoma increases with age as does the incidence of ovulatory disorders. Endometrial biopsy should always be performed prior to clomiphene citrate therapy in this population.
- Other Impediments to Pregnancy. Impediments to pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinemia, and male factor infertility.
- Uterine Fibroids. Caution should be exercised when using clomiphene citrate in patients with uterine fibroids due to the potential for further enlargement of the fibroids.
- There are no adequate or well-controlled studies that demonstrate the effectiveness of clomiphene citrate in the treatment of male infertility. In addition, testicular tumors and gynecomastia have been reported in males using clomiphene. The cause and effect relationship between reports of testicular tumors and the administration of clomiphene citrate is not known.
- Although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (i.e., clomiphene citrate in conjunction with other ovulation-inducing drugs). Similarly, there is no standard clomiphene citrate regimen for ovulation induction in vitro fertilization programs to produce ova for fertilization and reintroduction. Therefore, clomiphene citrate is not recommended for these uses.
# Dosage
General Considerations
- The workup and treatment of candidates for clomiphene citrate therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene citrate only after careful diagnostic evaluation. The plan of therapy should be outlined in advance. Impediments to achieving the goal of therapy must be excluded or adequately treated before beginning clomiphene citrate. The therapeutic objective should be balanced with potential risks and discussed with the patient and others involved in the achievement of a pregnancy.
- Ovulation most often occurs from 5 to 10 days after a course of clomiphene citrate. Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time.
Recommended Dosage
- 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. 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 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 six cycles.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Clomiphene in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Clomiphene in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Clomiphene in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Clomiphene in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Clomiphene in pediatric patients.
# Contraindications
Hypersensitivity
- Clomiphene citrate 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 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 therapy is contraindicated in patients with liver disease or a history of liver dysfunction.
Abnormal Uterine Bleeding
Clomiphene citrate is contraindicated in patients with abnormal uterine bleeding of undetermined origin.
Ovarian Cysts
- Clomiphene citrate is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome.
Other
- Clomiphene citrate 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 Symptons
- 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. 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 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 after-images. 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 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 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 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 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. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiphene citrate. 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 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 therapy usually regress spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent clomiphene citrate 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.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trial Adverse Events. Clomiphene citrate, 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 trials: 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 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 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 the 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.
- Body as a Whole: Fever, tinnitus, weakness
- Cardiovascular: Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis
- Central Nervous System: Migraine headache, paresthesia, seizure, stroke, syncope
- Dermatologic: Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus, urticaria
- Fetal/Neonatal Anomalies:
- 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
- Genitourinary: Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage.
- Hepatic: Transaminases increased, hepatitis.
- Musculoskeletal: Arthralgia, back pain, myalgia.
- Neoplasms: 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);
- Psychiatric: Anxiety, irritability, mood changes, psychosis.
- Visual Disorders: 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.
- Other: Leukocytosis, thyroid disorder.
# Drug Interactions
- Drug interactions with clomiphene citrate have not been documented.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
### Fetal Risk Summary
Pregnancy Category X.Clomiphene citrate use in pregnant women is contraindicated, as clomiphene citrate 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 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 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 increase rate of spontaneous abortion among subfertile women treated with clomiphene 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):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clomiphene in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Clomiphene during labor and delivery.
### Nursing Mothers
- It is not known whether clomiphene citrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene citrate is administered to a nursing woman. In some patients, clomiphene citrate may reduce lactation.
### Pediatric Use
- There is no FDA guidance on the use of Clomiphene with respect to pediatric patients.
### Geriatic Use
- There is no FDA guidance on the use of Clomiphene with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Clomiphene with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Clomiphene with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Clomiphene in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Clomiphene in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Clomiphene in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Clomiphene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- There is limited information regarding Monitoring of Clomiphene in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Clomiphene in the drug label.
# Overdosage
# Overdosage
Signs and Symptoms
- Toxic effects accompanying acute overdosage of clomiphene citrate have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomiphene citrate therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.
- Oral LD50. The acute oral LD50 of clomiphene citrate is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known.
- Dialysis. It is not known if clomiphene citrate is dialyzable.
Treatment
- In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination.
# Pharmacology
## Mechanism of Action
- Clomiphene citrate is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, clomiphene citrate 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, spontaneous ovulatory menses have been noted in some patients after clomiphene citrate 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 C26H28CINO - C6H8O7 and a molecular weight of 598.10. 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 is a mixture of two geometric isomers containing between 30% and 50% of the cis-isomer.
- Each off-white debossed tablet contains 50 mg clomiphene citrate USP. The tablet also contains the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, pregelatinized corn starch, and sucrose.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Clomiphene 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 therapy.
## Nonclinical Toxicology
Carcinogenesisand Mutagenesis andImpairment of Fertility
- 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 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, 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, 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.
- The overall survival of infants from multiple pregnancies including spontaneous abortions, stillbirths, and neonatal deaths is 73%.
Fetal/Neonatal Anomalies and Mortality The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with clomiphene citrate 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 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
- Clomiphene citrate tablets, USP, 50 mg are round, off-white, debossed “Par 701” with bisect on one side and plain on the other. They are supplied in blisterpack dispensing bottles of 5 (NDC 54868-3059-0);
- Blisterpack dispensing bottles of 10 (NDC 54868-3059-1);
and bottles of 30 (NDC 54868-3059-2).
## Storage
- Store at controlled room temperature 15°-30°C (59°-86°F). Protect from heat, light, and excessive humidity, and store in closed containers.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Information for Patients
- The purpose and risks of clomiphene citrate therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiphene citrate 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 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. 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.
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 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 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, the proportion of neural tube defects has been high among pregnancies associated with ovulation induced by clomiphene citrate, but this has not been supported by data from population-based studies.
# Precautions with Alcohol
- Alcohol-Clomiphene 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
- A® — B®
# Drug Shortage Status
# Price | Clomiphene
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Clomiphene is an endocrine metabolic agent that is FDA approved for the treatment of ovulatory dysfunction in women desiring pregnancy. Common adverse reactions include abdominal bloating, abdominal discomfort, abdominal distention, nausea, vomiting, headache, visual disturbances, pain of breast.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Clomiphene citrate is indicated for the treatment of ovulatory dysfunction in women desiring pregnancy. Impediments to achieving pregnancy must be excluded or adequately treated before beginning clomiphene citrate therapy. Those patients most likely to achieve success with clomiphene therapy include patients with polycystic ovary syndrome: Ovarian Hyperstimulation Syndrome), amenorrhea-galactorrhea syndrome, psychogenic amenorrhea, post-oral-contraceptive amenorrhea, and certain cases of secondary amenorrhea of undetermined etiology.
- Properly timed coitus in relationship to ovulation is important. A basal body temperature graph or other appropriate tests may help the patient and her physician determine if ovulation occurred. Once ovulation has been established, each course of clomiphene citrate should be started on or about the 5th day of the cycle. Long-term cyclic therapy is not recommended beyond a total of about six cycles (including three ovulatory cycles).
- Clomiphene citrate is indicated only in patients with demonstrated ovulatory dysfunction who meet the conditions described below:
- Patients who are not pregnant.
- Patients without ovarian cysts. Clomiphene citrate should not be used in patients with ovarian enlargement except those with polycystic ovary syndrome.
- Pelvic examination is necessary prior to the first and each subsequent course of clomiphene citrate treatment.
- Patients without abnormal vaginal bleeding. If abnormal vaginal bleeding is present, the patient should be carefully evaluated to ensure that neoplastic lesions are not present.
- Patients with normal liver function.
- In addition, patients selected for clomiphene citrate therapy should be evaluated in regard to the following:
- Estrogen Levels. Patients should have adequate levels of endogenous estrogen (as estimated from vaginal smears, endometrial biopsy, assay of urinary estrogen, or from bleeding in response to progesterone). Reduced estrogen levels, while less favorable, do not preclude successful therapy.
- Primary Pituitary or Ovarian Failure. Clomiphene citrate therapy cannot be expected to substitute for specific treatment of other causes of ovulatory failure.
- Endometriosis and Endometrial Carcinoma. The incidence of endometriosis and endometrial carcinoma increases with age as does the incidence of ovulatory disorders. Endometrial biopsy should always be performed prior to clomiphene citrate therapy in this population.
- Other Impediments to Pregnancy. Impediments to pregnancy can include thyroid disorders, adrenal disorders, hyperprolactinemia, and male factor infertility.
- Uterine Fibroids. Caution should be exercised when using clomiphene citrate in patients with uterine fibroids due to the potential for further enlargement of the fibroids.
- There are no adequate or well-controlled studies that demonstrate the effectiveness of clomiphene citrate in the treatment of male infertility. In addition, testicular tumors and gynecomastia have been reported in males using clomiphene. The cause and effect relationship between reports of testicular tumors and the administration of clomiphene citrate is not known.
- Although the medical literature suggests various methods, there is no universally accepted standard regimen for combined therapy (i.e., clomiphene citrate in conjunction with other ovulation-inducing drugs). Similarly, there is no standard clomiphene citrate regimen for ovulation induction in vitro fertilization programs to produce ova for fertilization and reintroduction. Therefore, clomiphene citrate is not recommended for these uses.
# Dosage
General Considerations
- The workup and treatment of candidates for clomiphene citrate therapy should be supervised by physicians experienced in management of gynecologic or endocrine disorders. Patients should be chosen for therapy with clomiphene citrate only after careful diagnostic evaluation. The plan of therapy should be outlined in advance. Impediments to achieving the goal of therapy must be excluded or adequately treated before beginning clomiphene citrate. The therapeutic objective should be balanced with potential risks and discussed with the patient and others involved in the achievement of a pregnancy.
- Ovulation most often occurs from 5 to 10 days after a course of clomiphene citrate. Coitus should be timed to coincide with the expected time of ovulation. Appropriate tests to determine ovulation may be useful during this time.
Recommended Dosage
- 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. 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 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 six cycles.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Clomiphene in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Clomiphene in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Clomiphene in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Clomiphene in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Clomiphene in pediatric patients.
# Contraindications
Hypersensitivity
- Clomiphene citrate 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 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 therapy is contraindicated in patients with liver disease or a history of liver dysfunction.
Abnormal Uterine Bleeding
Clomiphene citrate is contraindicated in patients with abnormal uterine bleeding of undetermined origin.
Ovarian Cysts
- Clomiphene citrate is contraindicated in patients with ovarian cysts or enlargement not due to polycystic ovarian syndrome.
Other
- Clomiphene citrate 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 Symptons
- 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. 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 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 after-images. 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 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 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 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 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. Some patients with polycystic ovary syndrome who are unusually sensitive to gonadotropin may have an exaggerated response to usual doses of clomiphene citrate. 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 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 therapy usually regress spontaneously within a few days or weeks after discontinuing treatment. The potential benefit of subsequent clomiphene citrate 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.
# Adverse Reactions
## Clinical Trials Experience
Clinical Trial Adverse Events. Clomiphene citrate, 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 trials: 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 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 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 the 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.
- Body as a Whole: Fever, tinnitus, weakness
- Cardiovascular: Arrhythmia, chest pain, edema, hypertension, palpitation, phlebitis, pulmonary embolism, shortness of breath, tachycardia, thrombophlebitis
- Central Nervous System: Migraine headache, paresthesia, seizure, stroke, syncope
- Dermatologic: Acne, allergic reaction, erythema, erythema multiforme, erythema nodosum, hypertrichosis, pruritus, urticaria
- Fetal/Neonatal Anomalies:
- 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
- Genitourinary: Endometriosis, ovarian cyst (ovarian enlargement or cysts could, as such, be complicated by adnexal torsion), ovarian hemorrhage, tubal pregnancy, uterine hemorrhage.
- Hepatic: Transaminases increased, hepatitis.
- Musculoskeletal: Arthralgia, back pain, myalgia.
- Neoplasms: 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);
- Psychiatric: Anxiety, irritability, mood changes, psychosis.
- Visual Disorders: 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.
- Other: Leukocytosis, thyroid disorder.
# Drug Interactions
- Drug interactions with clomiphene citrate have not been documented.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
### Fetal Risk Summary
Pregnancy Category X.Clomiphene citrate use in pregnant women is contraindicated, as clomiphene citrate 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 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 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 increase rate of spontaneous abortion among subfertile women treated with clomiphene 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):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clomiphene in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Clomiphene during labor and delivery.
### Nursing Mothers
- It is not known whether clomiphene citrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if clomiphene citrate is administered to a nursing woman. In some patients, clomiphene citrate may reduce lactation.
### Pediatric Use
- There is no FDA guidance on the use of Clomiphene with respect to pediatric patients.
### Geriatic Use
- There is no FDA guidance on the use of Clomiphene with respect to geriatric patients.
### Gender
- There is no FDA guidance on the use of Clomiphene with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Clomiphene with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Clomiphene in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Clomiphene in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Clomiphene in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Clomiphene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- There is limited information regarding Monitoring of Clomiphene in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Clomiphene in the drug label.
# Overdosage
# Overdosage
Signs and Symptoms
- Toxic effects accompanying acute overdosage of clomiphene citrate have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomiphene citrate therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.
- Oral LD50. The acute oral LD50 of clomiphene citrate is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known.
- Dialysis. It is not known if clomiphene citrate is dialyzable.
Treatment
- In the event of overdose, appropriate supportive measures should be employed in addition to gastrointestinal decontamination.
# Pharmacology
## Mechanism of Action
- Clomiphene citrate is a drug of considerable pharmacologic potency. With careful selection and proper management of the patient, clomiphene citrate 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, spontaneous ovulatory menses have been noted in some patients after clomiphene citrate therapy.
## Structure
- Clomiphene citrate tablets, USP is an orally administered, nonsteroidal, ovulatory stimulant designated chemically as 2-[p-(2chloro-1,2-diphenylvinyl)phenoxy] triethylamine citrate (1:1). It has the molecular formula of C26H28CINO • C6H8O7 and a molecular weight of 598.10. 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 is a mixture of two geometric isomers [cis (zuclomiphene) and trans (enclomiphene)] containing between 30% and 50% of the cis-isomer.
- Each off-white debossed tablet contains 50 mg clomiphene citrate USP. The tablet also contains the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, pregelatinized corn starch, and sucrose.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Clomiphene 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 therapy.
## Nonclinical Toxicology
Carcinogenesisand Mutagenesis andImpairment of Fertility
- 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 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, 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, 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.
- The overall survival of infants from multiple pregnancies including spontaneous abortions, stillbirths, and neonatal deaths is 73%.
Fetal/Neonatal Anomalies and Mortality The following fetal abnormalities have been reported subsequent to pregnancies following ovulation induction therapy with clomiphene citrate 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 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
- Clomiphene citrate tablets, USP, 50 mg are round, off-white, debossed “Par 701” with bisect on one side and plain on the other. They are supplied in blisterpack dispensing bottles of 5 (NDC 54868-3059-0);
- Blisterpack dispensing bottles of 10 (NDC 54868-3059-1);
and bottles of 30 (NDC 54868-3059-2).
## Storage
- Store at controlled room temperature 15°-30°C (59°-86°F). Protect from heat, light, and excessive humidity, and store in closed containers.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
### Information for Patients
- The purpose and risks of clomiphene citrate therapy should be presented to the patient before starting treatment. It should be emphasized that the goal of clomiphene citrate 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 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. 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.
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 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 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, the proportion of neural tube defects has been high among pregnancies associated with ovulation induced by clomiphene citrate, but this has not been supported by data from population-based studies.
# Precautions with Alcohol
- Alcohol-Clomiphene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- CLOMIPHENE CITRATE ®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Clomiphene | |
f53883b27623868082b22663f07d855c6d84850a | wikidoc | Clonorchis | Clonorchis
The Clonorchis sinensis is a human liver fluke in the class Trematoda, Phylum Platyhelminthes. This parasite lives in the liver of humans, and is found mainly in the common bile duct and gall bladder, feeding on bile. These animals, which are believed to be the third most prevalent worm parasite in the world, are endemic to Japan, China, Taiwan, and Southeast Asia, currently infecting an estimated 30,000,000 humans.
# Life cycle
The egg of a Clonorchis sinensis (commonly: human liver fluke), which contains the miracidium that develops into the adult form, floats in freshwater until it is eaten by a snail.
Once inside of the snail body, the miracidium hatches from the egg, and parasitically grows inside of the snail. The miracidium develops into a sporocyst, which in turn house the asexual reproduction of redia, the next stage. The redia themselves house the asexual reproduction of free-swimming cercaria. This system of asexual reproduction allows for an exponential multiplication of cercaria individuals from one miracidium. This aids the Clonorchis in reproduction, because it enables the miracidium to captilatize on one chance occasion of passively being eaten by a snail before the egg dies.
Once the redia mature, having grown inside the snail body until this point, they actively bore out of the snail body into the freshwater environment. There, instead of waiting to be consumed by a host (as is the case in their egg stage), they seek out a fish. Boring their way into the fish's body, they again become parasites of their new hosts.
Once inside of the fish muscle, the cercaria create a protective metacercarial cyst with which to encapsulate their bodies. This protective cyst proves useful when the fish muscle is consumed by a human. The acid-resistant cyst enables the metacercaria to avoid being digested by the human gastric acids, and allows the metacercaria to reach the small intestine unharmed. Reaching the small intestines, the metacercaria navigate toward the human liver, which becomes its final habitat. Clonorchis feed on human bile created by the liver. In the human liver, the mature Clonorchis reaches its stage of sexual reproduction. The hermaphroditic adults produce eggs every 1–30 seconds, resulting in the rapid multiplication of inhabitants in the liver.
# Effects on human health
Dwelling in the bile ducts, Clonorchis induces an inflammatory reaction, epithelial hyperplasia and sometimes even cholangiocarcinoma, the incidence of which is raised in fluke-infested areas.
One adverse effect of Clonorchis is the possibility for the adult metacercaria to consume all bile created in the liver, which would inhibit the host human from digesting, especially fats. Another possibility is obstruction of the bile duct by the parasite or its eggs, leading to biliary obstruction and cholangitis (specifically oriental cholangitis).
# Treatment
Praziquantel or albendazole. | Clonorchis
The Clonorchis sinensis is a human liver fluke in the class Trematoda, Phylum Platyhelminthes. This parasite lives in the liver of humans, and is found mainly in the common bile duct and gall bladder, feeding on bile. These animals, which are believed to be the third most prevalent worm parasite in the world, are endemic to Japan, China, Taiwan, and Southeast Asia, currently infecting an estimated 30,000,000 humans.
# Life cycle
The egg of a Clonorchis sinensis (commonly: human liver fluke), which contains the miracidium that develops into the adult form, floats in freshwater until it is eaten by a snail.
Once inside of the snail body, the miracidium hatches from the egg, and parasitically grows inside of the snail. The miracidium develops into a sporocyst, which in turn house the asexual reproduction of redia, the next stage. The redia themselves house the asexual reproduction of free-swimming cercaria. This system of asexual reproduction allows for an exponential multiplication of cercaria individuals from one miracidium. This aids the Clonorchis in reproduction, because it enables the miracidium to captilatize on one chance occasion of passively being eaten by a snail before the egg dies.
Once the redia mature, having grown inside the snail body until this point, they actively bore out of the snail body into the freshwater environment. There, instead of waiting to be consumed by a host (as is the case in their egg stage), they seek out a fish. Boring their way into the fish's body, they again become parasites of their new hosts.
Once inside of the fish muscle, the cercaria create a protective metacercarial cyst with which to encapsulate their bodies. This protective cyst proves useful when the fish muscle is consumed by a human. The acid-resistant cyst enables the metacercaria to avoid being digested by the human gastric acids, and allows the metacercaria to reach the small intestine unharmed. Reaching the small intestines, the metacercaria navigate toward the human liver, which becomes its final habitat. Clonorchis feed on human bile created by the liver. In the human liver, the mature Clonorchis reaches its stage of sexual reproduction. The hermaphroditic adults produce eggs every 1–30 seconds, resulting in the rapid multiplication of inhabitants in the liver.
# Effects on human health
Dwelling in the bile ducts, Clonorchis induces an inflammatory reaction, epithelial hyperplasia and sometimes even cholangiocarcinoma, the incidence of which is raised in fluke-infested areas.[1]
One adverse effect of Clonorchis is the possibility for the adult metacercaria to consume all bile created in the liver, which would inhibit the host human from digesting, especially fats. Another possibility is obstruction of the bile duct by the parasite or its eggs, leading to biliary obstruction and cholangitis (specifically oriental cholangitis).
# Treatment
Praziquantel or albendazole. | https://www.wikidoc.org/index.php/Clonorchis | |
bfdf242b96769fc12f84fd992b126ced897eee7a | wikidoc | Open shell | Open shell
In the context of atomic orbitals, an open shell is a valence shell which is not completely filled with electrons or that has not given all of its valence electrons through chemical bonds with other atoms or molecules during a chemical reaction. Atoms generally reach a noble gas configuration in a molecule. The Noble gases (He, Ne, Ar, Kr, Xe, Rn) are not reactive and have configurations 1s2 (He), 1s22s22p6 (Ne), 1s22s22p63s23p6 (Ar), etc.
For molecules it signifies that there are unpaired electrons. In molecular orbital theory, this leads to molecular orbitals that are singly occupied. In computational chemistry implementations of molecular orbital theory, open shell molecules have to be handled by either the restricted Open-shell Hartree-Fock method or the unrestricted Hartree-Fock method.
Likewise a closed shell or closed shell configuration is obtained with a completely filled valence shell. This configuration is very stable . In another meaning a closed shell configuration corresponds to state with all molecular orbitals doubly occupied or empty (a singlet state) | Open shell
In the context of atomic orbitals, an open shell is a valence shell which is not completely filled with electrons or that has not given all of its valence electrons through chemical bonds with other atoms or molecules during a chemical reaction. Atoms generally reach a noble gas configuration in a molecule. The Noble gases (He, Ne, Ar, Kr, Xe, Rn) are not reactive and have configurations 1s2 (He), 1s22s22p6 (Ne), 1s22s22p63s23p6 (Ar), etc.
For molecules it signifies that there are unpaired electrons. In molecular orbital theory, this leads to molecular orbitals that are singly occupied. In computational chemistry implementations of molecular orbital theory, open shell molecules have to be handled by either the restricted Open-shell Hartree-Fock method or the unrestricted Hartree-Fock method.
Likewise a closed shell or closed shell configuration is obtained with a completely filled valence shell. This configuration is very stable [1]. In another meaning a closed shell configuration corresponds to state with all molecular orbitals doubly occupied or empty (a singlet state) [2] | https://www.wikidoc.org/index.php/Closed_shell | |
5dacf1fcff0ecb3fb20073fa03a574c1679e3c00 | wikidoc | Clotiapine | Clotiapine
# Overview
Clotiapine (Entumine) is an atypical antipsychotic of the dibenzothiazepine chemical class. It was first introduced in a few European countries (namely, Belgium, Italy, Spain and Switzerland), Argentina, Taiwan and Israel in 1970.
Some sources regard clotiapine as a typical antipsychotic rather than atypical due to its high incidence of extrapyramidal side effects compared to the atypicals like clozapine and quetiapine, to which it is structurally related.Despite its profile of a relatively high incidence of extrapyramidal side effects it has demonstrated efficacy in treatment-resistant schizophrenic patients according to a number of psychiatrists with clinical experience with it, some weak clinical evidence supports this view too.
# Synthesis
Ullmann condensation of the substituted thiosalyciclic acid with ortho-chloronitrobenzene results in the displacement
-f chlorine by thiophenoxide and the formation of the thioether . The nitro group in this last intermediate is then reduced to an aniline ; the resulting amino acid is then cyclized thermally to the lactam . Treatment of that with phosphorus oxychloride gives the imino chloride. Reaction with N-methylpiperazine leads to the replacement of chlorine by nitrogen and the formation of clothiapine . | Clotiapine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Clotiapine (Entumine) is an atypical antipsychotic of the dibenzothiazepine chemical class. It was first introduced in a few European countries (namely, Belgium, Italy, Spain and Switzerland), Argentina, Taiwan and Israel in 1970.
Some sources regard clotiapine as a typical antipsychotic rather than atypical due to its high incidence of extrapyramidal side effects compared to the atypicals like clozapine and quetiapine, to which it is structurally related.Despite its profile of a relatively high incidence of extrapyramidal side effects it has demonstrated efficacy in treatment-resistant schizophrenic patients according to a number of psychiatrists with clinical experience with it, some weak clinical evidence supports this view too.
# Synthesis
Ullmann condensation of the substituted thiosalyciclic acid with ortho-chloronitrobenzene results in the displacement
of chlorine by thiophenoxide and the formation of the thioether . The nitro group in this last intermediate is then reduced to an aniline ; the resulting amino acid is then cyclized thermally to the lactam . Treatment of that with phosphorus oxychloride gives the imino chloride. Reaction with N-methylpiperazine leads to the replacement of chlorine by nitrogen and the formation of clothiapine . | https://www.wikidoc.org/index.php/Clotiapine | |
ac65d0d57eefa02a5edbb632abba5ba9bd3757e0 | wikidoc | Cloxazolam | Cloxazolam
# Overview
Cloxazolam (marketed under brand name Sepazon, Olcadil (Brazil, Portugal and Spain), Akton (Belgium), Lubalix (Switzerland) is a drug which is a benzodiazepine derivative. Cloxazolam is metabolised into the active metabolite chlordesmethyldiazepam (delorazepam). It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.
# Indications
Cloxazolam's main use is as an anti-anxiety drug.
# Side effects
An increased heart rate may occur as an adverse effect of cloxazolam.
# Pharmacology
The pharmacological effects of cloxazolam are a result of mainly its active metabolites, thus cloxazolam is a prodrug. The main site of action of cloxazolam and its active metabolites are the benzodiazepine receptor.
The pharmacological actions of benzodiazepines at the GABAa receptor are similar to those of neurosteroids. Neuroactive steroids are positive allosteric modulators of the GABAa receptor, enhancing GABA function and in turn have effects on mood and other functions. Many benzodiazepines (diazepam, medazepam, estazolam, temazepam, flunitrazepam and nitrazepam) potently inhibit the enzymes involved in the metabolism of neurosteroids. The tetrahydroxazole ring that cloxazolam and oxazolam have decreases the inhibitory potency of benzodiazepines on neurosteroids. Thus there could be subtle differences between cloxazolam and other benzodiazepines. However, because the parent prodrugs of cloxazolam and oxazolam were tested rather than the active metabolites, this is purely speculative. | Cloxazolam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Cloxazolam[1] (marketed under brand name Sepazon, Olcadil (Brazil, Portugal and Spain), Akton (Belgium), Lubalix (Switzerland) is a drug which is a benzodiazepine derivative.[2] Cloxazolam is metabolised into the active metabolite chlordesmethyldiazepam (delorazepam).[3] It possesses anxiolytic,[4] anticonvulsant,[5] hypnotic,[6] sedative[7] and skeletal muscle relaxant properties.[8]
# Indications
Cloxazolam's main use is as an anti-anxiety drug.[9]
# Side effects
An increased heart rate may occur as an adverse effect of cloxazolam.[10]
# Pharmacology
The pharmacological effects of cloxazolam are a result of mainly its active metabolites, thus cloxazolam is a prodrug. The main site of action of cloxazolam and its active metabolites are the benzodiazepine receptor.[11]
The pharmacological actions of benzodiazepines at the GABAa receptor are similar to those of neurosteroids. Neuroactive steroids are positive allosteric modulators of the GABAa receptor, enhancing GABA function and in turn have effects on mood and other functions. Many benzodiazepines (diazepam, medazepam, estazolam, temazepam, flunitrazepam and nitrazepam) potently inhibit the enzymes involved in the metabolism of neurosteroids. The tetrahydroxazole ring that cloxazolam and oxazolam have decreases the inhibitory potency of benzodiazepines on neurosteroids. Thus there could be subtle differences between cloxazolam and other benzodiazepines.[12] However, because the parent prodrugs of cloxazolam and oxazolam were tested rather than the active metabolites, this is purely speculative. | https://www.wikidoc.org/index.php/Cloxazolam | |
76e0897482e6fd89be6025c69047b44c3e9972c2 | wikidoc | Cluttering | Cluttering
# Background
Cluttering (also called tachyphemia) is a speech disorder and a communication disorder characterized by speech that is difficult for listeners to understand due to rapid speaking rate, erratic rhythm, poor syntax or grammar, and words or groups of words unrelated to the sentence. Cluttering has in the past been viewed as a fluency disorder.
# Presentation
The person with cluttering may experience a short attention span, poor concentration, poorly organized thinking, inability to listen, and a lack of awareness that one's speech is unintelligible.
Cluttering is sometimes confused with stuttering. Both communication disorders break the normal flow of speech. However, while stuttering is most often analyzed as a speech disorder, cluttering is a language disorder. In other words, a stutterer has a coherent pattern of thoughts, but can't say it; in contrast, a clutterer has no problem putting thoughts into words, but those thoughts become disorganized during speaking. Cluttering not only effects speech, but affects thought patterns, writing, typing, and conversation.
Stutterers are usually dysfluent on initial sounds, when beginning to speak, and become more fluent towards the ends of utterances. In contrast, clutterers are most clear at the start of utterances, but their speaking rate increases and intelligibility decreases towards the end of utterances.
Stuttering is characterized by struggle behavior, such as overtense speech production muscles. Cluttering, in contrast, is effortless.
To compare, a stutterer trying to say "I want to go to the store," might sound like "I wa-wa-want to g-g-go to the sssssssssstore." In contrast, a clutterer might say, "I want to go to the st...uh...place where you buy...market st-st-store."
Cluttering is also characterized by slurred speech, especially dropped or distorted /r/ and /l/ sounds; and monotone speech that starts loud and trails off into a murmur.
Clutterers often also have reading and writing disorders, especially sprawling, disorderly handwriting, which poorly integrate ideas and space.
A clutterer described the feeling associated with a clutter as:
Another clutterer wrote on an Internet support group:
# Related Disorders
Cluttering can often be confused with language delay, language disorder, learning disabilities, and attention deficit disorder.
## Cluttering versus Stuttering
Cluttering and stuttering sound very similar to the lay ear, especially when they are at their worst. However, they are markedly different disorders and clutterers and stutterers are very different.
Stutterers:
- Are very aware of their disorder
- Perform worse when speaking under stress
- Have a hard time fluently giving short answers
- Often have inhibited, neat handwriting
- Therapy focuses on relaxation techniques, calling attention away from speech
- Are typically withdrawn, shy, or introverted
- Typically were fluent, but then started stuttering
- Know exactly what they want to say but cannot say it
- Have organized speech
- Have good listening skills
Clutterers:
- Are very unaware of their disorder
- Perform better when speaking under stress
- Have a hard time fluently giving long answers
- Have hasty, repetitious, uninhibited, messy handwriting
- Have little to no fear of their speech and are careless in speech
- Therapy focuses on calling attention to speech details
- Are typically outgoing or extroverted
- Typically were never very fluent
- Do not know exactly what they want to say, but say it anyway
- Have disorganized, tangential, grammatically incorrect speech with word substitutions
- Are impatient listeners, frequently interrupt, and have poor turn-taking skills in conversation
# Treatment
Because clutterers have poor awareness of their disorder, they may be indifferent or even hostile to speech-language pathologists. Treatment for cluttering usually takes longer than stuttering treatment. Delayed auditory feedback (DAF) is usually used to produce a more deliberate, exaggerated oral-motor response pattern. Other treatment components include improving narrative structure with story-telling picture books, turn-taking practice, pausing practice, and language therapy.
# History
Battaros was a legendary Libyan king who spoke quickly and in a disorderly fashion. Others who spoke as he did were said to suffer from battarismus. This is the earliest record of the speech disorder of cluttering.
In the 1960's, cluttering was called tachyphemia, a word derived from the Greek for "fast speech." This word is currently not used to describe cluttering because fast speech is not a required element of cluttering.
Deso Weiss described cluttering as the outward manifestation of a "central language imbalance." In Weiss's book on cluttering, he used Central Language Imbalance or CLI as synonymous with what cluttering is described as today.
Over the past twenty years, Kenneth O. St. Louis, Lawrence J. Raphael, Florence L. Myers, and Klaas Bakker have been working to standardize a definition of cluttering. Judith Kuster maintains a robust section of cluttering resources and articles in her Stuttering Homepage.
The first conference held specifically on cluttering was held in May of 2007 in Razlog, Bulgaria. It was called, "The First World Conference on Cluttering," and had over 60 participants from across North America, Europe, the Middle East and Asia. It was held in Bulgaria partly because of cluttering research efforts by Professors Dobrinka Georgieva and Katya Dionissieva of Neofit Rilski. Part of the conference was awarding the first Deso Weiss Award for Excellence in Cluttering, which went to Kenneth St. Louis for his contributions for understanding and knowledge about cluttering.
# Cluttering Confusion
Spoonerisms, malapropisms, Colemanballs, and Freudian slips are examples of cluttering. Stuttering as a common term often refers the speech disorder of cluttering, rather than to the speech disorder of stuttering. Cluttered speech is exhibited by normal speakers, and is often referred to as stuttering--this is especially true when the speaker is nervous, where nervous speech more closely resembles cluttering than stuttering.
People with ADD or ADHD may have many of the same symptoms as clutterers, including being inattentive, restless, short tempered, and impatient.
# Famous Clutterers
Weiss claimed that Battaros, Demosthenes, Pericles, Justinian, Bismarck, and Winston Churchill were clutterers. He says about these people, "Each of these contributors to world history viewed his world holistically, and was not deflected by exaggerated attention to small details. Perhaps then, they excelled because of, rather than in spite of, their ." | Cluttering
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Cluttering (also called tachyphemia) is a speech disorder and a communication disorder characterized by speech that is difficult for listeners to understand due to rapid speaking rate, erratic rhythm, poor syntax or grammar, and words or groups of words unrelated to the sentence. Cluttering has in the past been viewed as a fluency disorder[1].
# Presentation
The person with cluttering may experience a short attention span, poor concentration, poorly organized thinking, inability to listen, and a lack of awareness that one's speech is unintelligible.
Cluttering is sometimes confused with stuttering. Both communication disorders break the normal flow of speech. However, while stuttering is most often analyzed as a speech disorder, cluttering is a language disorder. In other words, a stutterer has a coherent pattern of thoughts, but can't say it; in contrast, a clutterer has no problem putting thoughts into words, but those thoughts become disorganized during speaking. Cluttering not only effects speech, but affects thought patterns, writing, typing, and conversation[2].
Stutterers are usually dysfluent on initial sounds, when beginning to speak, and become more fluent towards the ends of utterances. In contrast, clutterers are most clear at the start of utterances, but their speaking rate increases and intelligibility decreases towards the end of utterances.
Stuttering is characterized by struggle behavior, such as overtense speech production muscles. Cluttering, in contrast, is effortless.
To compare, a stutterer trying to say "I want to go to the store," might sound like "I wa-wa-want to g-g-go to the sssssssssstore." In contrast, a clutterer might say, "I want to go to the st...uh...place where you buy...market st-st-store."
Cluttering is also characterized by slurred speech, especially dropped or distorted /r/ and /l/ sounds; and monotone speech that starts loud and trails off into a murmur.
Clutterers often also have reading and writing disorders, especially sprawling, disorderly handwriting, which poorly integrate ideas and space.[3]
A clutterer described the feeling associated with a clutter as:
Another clutterer wrote on an Internet support group:
# Related Disorders
Cluttering can often be confused with language delay, language disorder, learning disabilities, and attention deficit disorder[5].
## Cluttering versus Stuttering
Cluttering and stuttering sound very similar to the lay ear, especially when they are at their worst. However, they are markedly different disorders and clutterers and stutterers are very different.
Stutterers:
- Are very aware of their disorder
- Perform worse when speaking under stress
- Have a hard time fluently giving short answers
- Often have inhibited, neat handwriting
- Therapy focuses on relaxation techniques, calling attention away from speech
- Are typically withdrawn, shy, or introverted
- Typically were fluent, but then started stuttering
- Know exactly what they want to say but cannot say it
- Have organized speech
- Have good listening skills
Clutterers:
- Are very unaware of their disorder
- Perform better when speaking under stress
- Have a hard time fluently giving long answers
- Have hasty, repetitious, uninhibited, messy handwriting
- Have little to no fear of their speech and are careless in speech
- Therapy focuses on calling attention to speech details
- Are typically outgoing or extroverted
- Typically were never very fluent
- Do not know exactly what they want to say, but say it anyway
- Have disorganized, tangential, grammatically incorrect speech with word substitutions
- Are impatient listeners, frequently interrupt, and have poor turn-taking skills in conversation
# Treatment
Because clutterers have poor awareness of their disorder, they may be indifferent or even hostile to speech-language pathologists. Treatment for cluttering usually takes longer than stuttering treatment. Delayed auditory feedback (DAF) is usually used to produce a more deliberate, exaggerated oral-motor response pattern. Other treatment components include improving narrative structure with story-telling picture books, turn-taking practice, pausing practice, and language therapy.
# History
Battaros was a legendary Libyan king who spoke quickly and in a disorderly fashion. Others who spoke as he did were said to suffer from battarismus.[6] This is the earliest record of the speech disorder of cluttering.
In the 1960's, cluttering was called tachyphemia, a word derived from the Greek for "fast speech." This word is currently not used to describe cluttering because fast speech is not a required element of cluttering.
Deso Weiss described cluttering as the outward manifestation of a "central language imbalance." In Weiss's book on cluttering, he used Central Language Imbalance or CLI as synonymous with what cluttering is described as today.[7]
Over the past twenty years, Kenneth O. St. Louis, Lawrence J. Raphael, Florence L. Myers, and Klaas Bakker have been working to standardize a definition of cluttering. Judith Kuster maintains a robust section of cluttering resources and articles in her Stuttering Homepage.[8]
The first conference held specifically on cluttering was held in May of 2007[9] in Razlog, Bulgaria. It was called, "The First World Conference on Cluttering," and had over 60 participants from across North America, Europe, the Middle East and Asia.[10] It was held in Bulgaria partly because of cluttering research efforts by Professors Dobrinka Georgieva and Katya Dionissieva of Neofit Rilski.[11] Part of the conference was awarding the first Deso Weiss Award for Excellence in Cluttering, which went to Kenneth St. Louis for his contributions for understanding and knowledge about cluttering.[12]
# Cluttering Confusion
Spoonerisms, malapropisms, Colemanballs, and Freudian slips are examples of cluttering. Stuttering as a common term often refers the speech disorder of cluttering, rather than to the speech disorder of stuttering. Cluttered speech is exhibited by normal speakers, and is often referred to as stuttering--this is especially true when the speaker is nervous, where nervous speech more closely resembles cluttering than stuttering.
People with ADD or ADHD may have many of the same symptoms as clutterers, including being inattentive, restless, short tempered, and impatient.
# Famous Clutterers
Weiss claimed that Battaros, Demosthenes, Pericles, Justinian, Bismarck, and Winston Churchill were clutterers. He says about these people, "Each of these contributors to world history viewed his world holistically, and was not deflected by exaggerated attention to small details. Perhaps then, they excelled because of, rather than in spite of, their [cluttering]." [13] | https://www.wikidoc.org/index.php/Cluttering | |
417ffc1e87b063b46ff29ef8588568377e5bdf10 | wikidoc | Co-codamol | Co-codamol
Co-codamol (BAN) is a non-proprietary name used to denote a combination of codeine phosphate and paracetamol (acetaminophen). Co-codamol tablets are used for the relief of mild/moderate (or in the case of 30/500mg - severe) pain.
Three strengths are available:
- 8mg of codeine phosphate per tablet
- 15mg of codeine phosphate per tablet
- 30mg of codeine phosphate per tablet (available in capsules as Tylex and Kapake, available in tablets as Solpadol).
Formulations contain from 300 mg to 1000 mg of paracetamol per tablet. In the United Kingdom the 500+15 mg and 500+30 mg tablets are available only with a prescription, and the 500+8 strength is available over the counter. This is also the case in Australia, however 500+15 mg tablets in packs of 12 or less are Schedule 3 (Pharmacist Only Medicine). Manufacturer directions state not to exceed more than the recommended dosage of two tablets every four hours, and no more than eight in a 24 hour period. Other drugs containing paracetamol should be avoided.
In the United States, Tylenol produces tablets containing 8, 15, and 30 milligrams, named Tylenol No.1, 2, and 3, respectively. There is also a Tylenol 4 containing 60mg of codeine. All tablets contain 300mg of paracetemol. No Tylenol w/Codeine Products in the USA contain Caffeine. In Canadian preparations Tylenol #2 & #3 contain 15mg caffeine.
Co-codamol is marketed in the United States and Canada as Tylenol 3 with Codeine, in the UK as both Solpadeine and Solpadol and in Australia as Panadeine, Panadeine 15 and Panadeine Forte.
# Side effects
Side effects can include: skin rashes, hypersensitivity reaction, constipation, fainting (syncope or near syncope), nausea and/or vomiting, confusion, loss of short-term memory, drowsiness, changes in blood, easy bruising and bleeding gums. | Co-codamol
Co-codamol (BAN) is a non-proprietary name used to denote a combination of codeine phosphate and paracetamol (acetaminophen). Co-codamol tablets are used for the relief of mild/moderate (or in the case of 30/500mg - severe) pain.
Three strengths are available:
- 8mg of codeine phosphate per tablet
- 15mg of codeine phosphate per tablet
- 30mg of codeine phosphate per tablet (available in capsules as Tylex and Kapake, available in tablets as Solpadol).
Formulations contain from 300 mg to 1000 mg of paracetamol per tablet[1]. In the United Kingdom the 500+15 mg and 500+30 mg tablets are available only with a prescription, and the 500+8 strength is available over the counter. This is also the case in Australia, however 500+15 mg tablets in packs of 12 or less are Schedule 3 (Pharmacist Only Medicine). Manufacturer directions state not to exceed more than the recommended dosage of two tablets every four hours, and no more than eight in a 24 hour period. Other drugs containing paracetamol should be avoided.
In the United States, Tylenol produces tablets containing 8, 15, and 30 milligrams, named Tylenol No.1, 2, and 3, respectively. There is also a Tylenol 4 containing 60mg of codeine. All tablets contain 300mg of paracetemol. No Tylenol w/Codeine Products in the USA contain Caffeine. In Canadian preparations Tylenol #2 & #3 contain 15mg caffeine.
Co-codamol is marketed in the United States and Canada as Tylenol 3 with Codeine, in the UK as both Solpadeine and Solpadol and in Australia as Panadeine, Panadeine 15 and Panadeine Forte.
# Side effects
Side effects can include: skin rashes, hypersensitivity reaction, constipation, fainting (syncope or near syncope), nausea and/or vomiting, confusion, loss of short-term memory, drowsiness, changes in blood, easy bruising and bleeding gums.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Co-codamol | |
1ae024e9f5a1c4471e6489bcaa130fde3da1b027 | wikidoc | Cobicistat | Cobicistat
# 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
Cobicistat is an anti-infective agent that is FDA approved for the treatment of HIV-1 infection. Common adverse reactions include jaundice and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Cobicistat is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection.
- Dosage:
- Cobicistat 150 mg orally once daily plus atazanavir 300 mg orally once daily; or
- Cobicistat 150 mg orally once daily plus darunavir 800 mg orally once daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cobicistat in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cobicistat in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness not established in pediatric patients younger than 18 years
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cobicistat in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cobicistat in pediatric patients.
# Contraindications
The concomitant use of Cobicistat with atazanavir or darunavir and the following drugs (see TABLE 2) is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect
# Warnings
Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating Cobicistat, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.
Prior to initiating therapy with Cobicistat, assess estimated creatinine clearance. Dosage recommendations are not available for drugs that require dosage adjustments in Cobicistat-treated patients with renal impairment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
Although Cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when Cobicistat was used in an antiretroviral regimen that contained tenofovir DF.
- Coadministration of Cobicistat and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with Cobicistat.
- Document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when Cobicistat is used with tenofovir DF. Measure serum phosphorus in patients with or at risk for renal impairment when used with tenofovir DF.
- Coadministration of Cobicistat and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.
In the clinical trials of Cobicistat over 48 weeks (N=771), 6 (1.5%) subjects treated with Cobicistat coadministered with atazanavir and TRUVADA® and 6 (1.6%) subjects treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study drug due to a renal adverse event. Five of the 6 subjects (1.3% overall) in the Cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 2 of 6 subjects (0.5% overall) in the ritonavir group. None of the 5 subjects in the Cobicistat group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 5 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of Cobicistat coadministered with atazanavir and TRUVADA. Renal replacement therapy was not required in any subject.
Initiation of Cobicistat, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving Cobicistat may increase plasma concentration of these medications which may increase the risk of clinically significant adverse reactions (including life-threatening or fatal reactions) associated with the concomitant medications. Coadministration of Cobicistat with atazanavir or darunavir in combination with CYP3A inducers may lead to lower exposure of cobicistat and atazanavir or darunavir and loss of efficacy of atazanavir or darunavir and possible resistance. Therefore, consider the potential for drug interactions prior to and during Cobicistat therapy; review concomitant medications during Cobicistat therapy; and monitor for the adverse reactions associated with the concomitant drugs.
Cobicistat or ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain Cobicistat interactions.
The following antiretrovirals are not recommended in combination with Cobicistat because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance:
- More than one antiretroviral that requires pharmacokinetic enhancement (i.e., two protease inhibitors or a protease inhibitor in combination with elvitegravir)
- Darunavir in combination with efavirenz, nevirapine, or etravirine
- Atazanavir in combination with etravirine
- Atazanavir in combination with efavirenz in treatment-experienced patients
- Darunavir 600 mg twice daily
- Other HIV-1 protease inhibitors including fosamprenavir, saquinavir, or tipranavir
Cobicistat in combination with STRIBILD® fixed-dose combination tablets (elvitegravir, cobicistat, emtricitabine, tenofovir DF) is not recommended because cobicistat is a component of STRIBILD.
Cobicistat in combination with lopinavir/ritonavir or regimens containing ritonavir is not recommended due to similar effects of Cobicistat and ritonavir on CYP3A.
# 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 safety of Cobicistat has been established from a Phase 2 trial, Study 105, and a Phase 3 trial, Study 114. In the pooled analysis, 771 HIV-1 infected, antiretroviral treatment-naïve adults received for at least 48 weeks:
- Cobicistat coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=394) or;
- ritonavir coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA ) (N=377).
The most common adverse reactions (all Grades) and reported in >10% of subjects in the Cobicistat group were jaundice (13%), ocular icterus (15%), and nausea (12%); the most common adverse reactions in the ritonavir group were jaundice (11%), ocular icterus (17%), nausea (11%), and diarrhea (11%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 7% in both the Cobicistat and ritonavir group. Table 3 displays the frequency of adverse reactions (Grades 2–4) occurring in at least 2% of subjects in the Cobicistat group in pooled Studies 105 and 114.
Nephrolithiasis has previously been identified in patients receiving atazanavir. In the pooled analysis of Studies 105 and 114 through 48 weeks, 8 subjects (2%) receiving Cobicistat coadministered with atazanavir and TRUVADA developed nephrolithiasis compared with no subjects receiving ritonavir coadministered with atazanavir and TRUVADA. Median time to onset of nephrolithiasis in the Cobicistat group was 24 weeks. Causality in these cases could not be determined with certainty, but the majority of renal stone events were not serious and no subject discontinued study drug.
Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of subjects receiving Cobicistat coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator's assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with Cobicistat and with greater frequency compared with ritonavir.
- Gastrointestinal Disorders: diarrhea, vomiting, upper abdominal pain
- General Disorders and Administration Site Conditions: fatigue
- Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
- Nervous System Disorders: headache
- Psychiatric Disorders: depression, abnormal dreams, insomnia
- Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired
Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects in the Cobicistat group in Studies 105 and 114 is presented in Table 4.
Increase in Serum Creatinine: Cobicistat causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. In Studies 105 and 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with Cobicistat, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 48 weeks of treatment was -13.4 ± 15.2 mL/min in the Cobicistat group and -9.1 ± 14.7 mL/min in the ritonavir group.
Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5. In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown.
## Postmarketing Experience
There is limited information regarding Cobicistat Postmarketing Experience in the drug label.
# Drug Interactions
Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may be increased if those drugs are coadministered with Cobicistat.
Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.
Coadministration of Cobicistat with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6.
Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A.
Coadministration of Cobicistat with atazanavir or darunavir in combination with drugs that induce CYP3A activity have the potential to decrease plasma concentrations of cobicistat, atazanavir and darunavir, which may lead to loss of therapeutic effect and development of resistance (see TABLE 6).
Coadministration of Cobicistat with atazanavir or darunavir in combination with other drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat, atazanavir and darunavir (see TABLE 6).
Coadministration of Cobicistat with fosamprenavir, saquinavir, or tipranavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Use of Cobicistat with lopinavir is not recommended because lopinavir is co-formulated with ritonavir.
Drug interaction trials were not conducted for Cobicistat in combination with atazanavir or darunavir. As a single entity, drug interaction trials were conducted with Cobicistat and desipramine, digoxin, and efavirenz. Drug interaction trials of Cobicistat coadministered with elvitegravir were conducted that included rosuvastatin and rifabutin.
Table 6 provides dosing recommendations as a result of drug interactions with Cobicistat. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect.
In Table 6, if not specifically stated, the drug interaction information applies to both coadministered agents: Cobicistat coadministered with atazanavir or darunavir.
In addition to the drug interactions noted in Table 6, Cobicistat is not recommended for use in combination with STRIBILD tablets, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement.
Evaluate whether dosing adjustments of concomitant medications or coadministered antiretroviral drugs are necessary in:
- Patients on a stable concomitant medication who initiate or switch to a Cobicistat-containing regimen
- Patients on a Cobicistat-containing regimen who initiate a new concomitant medication
- Patients initiating a Cobicistat-containing regimen and a new concomitant medication simultaneously
Under these circumstances, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate.
No dose adjustment is required when tenofovir DF or rilpivirine are coadministered with Cobicistat and atazanavir or darunavir.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled trials of Cobicistat in pregnant women. Because animal reproduction studies are not always predictive of human response, Cobicistat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Studies of cobicistat in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 1.4 and 3.3 times higher than the exposure in humans at the recommended daily dose of 150 mg.
Pregnancy Category (AUS): B1
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cobicistat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cobicistat during labor and delivery.
### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that cobicistat is secreted in milk. It is not known whether cobicistat is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, instruct mothers not to breastfeed.
### Pediatric Use
Safety and effectiveness of Cobicistat in pediatric patients less than 18 years of age have not been established.
### Geriatic Use
Clinical trials of Cobicistat did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat.
### Race
Population pharmacokinetic analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat.
### Renal Impairment
No dosage adjustment of Cobicistat is required in patients with renal impairment, including those with severe renal impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. Cobicistat is coadministered with atazanavir or darunavir; therefore, refer to the prescribing information for atazanavir or darunavir for information regarding dosing recommendations of these drugs in patients with renal impairment.
Cobicistat has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosing adjustment for renal impairment when used in combination with Cobicistat.
### Hepatic Impairment
No dosing adjustment of Cobicistat is necessary for patients with mild-to-moderate hepatic impairment. No data are available in patients with severe hepatic impairment. Cobicistat is coadministered with atazanavir or darunavir and other antiretroviral drugs; therefore, refer to the prescribing information of these other drugs for information regarding dosing recommendations in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.
### Immunocompromised Patients
There is no FDA guidance one the use of Cobicistat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Cobicistat Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Cobicistat and IV administrations.
# Overdosage
If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with Cobicistat consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.
As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
# Pharmacology
## Mechanism of Action
Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir.
## Structure
It has the following structural formula:
## Pharmacodynamics
The effect of Cobicistat on atazanavir pharmacokinetics was evaluated in the pharmacokinetic substudy (N=48) of Study 114 in which HIV-1 infected subjects received atazanavir 300 mg coadministered with Cobicistat 150 mg or atazanavir 300 mg coadministered with ritonavir 100 mg, both in combination with TRUVADA. The steady-state pharmacokinetic parameters of atazanavir were comparable when coadministered with Cobicistat versus ritonavir groups as shown in Table 7.
The effect of Cobicistat on darunavir was evaluated in a clinical study (Study 115) in 31 healthy subjects who received darunavir 800 mg in combination with Cobicistat 150 mg or ritonavir 100 mg, all once daily, for 10 days. With the exception of Ctau, the steady-state pharmacokinetic parameters of darunavir were comparable when coadministered with Cobicistat versus ritonavir as shown in Table 8, and these results were similar to those reported in previous clinical trials of darunavir 800 mg with ritonavir 100 mg once daily (refer to prescribing information for darunavir).
The effect of a single dose of cobicistat 250 mg and 400 mg (approximately 1.7 and 2.7 times the recommended dose) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 48 healthy subjects. In this study, no significant QTc prolongation effect of cobicistat was detected. The dose of 400 mg Cobicistat is expected to cover a high exposure clinical scenario. Prolongation of the PR interval was noted in subjects receiving Cobicistat in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg of cobicistat.
The effect of Cobicistat on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50–79 mL/min, N=18). A statistically significant decrease in the estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFRCG) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (-11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of Cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate.
## Pharmacokinetics
A trial where subjects were instructed to take coadministered Cobicistat and darunavir with food, median cobicistat peak plasma concentrations were observed was approximately 3.5 hours post-dose. Steady-state cobicistat Cmax, AUCtau, and Ctau (mean ± SD), values were 0.99 ± 0.3 mcg/mL (n=60), 7.6 ± 3.7 mcg*hr/mL (n=59), and 0.03 ± 0.1 mcg/mL (n=59), respectively.
A food effect trial was not conducted for Cobicistat. In clinical trials, Cobicistat was coadministered with other antiretroviral agents under fed conditions, in accordance with the prescribing information for these agents. It is recommended that Cobicistat coadministered with atazanavir or darunavir be administered with food.
Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.
Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.
The terminal plasma half-life of cobicistat following administration of Cobicistat is approximately 3 to 4 hours. With single dose administration of cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.
## Nonclinical Toxicology
Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat.
In an analysis of treatment-failure subjects who received Cobicistat coadministered with atazanavir and TRUVADA in Study 114 through Week 48, evaluable genotypic data from paired baseline and treatment-failure isolates were available for 11 of the 12 virologic failures in the Cobicistat group . Among the 11 subjects, 2 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data was available for all 12 virologic failures and no subject had emergent resistance to any component of the regimen.
In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.
Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
# Clinical Studies
The activity of Cobicistat as a CYP3A inhibitor to increase the systemic exposures of atazanavir or darunavir has been demonstrated in pharmacokinetic trials. In these trials, the exposure of atazanavir or darunavir coadministered with Cobicistat 150 mg was consistent with those observed with ritonavir 100 mg. For clinical efficacy of darunavir/ritonavir 800/100 mg once daily, refer to the prescribing information for darunavir.
The safety and efficacy of Cobicistat coadministered with atazanavir were evaluated in a randomized, double-blind, active-controlled trial (Study 114) in HIV-1 infected treatment-naïve subjects with baseline estimated creatinine clearance above 70 mL/min (N=692). In Study 114, subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg + Cobicistat 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of tenofovir DF and 200 mg of emtricitabine once a day administered as single tablet TRUVADA. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).
The mean age of subjects was 37 years (range 19–70); 83% were male, 60% were White, 18% were Black and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 3.2–6.4). Forty percent of patients had baseline viral loads >100,000 copies/mL. The mean baseline CD4+ cell count was 352 cells/mm3 (range 1–1455) and 17% had CD4+ cell counts ≤200 cells/mm3.
Virologic outcomes in Study 114 through Week 48 are presented in Table 10. In Study 114, the mean increase from baseline in CD4+ cell count at Week 48 was 213 cells/mm3 in the Cobicistat group and 219 cells/mm3 in the ritonavir group.
# How Supplied
- Cobicistat tablets, 150 mg
- Each bottle contains 30 tablets (NDC 61958-1401-1)
## Storage
Store at 25 °C (77 °F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with Cobicistat. A Patient Package Insert for Cobicistat is available for patient information.
- Inform patients that they should remain under the care of a healthcare provider when using Cobicistat.
- Inform patients that Cobicistat must be taken at the same time as atazanavir or darunavir and with food once daily as prescribed. It is important to take Cobicistat and atazanavir or darunavir together on a regular dosing schedule and to avoid missing doses. Patients should be counseled about the risks of developing resistance to their HIV-1 medications.
Inform patients not to miss a dose of Cobicistat with atazanavir taken together or Cobicistat with darunavir taken together. If a dose of Cobicistat and atazanavir or darunavir is missed by less than 12 hours, the missed dose of Cobicistat with atazanavir or darunavir should be taken together right away. The next dose of Cobicistat with atazanavir or darunavir should be taken together as usual. If a dose of Cobicistat with atazanavir or darunavir is missed by more than 12 hours, the patient should wait and take the next dose at the usual time. If a dose of Cobicistat with atazanavir or darunavir is skipped, the patient should not double the next dose of Cobicistat with atazanavir or darunavir.
- Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when Cobicistat is used in combination with a tenofovir DF containing regimen.
- Inform patients that Cobicistat may interact with many drugs with potential serious implications and that some drugs should not be taken with Cobicistat. Patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.
- Inform patients that if they must take acid modifying medications during treatment with Cobicistat with atazanavir, the medications should be taken according to the following recommendations:
- an antacid medicine that contains aluminum or magnesium hydroxide: administer antacids at least 2 hours before or after Cobicistat with atazanavir.
- H2-receptor antagonists (e.g., famotidine): administer either at the same time or take Cobicistat with atazanavir a minimum of 10 hours after administering H2-receptor antagonists.
- Proton pump inhibitors (e.g.,omeprazole): take Cobicistat with atazanavir a minimum of 12 hours after administering proton pump inhibitors.
# Precautions with Alcohol
Alcohol-Cobicistat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tybost
# Look-Alike Drug Names
There is limited information regarding Cobicistat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Cobicistat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]
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# Overview
Cobicistat is an anti-infective agent that is FDA approved for the treatment of HIV-1 infection. Common adverse reactions include jaundice and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Cobicistat is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection.
- Dosage:
- Cobicistat 150 mg orally once daily plus atazanavir 300 mg orally once daily; or
- Cobicistat 150 mg orally once daily plus darunavir 800 mg orally once daily
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cobicistat in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cobicistat in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness not established in pediatric patients younger than 18 years
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Cobicistat in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Cobicistat in pediatric patients.
# Contraindications
The concomitant use of Cobicistat with atazanavir or darunavir and the following drugs (see TABLE 2) is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect
# Warnings
Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating Cobicistat, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.
Prior to initiating therapy with Cobicistat, assess estimated creatinine clearance. Dosage recommendations are not available for drugs that require dosage adjustments in Cobicistat-treated patients with renal impairment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
Although Cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when Cobicistat was used in an antiretroviral regimen that contained tenofovir DF.
- Coadministration of Cobicistat and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min because dose adjustment of tenofovir DF is required below 50 mL/min and such dose adjustments have not been established for coadministration with Cobicistat.
- Document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment when Cobicistat is used with tenofovir DF. Measure serum phosphorus in patients with or at risk for renal impairment when used with tenofovir DF.
- Coadministration of Cobicistat and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended.
In the clinical trials of Cobicistat over 48 weeks (N=771), 6 (1.5%) subjects treated with Cobicistat coadministered with atazanavir and TRUVADA® and 6 (1.6%) subjects treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study drug due to a renal adverse event. Five of the 6 subjects (1.3% overall) in the Cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 2 of 6 subjects (0.5% overall) in the ritonavir group. None of the 5 subjects in the Cobicistat group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 5 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of Cobicistat coadministered with atazanavir and TRUVADA. Renal replacement therapy was not required in any subject.
Initiation of Cobicistat, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving Cobicistat may increase plasma concentration of these medications which may increase the risk of clinically significant adverse reactions (including life-threatening or fatal reactions) associated with the concomitant medications. Coadministration of Cobicistat with atazanavir or darunavir in combination with CYP3A inducers may lead to lower exposure of cobicistat and atazanavir or darunavir and loss of efficacy of atazanavir or darunavir and possible resistance. Therefore, consider the potential for drug interactions prior to and during Cobicistat therapy; review concomitant medications during Cobicistat therapy; and monitor for the adverse reactions associated with the concomitant drugs.
Cobicistat or ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain Cobicistat interactions.
The following antiretrovirals are not recommended in combination with Cobicistat because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance:
- More than one antiretroviral that requires pharmacokinetic enhancement (i.e., two protease inhibitors or a protease inhibitor in combination with elvitegravir)
- Darunavir in combination with efavirenz, nevirapine, or etravirine
- Atazanavir in combination with etravirine
- Atazanavir in combination with efavirenz in treatment-experienced patients
- Darunavir 600 mg twice daily
- Other HIV-1 protease inhibitors including fosamprenavir, saquinavir, or tipranavir
Cobicistat in combination with STRIBILD® fixed-dose combination tablets (elvitegravir, cobicistat, emtricitabine, tenofovir DF) is not recommended because cobicistat is a component of STRIBILD.
Cobicistat in combination with lopinavir/ritonavir or regimens containing ritonavir is not recommended due to similar effects of Cobicistat and ritonavir on CYP3A.
# 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 safety of Cobicistat has been established from a Phase 2 trial, Study 105, and a Phase 3 trial, Study 114. In the pooled analysis, 771 HIV-1 infected, antiretroviral treatment-naïve adults received for at least 48 weeks:
- Cobicistat coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=394) or;
- ritonavir coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA ) (N=377).
The most common adverse reactions (all Grades) and reported in >10% of subjects in the Cobicistat group were jaundice (13%), ocular icterus (15%), and nausea (12%); the most common adverse reactions in the ritonavir group were jaundice (11%), ocular icterus (17%), nausea (11%), and diarrhea (11%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 7% in both the Cobicistat and ritonavir group. Table 3 displays the frequency of adverse reactions (Grades 2–4) occurring in at least 2% of subjects in the Cobicistat group in pooled Studies 105 and 114.
Nephrolithiasis has previously been identified in patients receiving atazanavir. In the pooled analysis of Studies 105 and 114 through 48 weeks, 8 subjects (2%) receiving Cobicistat coadministered with atazanavir and TRUVADA developed nephrolithiasis compared with no subjects receiving ritonavir coadministered with atazanavir and TRUVADA. Median time to onset of nephrolithiasis in the Cobicistat group was 24 weeks. Causality in these cases could not be determined with certainty, but the majority of renal stone events were not serious and no subject discontinued study drug.
Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of subjects receiving Cobicistat coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator's assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with Cobicistat and with greater frequency compared with ritonavir.
- Gastrointestinal Disorders: diarrhea, vomiting, upper abdominal pain
- General Disorders and Administration Site Conditions: fatigue
- Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
- Nervous System Disorders: headache
- Psychiatric Disorders: depression, abnormal dreams, insomnia
- Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired
Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects in the Cobicistat group in Studies 105 and 114 is presented in Table 4.
Increase in Serum Creatinine: Cobicistat causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. In Studies 105 and 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with Cobicistat, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 48 weeks of treatment was -13.4 ± 15.2 mL/min in the Cobicistat group and -9.1 ± 14.7 mL/min in the ritonavir group.
Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5. In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown.
## Postmarketing Experience
There is limited information regarding Cobicistat Postmarketing Experience in the drug label.
# Drug Interactions
Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may be increased if those drugs are coadministered with Cobicistat.
Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.
Coadministration of Cobicistat with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6.
Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A.
Coadministration of Cobicistat with atazanavir or darunavir in combination with drugs that induce CYP3A activity have the potential to decrease plasma concentrations of cobicistat, atazanavir and darunavir, which may lead to loss of therapeutic effect and development of resistance (see TABLE 6).
Coadministration of Cobicistat with atazanavir or darunavir in combination with other drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat, atazanavir and darunavir (see TABLE 6).
Coadministration of Cobicistat with fosamprenavir, saquinavir, or tipranavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Use of Cobicistat with lopinavir is not recommended because lopinavir is co-formulated with ritonavir.
Drug interaction trials were not conducted for Cobicistat in combination with atazanavir or darunavir. As a single entity, drug interaction trials were conducted with Cobicistat and desipramine, digoxin, and efavirenz. Drug interaction trials of Cobicistat coadministered with elvitegravir were conducted that included rosuvastatin and rifabutin.
Table 6 provides dosing recommendations as a result of drug interactions with Cobicistat. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect.
In Table 6, if not specifically stated, the drug interaction information applies to both coadministered agents: Cobicistat coadministered with atazanavir or darunavir.
In addition to the drug interactions noted in Table 6, Cobicistat is not recommended for use in combination with STRIBILD tablets, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement.
Evaluate whether dosing adjustments of concomitant medications or coadministered antiretroviral drugs are necessary in:
- Patients on a stable concomitant medication who initiate or switch to a Cobicistat-containing regimen
- Patients on a Cobicistat-containing regimen who initiate a new concomitant medication
- Patients initiating a Cobicistat-containing regimen and a new concomitant medication simultaneously
Under these circumstances, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate.
No dose adjustment is required when tenofovir DF or rilpivirine are coadministered with Cobicistat and atazanavir or darunavir.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled trials of Cobicistat in pregnant women. Because animal reproduction studies are not always predictive of human response, Cobicistat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Studies of cobicistat in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 1.4 and 3.3 times higher than the exposure in humans at the recommended daily dose of 150 mg.
Pregnancy Category (AUS): B1
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cobicistat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Cobicistat during labor and delivery.
### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that cobicistat is secreted in milk. It is not known whether cobicistat is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, instruct mothers not to breastfeed.
### Pediatric Use
Safety and effectiveness of Cobicistat in pediatric patients less than 18 years of age have not been established.
### Geriatic Use
Clinical trials of Cobicistat did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat.
### Race
Population pharmacokinetic analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat.
### Renal Impairment
No dosage adjustment of Cobicistat is required in patients with renal impairment, including those with severe renal impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects. Cobicistat is coadministered with atazanavir or darunavir; therefore, refer to the prescribing information for atazanavir or darunavir for information regarding dosing recommendations of these drugs in patients with renal impairment.
Cobicistat has been shown to decrease estimated creatinine clearance without affecting actual renal glomerular function. Dosing recommendations are not available for drugs that require dosing adjustment for renal impairment when used in combination with Cobicistat.
### Hepatic Impairment
No dosing adjustment of Cobicistat is necessary for patients with mild-to-moderate hepatic impairment. No data are available in patients with severe hepatic impairment. Cobicistat is coadministered with atazanavir or darunavir and other antiretroviral drugs; therefore, refer to the prescribing information of these other drugs for information regarding dosing recommendations in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.
### Immunocompromised Patients
There is no FDA guidance one the use of Cobicistat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Cobicistat Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Cobicistat and IV administrations.
# Overdosage
If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with Cobicistat consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.
As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
# Pharmacology
## Mechanism of Action
Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir.
## Structure
It has the following structural formula:
## Pharmacodynamics
The effect of Cobicistat on atazanavir pharmacokinetics was evaluated in the pharmacokinetic substudy (N=48) of Study 114 in which HIV-1 infected subjects received atazanavir 300 mg coadministered with Cobicistat 150 mg or atazanavir 300 mg coadministered with ritonavir 100 mg, both in combination with TRUVADA. The steady-state pharmacokinetic parameters of atazanavir were comparable when coadministered with Cobicistat versus ritonavir groups as shown in Table 7.
The effect of Cobicistat on darunavir was evaluated in a clinical study (Study 115) in 31 healthy subjects who received darunavir 800 mg in combination with Cobicistat 150 mg or ritonavir 100 mg, all once daily, for 10 days. With the exception of Ctau, the steady-state pharmacokinetic parameters of darunavir were comparable when coadministered with Cobicistat versus ritonavir as shown in Table 8, and these results were similar to those reported in previous clinical trials of darunavir 800 mg with ritonavir 100 mg once daily (refer to prescribing information for darunavir).
The effect of a single dose of cobicistat 250 mg and 400 mg (approximately 1.7 and 2.7 times the recommended dose) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 48 healthy subjects. In this study, no significant QTc prolongation effect of cobicistat was detected. The dose of 400 mg Cobicistat is expected to cover a high exposure clinical scenario. Prolongation of the PR interval was noted in subjects receiving Cobicistat in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg of cobicistat.
The effect of Cobicistat on serum creatinine was investigated in a trial in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50–79 mL/min, N=18). A statistically significant decrease in the estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFRCG) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (-9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (-11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment of Cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate.
## Pharmacokinetics
A trial where subjects were instructed to take coadministered Cobicistat and darunavir with food, median cobicistat peak plasma concentrations were observed was approximately 3.5 hours post-dose. Steady-state cobicistat Cmax, AUCtau, and Ctau (mean ± SD), values were 0.99 ± 0.3 mcg/mL (n=60), 7.6 ± 3.7 mcg*hr/mL (n=59), and 0.03 ± 0.1 mcg/mL (n=59), respectively.
A food effect trial was not conducted for Cobicistat. In clinical trials, Cobicistat was coadministered with other antiretroviral agents [see CLINICAL STUDIES (14)] under fed conditions, in accordance with the prescribing information for these agents. It is recommended that Cobicistat coadministered with atazanavir or darunavir be administered with food.
Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.
Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.
The terminal plasma half-life of cobicistat following administration of Cobicistat is approximately 3 to 4 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.
## Nonclinical Toxicology
Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat.
In an analysis of treatment-failure subjects who received Cobicistat coadministered with atazanavir and TRUVADA in Study 114 through Week 48, evaluable genotypic data from paired baseline and treatment-failure isolates were available for 11 of the 12 virologic failures in the Cobicistat group [3%, 11/344]. Among the 11 subjects, 2 developed the emtricitabine-associated resistance substitution M184V. No subject developed the tenofovir-associated resistance substitution K65R or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data was available for all 12 virologic failures [3%, 12/348] and no subject had emergent resistance to any component of the regimen.
In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.
Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
# Clinical Studies
The activity of Cobicistat as a CYP3A inhibitor to increase the systemic exposures of atazanavir or darunavir has been demonstrated in pharmacokinetic trials. In these trials, the exposure of atazanavir or darunavir coadministered with Cobicistat 150 mg was consistent with those observed with ritonavir 100 mg. For clinical efficacy of darunavir/ritonavir 800/100 mg once daily, refer to the prescribing information for darunavir.
The safety and efficacy of Cobicistat coadministered with atazanavir were evaluated in a randomized, double-blind, active-controlled trial (Study 114) in HIV-1 infected treatment-naïve subjects with baseline estimated creatinine clearance above 70 mL/min (N=692). In Study 114, subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg + Cobicistat 150 mg once daily or atazanavir 300 mg + ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of tenofovir DF and 200 mg of emtricitabine once a day administered as single tablet TRUVADA. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL).
The mean age of subjects was 37 years (range 19–70); 83% were male, 60% were White, 18% were Black and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range 3.2–6.4). Forty percent of patients had baseline viral loads >100,000 copies/mL. The mean baseline CD4+ cell count was 352 cells/mm3 (range 1–1455) and 17% had CD4+ cell counts ≤200 cells/mm3.
Virologic outcomes in Study 114 through Week 48 are presented in Table 10. In Study 114, the mean increase from baseline in CD4+ cell count at Week 48 was 213 cells/mm3 in the Cobicistat group and 219 cells/mm3 in the ritonavir group.
# How Supplied
- Cobicistat tablets, 150 mg
- Each bottle contains 30 tablets (NDC 61958-1401-1)
## Storage
Store at 25 °C (77 °F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with Cobicistat. A Patient Package Insert for Cobicistat is available for patient information.
- Inform patients that they should remain under the care of a healthcare provider when using Cobicistat.
- Inform patients that Cobicistat must be taken at the same time as atazanavir or darunavir and with food once daily as prescribed. It is important to take Cobicistat and atazanavir or darunavir together on a regular dosing schedule and to avoid missing doses. Patients should be counseled about the risks of developing resistance to their HIV-1 medications.
Inform patients not to miss a dose of Cobicistat with atazanavir taken together or Cobicistat with darunavir taken together. If a dose of Cobicistat and atazanavir or darunavir is missed by less than 12 hours, the missed dose of Cobicistat with atazanavir or darunavir should be taken together right away. The next dose of Cobicistat with atazanavir or darunavir should be taken together as usual. If a dose of Cobicistat with atazanavir or darunavir is missed by more than 12 hours, the patient should wait and take the next dose at the usual time. If a dose of Cobicistat with atazanavir or darunavir is skipped, the patient should not double the next dose of Cobicistat with atazanavir or darunavir.
- Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when Cobicistat is used in combination with a tenofovir DF containing regimen.
- Inform patients that Cobicistat may interact with many drugs with potential serious implications and that some drugs should not be taken with Cobicistat. Patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.
- Inform patients that if they must take acid modifying medications during treatment with Cobicistat with atazanavir, the medications should be taken according to the following recommendations:
- an antacid medicine that contains aluminum or magnesium hydroxide: administer antacids at least 2 hours before or after Cobicistat with atazanavir.
- H2-receptor antagonists (e.g., famotidine): administer either at the same time or take Cobicistat with atazanavir a minimum of 10 hours after administering H2-receptor antagonists.
- Proton pump inhibitors (e.g.,omeprazole): take Cobicistat with atazanavir a minimum of 12 hours after administering proton pump inhibitors.
# Precautions with Alcohol
Alcohol-Cobicistat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tybost [1]
# Look-Alike Drug Names
There is limited information regarding Cobicistat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Cobicistat | |
0d70167a42f175a6c9e5c37cc779172c80025e85 | wikidoc | Coccydynia | Coccydynia
Synonyms and keywords: Coccygodynia, coccygeal pain, coccyx pain, coccaglia or (in layperson's terms) buttache.
# Overview
Coccydynia is a medical term meaning pain in the coccyx or tailbone area, usually brought on by sitting.
# Natural History
In many cases the exact cause is not known.
Coccydynia is often reported following a fall or after childbirth. In some cases, persistent pressure from activities like bicycling may cause the onset of coccyx pain. Coccydynia due to these causes usually is not permanent, but it may become very persistent and chronic if not controlled.
Rarely, coccydynia is due to the undiagnosed presence of a sacrococcygeal teratoma or other tumor in the vicinity of the coccyx. In these cases, appropriate treatment usually involves surgery and/or chemotherapy.
# Diagnosis
A number of different conditions can cause pain in the general area of the coccyx, but not all involve the coccyx and the muscles attached to it. The first task of diagnosis is to determine whether the pain is related to the coccyx. Physical examination, high resolution x-rays and MRI scans can rule out various causes unrelated to the coccyx, such as Tarlov cysts and pain referred from higher up the spine. Note that, contrary to most anatomical text books, most coccyxes consist of several segments: 'fractured coccyx' is often diagnosed when the coccyx is in fact normal or just dislocated at an intercoccygeal joint .
A simple test to determine whether the coccyx is involved is injection of local anesthetic into the area. If the pain relates to the coccyx, this should produce immediate relief .
If the anesthetic test proves positive, then a dynamic (sit/stand) x-ray or MRI scan may show whether the coccyx dislocates when the patient sits .
Use of dynamic x-rays on 208 patients who gave positive results with the anesthetic test showed:
- 22% Posterior luxation (partial dislocation of the coccyx backwards when sitting)
- 5% Anterior luxation (partial dislocation of the coccyx forwards when sitting)
- 27% Hypermobility (excessive flexing of the coccyx forwards and upwards when sitting)
- 14% Spicule (bony spur) on the coccyx
- 31% Not possible to identify the cause of pain
This study found that the pattern of lesions was different depending on the obesity of the patients: obese patients were most likely to have posterior luxation of the coccyx, while thin patients were most likely to have coccygeal spicules.
# Clinical Features
Activities that put pressure on the affected area are bicycling, horseback riding, and other activities such as increased sitting that put direct stress on the coccyx. The medical condition is often characterized by pain that worsens with constipation and may be relieved with bowel movement. Rarely, even sexual intercourse can aggravate symptoms.
# Non-Surgical Treatment
Since sitting on the affected area may aggravate the condition, a cushion with a cutout at the back under the coccyx is recommended (the donut cushion traditionally recommended by doctors is generally useless for this condition). If there is tailbone pain with bowel movements, then stool softeners and increased fiber in the diet may help. For prolonged cases, anti-inflammatory or pain-relieving drugs may be prescribed. The use of anti-depressants such as Elavil (amiltriptyline) may help alleviate constant pain. Local nerve blocks are often beneficial. Tailbone pain doctors specializing in Physical Medicine and Rehabilitation at New Jersey Medical School have published that sometimes even just a single local nerve block injection at the ganglion impar can give 100% relief of coccydynia when performed under fluoroscopic guidance. Reference Foye 2006
# Surgical Treatment
In rare cases, surgery to remove the coccyx (coccygectomy) may be required.
# Related Chapters
- Ganglion impar
- Coccyx (tailbone) | Coccydynia
Template:DiseaseDisorder infobox
Editor-In-Chief: Patrick Foye, MD, Associate Professor, and Director, Coccyx Pain Service, New Jersey Medical School [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Synonyms and keywords: Coccygodynia, coccygeal pain, coccyx pain, coccaglia or (in layperson's terms) buttache.
# Overview
Coccydynia is a medical term meaning pain in the coccyx or tailbone area, usually brought on by sitting.
# Natural History
In many cases the exact cause is not known.
Coccydynia is often reported following a fall or after childbirth. In some cases, persistent pressure from activities like bicycling may cause the onset of coccyx pain. [1] Coccydynia due to these causes usually is not permanent, but it may become very persistent and chronic if not controlled.
Rarely, coccydynia is due to the undiagnosed presence of a sacrococcygeal teratoma or other tumor in the vicinity of the coccyx. In these cases, appropriate treatment usually involves surgery and/or chemotherapy.
# Diagnosis
A number of different conditions can cause pain in the general area of the coccyx, but not all involve the coccyx and the muscles attached to it. The first task of diagnosis is to determine whether the pain is related to the coccyx. Physical examination, high resolution x-rays and MRI scans can rule out various causes unrelated to the coccyx, such as Tarlov cysts and pain referred from higher up the spine. Note that, contrary to most anatomical text books, most coccyxes consist of several segments: 'fractured coccyx' is often diagnosed when the coccyx is in fact normal or just dislocated at an intercoccygeal joint [2] [3].
A simple test to determine whether the coccyx is involved is injection of local anesthetic into the area. If the pain relates to the coccyx, this should produce immediate relief [4].
If the anesthetic test proves positive, then a dynamic (sit/stand) x-ray or MRI scan may show whether the coccyx dislocates when the patient sits [5].
Use of dynamic x-rays on 208 patients who gave positive results with the anesthetic test showed:
- 22% Posterior luxation (partial dislocation of the coccyx backwards when sitting)
- 5% Anterior luxation (partial dislocation of the coccyx forwards when sitting)
- 27% Hypermobility (excessive flexing of the coccyx forwards and upwards when sitting)
- 14% Spicule (bony spur) on the coccyx
- 31% Not possible to identify the cause of pain
This study found that the pattern of lesions was different depending on the obesity of the patients: obese patients were most likely to have posterior luxation of the coccyx, while thin patients were most likely to have coccygeal spicules.
# Clinical Features
Activities that put pressure on the affected area are bicycling, horseback riding, and other activities such as increased sitting that put direct stress on the coccyx. The medical condition is often characterized by pain that worsens with constipation and may be relieved with bowel movement. Rarely, even sexual intercourse can aggravate symptoms.
# Non-Surgical Treatment
Since sitting on the affected area may aggravate the condition, a cushion with a cutout at the back under the coccyx is recommended (the donut cushion traditionally recommended by doctors is generally useless for this condition). If there is tailbone pain with bowel movements, then stool softeners and increased fiber in the diet may help. For prolonged cases, anti-inflammatory or pain-relieving drugs may be prescribed. The use of anti-depressants such as Elavil (amiltriptyline) may help alleviate constant pain. Local nerve blocks are often beneficial. Tailbone pain doctors specializing in Physical Medicine and Rehabilitation at New Jersey Medical School have published that sometimes even just a single local nerve block injection at the ganglion impar can give 100% relief of coccydynia when performed under fluoroscopic guidance. Reference Foye 2006
# Surgical Treatment
In rare cases, surgery to remove the coccyx (coccygectomy) may be required.
# Related Chapters
- Ganglion impar
- Coccyx (tailbone) | https://www.wikidoc.org/index.php/Coccydynia | |
dc713acd53beabbdf434ade926e6b7b58add9299 | wikidoc | Coercivity | Coercivity
In materials science, the coercivity, also called the coercive field, of a ferromagnetic material is the intensity of the applied magnetic field required to reduce the magnetization of that material to zero after the magnetization of the sample has been driven to saturation. Coercivity is usually measured in oersted or ampere/meter units and is denoted HC.
When the coercive field of a ferromagnet is large, the material is said to be a hard or permanent magnet. Permanent magnets find application in electric motors, magnetic recording media (e.g. hard drives, floppy disks, or magnetic tape) and magnetic separation. A ferromagnet with a low coercive field is said to be soft and may be used in microwave devices, magnetic shielding, transformers or recording heads.
Coercivity can be measured using a B-H Analyzer.
# Experimental determination
Typically the coercivity of a magnetic material is determined by measurement of the hysteresis loop or magnetization curve as illustrated in the figure. The apparatus used to acquire the data is typically a vibrating-sample or alternating-gradient magnetometer. The applied field where the data (called a magnetization curve) crosses zero is the coercivity. If an antiferromagnetic solid is present in the sample, the coercivities measured in increasing and decreasing fields may be unequal as a result of the exchange bias effect.
The coercivity of a material depends on the time scale over which a magnetization curve is measured. The magnetization of a material measured at an applied reversed field which is nominally smaller than the coercivity may, over a long time scale, slowly creep to zero. Creep occurs when reversal of magnetization by domain wall motion is thermally activated and is dominated by magnetic viscosity. The increasing value of coercivity at high frequencies is a serious obstacle to the increase of data rates in high-bandwidth magnetic recording, compounded by the fact that increased storage density typically requires a higher coercivity in the media.
# Theory
At the coercive field, the vector component of the magnetization of a ferromagnet measured along the applied field direction is zero. There are two primary modes of magnetization reversal: rotation and domain wall motion. When the magnetization of a material reverses by rotation, the magnetization component along the applied field is zero because the vector points in a direction orthogonal to the applied field. When the magnetization reverses by domain wall motion, the net magnetization is small in every vector direction because the moments of all the individual domains sum to zero. Magnetization curves dominated by rotation and magnetocrystalline anisotropy are found in relatively perfect magnetic materials used in fundamental research. Domain wall motion is a more important reversal mechanism in real engineering materials since defects like grain boundaries and impurities serve as nucleation sites for reversed-magnetization domains. The role of domain walls in determining coercivity is complex since defects may pin domain walls in addition to nucleating them. The dynamics of domain walls in ferromagnets is similar to that of grain boundaries and plasticity in metallurgy since both domain walls and grain boundaries are planar defects.
# Significance
As with any hysteretic process, the area inside the magnetization curve during one cycle is work that is performed on the magnet. Common dissipative processes in magnetic materials include magnetostriction and domain wall motion. The coercivity is a measure of the degree of magnetic hysteresis and therefore characterizes the lossiness of soft magnetic materials for their common applications.
The squareness (M(H=0)/Ms) and coercivity are figures of merit for hard magnets although energy product (saturation magnetization times coercivity) is most commonly quoted. The 1980s saw the development of rare earth boride magnets with high energy products but undesirably low Curie temperatures. Since the 1990s new exchange spring hard magnets with high coercivities have been developed. | Coercivity
In materials science, the coercivity, also called the coercive field, of a ferromagnetic material is the intensity of the applied magnetic field required to reduce the magnetization of that material to zero after the magnetization of the sample has been driven to saturation. Coercivity is usually measured in oersted or ampere/meter units and is denoted HC.
When the coercive field of a ferromagnet is large, the material is said to be a hard or permanent magnet. Permanent magnets find application in electric motors, magnetic recording media (e.g. hard drives, floppy disks, or magnetic tape) and magnetic separation. A ferromagnet with a low coercive field is said to be soft and may be used in microwave devices, magnetic shielding, transformers or recording heads.
Coercivity can be measured using a B-H Analyzer.
# Experimental determination
Typically the coercivity of a magnetic material is determined by measurement of the hysteresis loop or magnetization curve as illustrated in the figure. The apparatus used to acquire the data is typically a vibrating-sample or alternating-gradient magnetometer. The applied field where the data (called a magnetization curve) crosses zero is the coercivity. If an antiferromagnetic solid is present in the sample, the coercivities measured in increasing and decreasing fields may be unequal as a result of the exchange bias effect.
The coercivity of a material depends on the time scale over which a magnetization curve is measured. The magnetization of a material measured at an applied reversed field which is nominally smaller than the coercivity may, over a long time scale, slowly creep to zero. Creep occurs when reversal of magnetization by domain wall motion is thermally activated and is dominated by magnetic viscosity. The increasing value of coercivity at high frequencies is a serious obstacle to the increase of data rates in high-bandwidth magnetic recording, compounded by the fact that increased storage density typically requires a higher coercivity in the media.
# Theory
At the coercive field, the vector component of the magnetization of a ferromagnet measured along the applied field direction is zero. There are two primary modes of magnetization reversal: rotation and domain wall motion. When the magnetization of a material reverses by rotation, the magnetization component along the applied field is zero because the vector points in a direction orthogonal to the applied field. When the magnetization reverses by domain wall motion, the net magnetization is small in every vector direction because the moments of all the individual domains sum to zero. Magnetization curves dominated by rotation and magnetocrystalline anisotropy are found in relatively perfect magnetic materials used in fundamental research[1]. Domain wall motion is a more important reversal mechanism in real engineering materials since defects like grain boundaries and impurities serve as nucleation sites for reversed-magnetization domains. The role of domain walls in determining coercivity is complex since defects may pin domain walls in addition to nucleating them. The dynamics of domain walls in ferromagnets is similar to that of grain boundaries and plasticity in metallurgy since both domain walls and grain boundaries are planar defects.
# Significance
As with any hysteretic process, the area inside the magnetization curve during one cycle is work that is performed on the magnet. Common dissipative processes in magnetic materials include magnetostriction and domain wall motion. The coercivity is a measure of the degree of magnetic hysteresis and therefore characterizes the lossiness of soft magnetic materials for their common applications.
The squareness (M(H=0)/Ms)[citation needed] and coercivity are figures of merit for hard magnets although energy product (saturation magnetization times coercivity) is most commonly quoted. The 1980s saw the development of rare earth boride magnets with high energy products but undesirably low Curie temperatures. Since the 1990s new exchange spring hard magnets with high coercivities have been developed. | https://www.wikidoc.org/index.php/Coercivity | |
dc17cfc7f579f2349d4990a08a523b8b5cda1b6a | wikidoc | Colchicine | Colchicine
# Disclaimer
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# Overview
Colchicine is an alkaloid that is FDA approved for the treatment of gout flares in adults and familial mediterranean fever (FMF) in adults and children 4 years or older. Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting, and pharyngolaryngeal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Prophylaxis of Gout Flares:
- The recommended dosage of COLCRYS for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily. The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.
- Treatment of Gout Flares:
- The recommended dose of COLCRYS for treatment of a gout flare is 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1 hour period. COLCRYS may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.
- Dosing Information
- The recommended dosage of COLCRYS for FMF in adults is 1.2 mg to 2.4 mg daily.
- Concomitant Therapy:
- Co-administration of COLCRYS with drugs known to inhibit CYP3A4 and/or P-glycoprotein (P-gp) increases the risk of colchicine-induced toxic effects (Table 1). If patients are taking or have recently completed treatment with drugs listed in Table 1 within the prior 14 days, the dose adjustments are as shown on the table below.
- Prophylaxis of Gout Flares:
- For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring.
- Treatment of Gout Flares:
- For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks.
- Treatment of gout flares with COLCRYS is not recommended in patients with renal impairment who are receiving COLCRYS for prophylaxis.
- FMF:
- Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing dialysis. For these patients, the dosage should be reduced. Patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment should be monitored closely for adverse effects of COLCRYS. Dose reduction may be necessary. For patients with severe renal failure (Clcr less than 30 mL/minute), start with 0.3 mg/day; any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine. For patients undergoing dialysis, the total recommended starting dose should be 0.3 mg (half tablet) per day. Dosing can be increased with close monitoring. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Colchicine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Topical colchicine 0.5% or 1% (incorporated into hydrophilic ointment or gel).
- Dosing Information
- Colchicine dosage of greater than 1.5 mg/day.
- Dosing Information
- Oral colchicine 0.5 mg three times daily.
- Dosing Information
- Colchicine 0.5 milligrams twice daily.
- Dosing Information
- 10 mL 0.5% colchicine solution.
- Dosing Information
- Colchicine (0.6 milligram 3 times daily).
- Dosing Information
- Colchicine 1 to 2 mg on day 1 followed by 0.5 to 1 mg/day in 2 divided doses every 12 hours for 6 months.
- Dosing Information
- colchicine 1 mg every 12 hours.
- Dosing Information
- Prophylactic colchicine 0.6 milligram twice daily orally .
- Dosing Information
- Colchicine 0.02 milligram/kilogram/day for 2 to 4 months.
- Dosing Information
- Colchicine (0.5 to 0.6 milligram 2 to 3 times daily).
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The recommended dosage of COLCRYS for FMF in pediatric patients 4 years of age and older is based on age. The following daily doses may be given as a single or divided dose twice daily:
Children 4 – 6 years: 0.3 mg to 1.8 mg daily
Children 6 – 12 years: 0.9 mg to 1.8 mg daily
Adolescents older than 12 years: 1.2 mg to 2.4 mg daily
- Children 4 – 6 years: 0.3 mg to 1.8 mg daily
- Children 6 – 12 years: 0.9 mg to 1.8 mg daily
- Adolescents older than 12 years: 1.2 mg to 2.4 mg daily
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Colchicine in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Colchicine 0.5 milligrams twice daily.
- Dosing Information
- Colchicine (0.25 to 0.5 milligrams daily for 6 months).
# Contraindications
- Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses.
# Warnings
### Precautions
- Fatal Overdose
- Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. COLCRYS should be kept out of the reach of children.
- Blood Dyscrasias
- Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.
- Drug Interactions
- Colchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient's dose of colchicine may need to be reduced or interrupted. Use of COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment.
- Neuromuscular Toxicity
- Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves associated with myotoxicity) or cyclosporine with COLCRYS may potentiate the development of myopathy. Once colchicine is stopped, the symptoms generally resolve within 1 week to several months.
# Adverse Reactions
## Clinical Trials Experience
Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.
In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over 1 hour) of COLCRYS compared to 77% of patients taking a non-recommended high-dose (4.8 mg over 6 hours) of colchicine and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with COLCRYS treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the non-recommended high-dose colchicine regimen but did not occur in the recommended low-dose COLCRYS regimen.
## Postmarketing Experience
- Serious toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous systems.
- These most often occur with excessive accumulation or overdosage.
- The following adverse reactions have been reported with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine.
Sensory motor neuropathy
Alopecia, maculopapular rash, purpura, rash
Abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting
Leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia
Elevated AST, elevated ALT
Myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis
Azoospermia, oligospermia
# Drug Interactions
- COLCRYS (colchicine) is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If COLCRYS is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.
- Physicians should ensure that patients are suitable candidates for treatment with COLCRYS and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of COLCRYS toxicity should be evaluated promptly and, if toxicity is suspected, COLCRYS should be discontinued immediately.
- Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth, or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever (FMF). Although animal reproductive and developmental studies were not conducted with COLCRYS, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity, teratogenicity, and altered postnatal development at exposures within or above the clinical therapeutic range. COLCRYS 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 Colchicine in women who are pregnant.
### Labor and Delivery
- The effect of colchicine on labor and delivery is unknown.
### Nursing Mothers
- Colchicine is excreted into human milk. Limited information suggests that exclusively breast-fed infants receive less than 10 percent of the maternal weight-adjusted dose. While there are no published reports of adverse effects in breast-feeding infants of mothers taking colchicine, colchicine can affect gastrointestinal cell renewal and permeability. Caution should be exercised and breast-feeding infants should be observed for adverse effects when COLCRYS is administered to a nursing woman.
### Pediatric Use
- The safety and efficacy of colchicine in children of all ages with FMF has been evaluated in uncontrolled studies. There does not appear to be an adverse effect on growth in children with FMF treated long-term with colchicine. Gout is rare in pediatric patients, safety and effectiveness of colchicine in pediatric patients has not been established.
### Geriatic Use
- Clinical studies with colchicine for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease, or other drug therapy.
### Gender
There is no FDA guidance on the use of Colchicine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Colchicine with respect to specific racial populations.
### Renal Impairment
- Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis.
- Prophylaxis of Gout Flares:
- For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring.
- Treatment of Gout Flares:
- For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks.
- FMF
- Although, pharmacokinetics of colchicine in patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Clcr less than 30 mL/minute) and end-stage renal disease requiring dialysis, COLCRYS may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of COLCRYS.
### Hepatic Impairment
- The clearance of colchicine may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment, compared to healthy subjects.
- Prophylaxis of Gout Flares:
- For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment.
- Treatment of Gout Flares:
- For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended COLCRYS dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, for the treatment of gout flares in patients with severe impairment while the dose does not need to be adjusted, the treatment course should be repeated no more than once every 2 weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy.
- FMF
- In patients with severe hepatic disease, dose reduction should be considered with careful monitoring.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Colchicine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Colchicine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Colchicine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Colchicine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a 4-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities, such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions, such as myelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg.
The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, diarrhea, and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multi-organ failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion.
### Management
- Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Colchicine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism by which COLCRYS exerts its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β. Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules, and consequently prevents the activation, degranulation, and migration of neutrophils thought to mediate some gout symptoms.
## Structure
- Colchicine is an alkaloid chemically described as (S)N- (5,6,7,9-tetrahydro- 1,2,3, 10-tetramethoxy-9-oxobenzo heptalen-7-yl) acetamide with a molecular formula of C22H25NO6 and a molecular weight of 399.4. The structural formula of colchicine is given below.
- Colchicine occurs as a pale yellow powder that is soluble in water.
- COLCRYS® (colchicine, USP) tablets are supplied for oral administration as purple, film-coated, capsule-shaped tablets (0.1575" × 0.3030"), debossed with 'AR 374' on one side and scored on the other, containing 0.6 mg of the active ingredient colchicine USP. Inactive ingredients: carnauba wax, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Colchicine in the drug label.
## Pharmacokinetics
- Absorption
- In healthy adults, COLCRYS is absorbed when given orally, reaching a mean Cmax of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in 1 to 2 hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions.
- Following oral administration of COLCRYS given as 1.8 mg colchicine over 1 hour to healthy, young adults under fasting conditions, colchicine appears to be readily absorbed, reaching mean maximum plasma concentrations of 6.2 ng/mL at a median 1.81 hours (range: 1.0 to 2.5 hours). Following administration of the non-recommended high-dose regimen (4.8 mg over 6 hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours).
- After 10 days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6.0 ng/mL), occurring 1.3 to 1.4 hours post-dose (range 0.5 to 3.0 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5 below.
- In some subjects, secondary colchicine peaks are seen, occurring between 3 and 36 hours post-dose and ranging from 39% to 155% of the height of the initial peak. These observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation.
- Absolute bioavailability is reported to be approximately 45%.
- Administration of COLCRYS with food has no effect on the rate of colchicine absorption, but did decrease the extent of colchicine by approximately 15%. This is without clinical significance.
- Distribution
- The mean apparent volume of distribution in healthy young volunteers was approximately 5 to 8 L/kg.
- Colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration.
- Colchicine crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration). Colchicine also distributes into breast milk at concentrations similar to those found in the maternal serum.
- Metabolism
- Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine (2- and 3-DMC, respectively), and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2- and 3-DMC. Plasma levels of these metabolites are minimal (less than 5% of parent drug).
- Elimination/Excretion
- In healthy volunteers (n=12) 40 – 65% of 1 mg orally administered colchicine was recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination. Following multiple oral doses (0.6 mg twice daily), the mean elimination half-lives in young healthy volunteers (mean age 25 to 28 years of age) is 26.6 to 31.2 hours. Colchicine is a substrate of P-gp.
- Extracorporeal Elimination: Colchicine is not removed by hemodialysis.
- Special Populations
- There is no difference between men and women in the pharmacokinetic disposition of colchicine.
- Pediatric Patients: Pharmacokinetics of colchicine was not evaluated in pediatric patients.
- Elderly: Pharmacokinetics of colchicine has not been determined in elderly patients. A published report described the pharmacokinetics of 1 mg oral colchicine tablet in four elderly women compared to six young healthy males. The mean age of the four elderly women was 83 years (range 75 – 93), mean weight was 47 kg (38 – 61 kg) and mean creatinine clearance was 46 mL/min (range 25 – 75 mL/min). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males. However, it is possible that the higher exposure in the elderly subjects was due to decreased renal function.
- Renal impairment: Pharmacokinetics of colchicine in patients with mild and moderate renal impairment is not known. A published report described the disposition of colchicine (1 mg) in young adult men and women with FMF who had normal renal function or end-stage renal disease requiring dialysis. Patients with end-stage renal disease had 75% lower colchicine clearance (0.17 vs 0.73 L/hr/kg) and prolonged plasma elimination half-life (18.8 hrs vs 4.4 hrs) as compared to subjects with FMF and normal renal function.
- Hepatic impairment: Published reports on the pharmacokinetics of IV colchicine in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis, and normal renal function suggest wide inter-patient variability. In some subjects with mild to moderate cirrhosis, the clearance of colchicine is significantly reduced and plasma half-life prolonged compared to healthy subjects. In subjects with primary biliary cirrhosis, no consistent trends were noted. No pharmacokinetic data are available for patients with severe hepatic impairment (Child-Pugh C).
- Drug interactions:
- In vitro drug interactions:
- In vitro studies in human liver microsomes have shown that colchicine is not an inhibitor or inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 activity.
- In vivo drug interactions:
- The effects of co-administration of other drugs with COLCRYS on Cmax, AUC, and Cmin are summarized in Table 6 (effect of other drugs on colchicine) and Table 7 (effect of colchicine on other drugs). For information regarding clinical recommendations, see Table 1 in Dose Modification for Co-administration of Interacting Drugs.
- Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum® 1/35) co-administered with COLCRYS (0.6 mg b.i.d. × 14 days), hormone concentrations are not affected.
- In healthy volunteers given theophylline co-administered with COLCRYS (0.6 mg b.i.d. × 14 days), theophylline concentrations were not affected.
## Nonclinical Toxicology
- Carcinogenesis
- Carcinogenicity studies of colchicine have not been conducted. Due to the potential for colchicine to produce aneuploid cells (cells with an unequal number of chromosomes), there is theoretically an increased risk of malignancy.
- Mutagenesis
- Colchicine was negative for mutagenicity in the bacterial reverse mutation assay. In a chromosomal aberration assay in cultured human white blood cells, colchicine treatment resulted in the formation of micronuclei. Since published studies demonstrated that colchicine induces aneuploidy from the process of mitotic nondisjunction without structural DNA changes, colchicine is not considered clastogenic, although micronuclei are formed.
- Impairment of Fertility
- No studies of colchicine effects on fertility were conducted with COLCRYS. However, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. Reproductive studies also reported abnormal sperm morphology and reduced sperm counts in males, and interference with sperm penetration, second meiotic division, and normal cleavage in females when exposed to colchicine. Colchicine administered to pregnant animals resulted in fetal death and teratogenicity. These effects were dose dependent, with the timing of exposure critical for the effects on embryofetal development. The nonclinical doses evaluated were generally higher than an equivalent human therapeutic dose, but safety margins for reproductive and developmental toxicity could not be determined.
- Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare. A case report indicated that azoospermia was reversed when therapy was stopped. Case reports and epidemiology studies in female subjects on colchicine therapy have not established a clear relationship between colchicine use and female infertility. However, since the progression of FMF without treatment may result in infertility, the use of colchicine needs to be weighed against the potential risks.
# Clinical Studies
- The evidence for the efficacy of colchicine in patients with chronic gout is derived from the published literature. Two randomized clinical trials assessed the efficacy of colchicine 0.6 mg twice a day for the prophylaxis of gout flares in patients with gout initiating treatment with urate lowering therapy. In both trials, treatment with colchicine decreased the frequency of gout flares.
- The efficacy of a low dosage regimen of oral colchicine (COLCRYS total dose 1.8 mg over 1 hour) for treatment of gout flares was assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel group, 1 week, dose comparison study. Patients meeting American College of Rheumatology criteria for gout were randomly assigned to three groups: high-dose colchicine (1.2 mg, then 0.6 mg hourly × 6 hours ); low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour followed by 5 placebo doses hourly); or placebo (2 capsules, then 1 capsule hourly × 6 hours). Patients took the first dose within 12 hours of the onset of the flare and recorded pain intensity (11-point Likert scale) and adverse events over 72 hours. The efficacy of colchicine was measured based on response to treatment in the target joint, using patient self assessment of pain at 24 hours following the time of first dose as recorded in the diary. A responder was one who achieved at least a 50% reduction in pain score at the 24-hour post-dose assessment relative to the pre-treatment score and did not use rescue medication prior to the actual time of 24-hour post-dose assessment.
- Rates of response were similar for the recommended low-dose treatment group (38%) and the non-recommended high-dose group (33%) but were higher as compared to the placebo group (16%) as shown in Table 8.
- The evidence for the efficacy of colchicine in patients with FMF is derived from the published literature. Three randomized, placebo-controlled studies were identified. The three placebo-controlled studies randomized a total of 48 adult patients diagnosed with FMF and reported similar efficacy endpoints as well as inclusion and exclusion criteria.
- One of the studies randomized 15 patients with FMF to a 6-month crossover study during which 5 patients discontinued due to study non-compliance. The 10 patients completing the study experienced 5 attacks over the course of 90 days while treated with colchicine compared to 59 attacks over the course of 90 days while treated with placebo. Similarly, the second study randomized 22 patients with FMF to a 4-month crossover study during which 9 patients discontinued due to lack of efficacy while receiving placebo or study non-compliance. The 13 patients completing the study experienced 18 attacks over the course of 60 days while treated with colchicine compared to 68 attacks over the course of 60 days while treated with placebo. The third study was discontinued after an interim analysis of 6 of the 11 patients enrolled had completed the study; results could not be confirmed.
- Open-label experience with colchicine in adults and children with FMF is consistent with the randomized, controlled trial experience, and was utilized to support information on the safety profile of colchicine and for dosing recommendations.
# How Supplied
- COLCRYS® (colchicine, USP) tablets 0.6 mg, are purple, film-coated, capsule-shaped tablets, debossed with 'AR 374' on one side and scored on the other side.
- Store at 20° to 25°C (68° to 77°F).
- Protect from light.
- DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
## Storage
There is limited information regarding Colchicine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised to take COLCRYS as prescribed, even if they are feeling better. Patients should not alter the dose or discontinue treatment without consulting with their doctor. If a dose of COLCRYS is missed:
- For treatment of a gout flare when the patient is not being dosed for prophylaxis, take the missed dose as soon as possible.
- For treatment of a gout flare during prophylaxis, take the missed dose immediately, wait twelve hours, then resume the previous dosing schedule.
- For prophylaxis without treatment for a gout flare, or FMF, take the dose as soon as possible and then return to the normal dosing schedule. However, if a dose is skipped the patient should not double the next dose.
- Instruct patient that fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. COLCRYS should be kept out of the reach of children.
- Patients should be informed that bone marrow depression with agranulocytosis, aplastic anemia, and thrombocytopenia may occur with COLCRYS.
- Patients should be advised that many drugs or other substances may interact with COLCRYS and some interactions could be fatal. Therefore, patients should report to their healthcare provider all of the current medications they are taking, and check with their healthcare provider before starting any new medications, particularly antibiotics. Patients should also be advised to report the use of non-prescription medication or herbal products. Grapefruit and grapefruit juice may also interact and should not be consumed during COLCRYS treatment.
- Patients should be informed that muscle pain or weakness, tingling or numbness in fingers or toes may occur with COLCRYS alone or when it is used with certain other drugs. Patients developing any of these signs or symptoms must discontinue COLCRYS and seek medical evaluation immediately.
- COLCRYS® is a registered U.S. trademark of the URL Pharma, Inc. group of companies. © 2009 AR Holding Company, Inc., a URL Pharma, Inc. company
U.S. Patent Nos. 7,601,758; 7,619,004 and other patents pending,
# Precautions with Alcohol
- Alcohol-Colchicine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Colcrys®
# Look-Alike Drug Names
- colchicine® — Cortrosyn®
# Drug Shortage Status
# Price | Colchicine
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
Colchicine is an alkaloid that is FDA approved for the treatment of gout flares in adults and familial mediterranean fever (FMF) in adults and children 4 years or older. Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting, and pharyngolaryngeal pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Prophylaxis of Gout Flares:
- The recommended dosage of COLCRYS for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily. The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.
- Treatment of Gout Flares:
- The recommended dose of COLCRYS for treatment of a gout flare is 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1 hour period. COLCRYS may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.
- Dosing Information
- The recommended dosage of COLCRYS for FMF in adults is 1.2 mg to 2.4 mg daily.
- Concomitant Therapy:
- Co-administration of COLCRYS with drugs known to inhibit CYP3A4 and/or P-glycoprotein (P-gp) increases the risk of colchicine-induced toxic effects (Table 1). If patients are taking or have recently completed treatment with drugs listed in Table 1 within the prior 14 days, the dose adjustments are as shown on the table below.
- Prophylaxis of Gout Flares:
- For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring.
- Treatment of Gout Flares:
- For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks.
- Treatment of gout flares with COLCRYS is not recommended in patients with renal impairment who are receiving COLCRYS for prophylaxis.
- FMF:
- Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing dialysis. For these patients, the dosage should be reduced. Patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment should be monitored closely for adverse effects of COLCRYS. Dose reduction may be necessary. For patients with severe renal failure (Clcr less than 30 mL/minute), start with 0.3 mg/day; any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine. For patients undergoing dialysis, the total recommended starting dose should be 0.3 mg (half tablet) per day. Dosing can be increased with close monitoring. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Colchicine in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Topical colchicine 0.5% or 1% (incorporated into hydrophilic ointment or gel).
- Dosing Information
- Colchicine dosage of greater than 1.5 mg/day.
- Dosing Information
- Oral colchicine 0.5 mg three times daily.
- Dosing Information
- Colchicine 0.5 milligrams twice daily.
- Dosing Information
- 10 mL 0.5% colchicine solution.
- Dosing Information
- Colchicine (0.6 milligram 3 times daily).
- Dosing Information
- Colchicine 1 to 2 mg on day 1 followed by 0.5 to 1 mg/day in 2 divided doses every 12 hours for 6 months.[1]
- Dosing Information
- colchicine 1 mg every 12 hours.
- Dosing Information
- Prophylactic colchicine 0.6 milligram twice daily orally .
- Dosing Information
- Colchicine 0.02 milligram/kilogram/day for 2 to 4 months.
- Dosing Information
- Colchicine (0.5 to 0.6 milligram 2 to 3 times daily).
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The recommended dosage of COLCRYS for FMF in pediatric patients 4 years of age and older is based on age. The following daily doses may be given as a single or divided dose twice daily:
Children 4 – 6 years: 0.3 mg to 1.8 mg daily
Children 6 – 12 years: 0.9 mg to 1.8 mg daily
Adolescents older than 12 years: 1.2 mg to 2.4 mg daily
- Children 4 – 6 years: 0.3 mg to 1.8 mg daily
- Children 6 – 12 years: 0.9 mg to 1.8 mg daily
- Adolescents older than 12 years: 1.2 mg to 2.4 mg daily
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Colchicine in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Colchicine 0.5 milligrams twice daily.
- Dosing Information
- Colchicine (0.25 to 0.5 milligrams daily for 6 months).
# Contraindications
- Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses.
# Warnings
### Precautions
- Fatal Overdose
- Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. COLCRYS should be kept out of the reach of children.
- Blood Dyscrasias
- Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.
- Drug Interactions
- Colchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient's dose of colchicine may need to be reduced or interrupted. Use of COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment.
- Neuromuscular Toxicity
- Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves associated with myotoxicity) or cyclosporine with COLCRYS may potentiate the development of myopathy. Once colchicine is stopped, the symptoms generally resolve within 1 week to several months.
# Adverse Reactions
## Clinical Trials Experience
Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.
In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over 1 hour) of COLCRYS compared to 77% of patients taking a non-recommended high-dose (4.8 mg over 6 hours) of colchicine and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with COLCRYS treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the non-recommended high-dose colchicine regimen but did not occur in the recommended low-dose COLCRYS regimen.
## Postmarketing Experience
- Serious toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous systems.
- These most often occur with excessive accumulation or overdosage.
- The following adverse reactions have been reported with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine.
Sensory motor neuropathy
Alopecia, maculopapular rash, purpura, rash
Abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting
Leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia
Elevated AST, elevated ALT
Myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis
Azoospermia, oligospermia
# Drug Interactions
- COLCRYS (colchicine) is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If COLCRYS is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.
- Physicians should ensure that patients are suitable candidates for treatment with COLCRYS and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of COLCRYS toxicity should be evaluated promptly and, if toxicity is suspected, COLCRYS should be discontinued immediately.
- Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth, or teratogenic effects among pregnant women using colchicine to treat familial Mediterranean fever (FMF). Although animal reproductive and developmental studies were not conducted with COLCRYS, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity, teratogenicity, and altered postnatal development at exposures within or above the clinical therapeutic range. COLCRYS 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 Colchicine in women who are pregnant.
### Labor and Delivery
- The effect of colchicine on labor and delivery is unknown.
### Nursing Mothers
- Colchicine is excreted into human milk. Limited information suggests that exclusively breast-fed infants receive less than 10 percent of the maternal weight-adjusted dose. While there are no published reports of adverse effects in breast-feeding infants of mothers taking colchicine, colchicine can affect gastrointestinal cell renewal and permeability. Caution should be exercised and breast-feeding infants should be observed for adverse effects when COLCRYS is administered to a nursing woman.
### Pediatric Use
- The safety and efficacy of colchicine in children of all ages with FMF has been evaluated in uncontrolled studies. There does not appear to be an adverse effect on growth in children with FMF treated long-term with colchicine. Gout is rare in pediatric patients, safety and effectiveness of colchicine in pediatric patients has not been established.
### Geriatic Use
- Clinical studies with colchicine for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease, or other drug therapy.
### Gender
There is no FDA guidance on the use of Colchicine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Colchicine with respect to specific racial populations.
### Renal Impairment
- Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis.
- Prophylaxis of Gout Flares:
- For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring.
- Treatment of Gout Flares:
- For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks.
- FMF
- Although, pharmacokinetics of colchicine in patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Clcr less than 30 mL/minute) and end-stage renal disease requiring dialysis, COLCRYS may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of COLCRYS.
### Hepatic Impairment
- The clearance of colchicine may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment, compared to healthy subjects.
- Prophylaxis of Gout Flares:
- For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment.
- Treatment of Gout Flares:
- For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended COLCRYS dose is not required, but patients should be monitored closely for adverse effects of COLCRYS. However, for the treatment of gout flares in patients with severe impairment while the dose does not need to be adjusted, the treatment course should be repeated no more than once every 2 weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy.
- FMF
- In patients with severe hepatic disease, dose reduction should be considered with careful monitoring.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Colchicine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Colchicine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Colchicine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Colchicine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a 4-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities, such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions, such as myelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg.
The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, diarrhea, and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multi-organ failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion.
### Management
- Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Colchicine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism by which COLCRYS exerts its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β. Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules, and consequently prevents the activation, degranulation, and migration of neutrophils thought to mediate some gout symptoms.
## Structure
- Colchicine is an alkaloid chemically described as (S)N- (5,6,7,9-tetrahydro- 1,2,3, 10-tetramethoxy-9-oxobenzo [alpha] heptalen-7-yl) acetamide with a molecular formula of C22H25NO6 and a molecular weight of 399.4. The structural formula of colchicine is given below.
- Colchicine occurs as a pale yellow powder that is soluble in water.
- COLCRYS® (colchicine, USP) tablets are supplied for oral administration as purple, film-coated, capsule-shaped tablets (0.1575" × 0.3030"), debossed with 'AR 374' on one side and scored on the other, containing 0.6 mg of the active ingredient colchicine USP. Inactive ingredients: carnauba wax, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Colchicine in the drug label.
## Pharmacokinetics
- Absorption
- In healthy adults, COLCRYS is absorbed when given orally, reaching a mean Cmax of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in 1 to 2 hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions.
- Following oral administration of COLCRYS given as 1.8 mg colchicine over 1 hour to healthy, young adults under fasting conditions, colchicine appears to be readily absorbed, reaching mean maximum plasma concentrations of 6.2 ng/mL at a median 1.81 hours (range: 1.0 to 2.5 hours). Following administration of the non-recommended high-dose regimen (4.8 mg over 6 hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours).
- After 10 days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6.0 ng/mL), occurring 1.3 to 1.4 hours post-dose (range 0.5 to 3.0 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5 below.
- In some subjects, secondary colchicine peaks are seen, occurring between 3 and 36 hours post-dose and ranging from 39% to 155% of the height of the initial peak. These observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation.
- Absolute bioavailability is reported to be approximately 45%.
- Administration of COLCRYS with food has no effect on the rate of colchicine absorption, but did decrease the extent of colchicine by approximately 15%. This is without clinical significance.
- Distribution
- The mean apparent volume of distribution in healthy young volunteers was approximately 5 to 8 L/kg.
- Colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration.
- Colchicine crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration). Colchicine also distributes into breast milk at concentrations similar to those found in the maternal serum.
- Metabolism
- Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine (2- and 3-DMC, respectively), and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2- and 3-DMC. Plasma levels of these metabolites are minimal (less than 5% of parent drug).
- Elimination/Excretion
- In healthy volunteers (n=12) 40 – 65% of 1 mg orally administered colchicine was recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination. Following multiple oral doses (0.6 mg twice daily), the mean elimination half-lives in young healthy volunteers (mean age 25 to 28 years of age) is 26.6 to 31.2 hours. Colchicine is a substrate of P-gp.
- Extracorporeal Elimination: Colchicine is not removed by hemodialysis.
- Special Populations
- There is no difference between men and women in the pharmacokinetic disposition of colchicine.
- Pediatric Patients: Pharmacokinetics of colchicine was not evaluated in pediatric patients.
- Elderly: Pharmacokinetics of colchicine has not been determined in elderly patients. A published report described the pharmacokinetics of 1 mg oral colchicine tablet in four elderly women compared to six young healthy males. The mean age of the four elderly women was 83 years (range 75 – 93), mean weight was 47 kg (38 – 61 kg) and mean creatinine clearance was 46 mL/min (range 25 – 75 mL/min). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males. However, it is possible that the higher exposure in the elderly subjects was due to decreased renal function.
- Renal impairment: Pharmacokinetics of colchicine in patients with mild and moderate renal impairment is not known. A published report described the disposition of colchicine (1 mg) in young adult men and women with FMF who had normal renal function or end-stage renal disease requiring dialysis. Patients with end-stage renal disease had 75% lower colchicine clearance (0.17 vs 0.73 L/hr/kg) and prolonged plasma elimination half-life (18.8 hrs vs 4.4 hrs) as compared to subjects with FMF and normal renal function.
- Hepatic impairment: Published reports on the pharmacokinetics of IV colchicine in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis, and normal renal function suggest wide inter-patient variability. In some subjects with mild to moderate cirrhosis, the clearance of colchicine is significantly reduced and plasma half-life prolonged compared to healthy subjects. In subjects with primary biliary cirrhosis, no consistent trends were noted. No pharmacokinetic data are available for patients with severe hepatic impairment (Child-Pugh C).
- Drug interactions:
- In vitro drug interactions:
- In vitro studies in human liver microsomes have shown that colchicine is not an inhibitor or inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 activity.
- In vivo drug interactions:
- The effects of co-administration of other drugs with COLCRYS on Cmax, AUC, and Cmin are summarized in Table 6 (effect of other drugs on colchicine) and Table 7 (effect of colchicine on other drugs). For information regarding clinical recommendations, see Table 1 in Dose Modification for Co-administration of Interacting Drugs.
- Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum® 1/35) co-administered with COLCRYS (0.6 mg b.i.d. × 14 days), hormone concentrations are not affected.
- In healthy volunteers given theophylline co-administered with COLCRYS (0.6 mg b.i.d. × 14 days), theophylline concentrations were not affected.
## Nonclinical Toxicology
- Carcinogenesis
- Carcinogenicity studies of colchicine have not been conducted. Due to the potential for colchicine to produce aneuploid cells (cells with an unequal number of chromosomes), there is theoretically an increased risk of malignancy.
- Mutagenesis
- Colchicine was negative for mutagenicity in the bacterial reverse mutation assay. In a chromosomal aberration assay in cultured human white blood cells, colchicine treatment resulted in the formation of micronuclei. Since published studies demonstrated that colchicine induces aneuploidy from the process of mitotic nondisjunction without structural DNA changes, colchicine is not considered clastogenic, although micronuclei are formed.
- Impairment of Fertility
- No studies of colchicine effects on fertility were conducted with COLCRYS. However, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. Reproductive studies also reported abnormal sperm morphology and reduced sperm counts in males, and interference with sperm penetration, second meiotic division, and normal cleavage in females when exposed to colchicine. Colchicine administered to pregnant animals resulted in fetal death and teratogenicity. These effects were dose dependent, with the timing of exposure critical for the effects on embryofetal development. The nonclinical doses evaluated were generally higher than an equivalent human therapeutic dose, but safety margins for reproductive and developmental toxicity could not be determined.
- Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare. A case report indicated that azoospermia was reversed when therapy was stopped. Case reports and epidemiology studies in female subjects on colchicine therapy have not established a clear relationship between colchicine use and female infertility. However, since the progression of FMF without treatment may result in infertility, the use of colchicine needs to be weighed against the potential risks.
# Clinical Studies
- The evidence for the efficacy of colchicine in patients with chronic gout is derived from the published literature. Two randomized clinical trials assessed the efficacy of colchicine 0.6 mg twice a day for the prophylaxis of gout flares in patients with gout initiating treatment with urate lowering therapy. In both trials, treatment with colchicine decreased the frequency of gout flares.
- The efficacy of a low dosage regimen of oral colchicine (COLCRYS total dose 1.8 mg over 1 hour) for treatment of gout flares was assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel group, 1 week, dose comparison study. Patients meeting American College of Rheumatology criteria for gout were randomly assigned to three groups: high-dose colchicine (1.2 mg, then 0.6 mg hourly × 6 hours [4.8 mg total]); low-dose colchicine (1.2 mg, then 0.6 mg in 1 hour [1.8 mg total] followed by 5 placebo doses hourly); or placebo (2 capsules, then 1 capsule hourly × 6 hours). Patients took the first dose within 12 hours of the onset of the flare and recorded pain intensity (11-point Likert scale) and adverse events over 72 hours. The efficacy of colchicine was measured based on response to treatment in the target joint, using patient self assessment of pain at 24 hours following the time of first dose as recorded in the diary. A responder was one who achieved at least a 50% reduction in pain score at the 24-hour post-dose assessment relative to the pre-treatment score and did not use rescue medication prior to the actual time of 24-hour post-dose assessment.
- Rates of response were similar for the recommended low-dose treatment group (38%) and the non-recommended high-dose group (33%) but were higher as compared to the placebo group (16%) as shown in Table 8.
- The evidence for the efficacy of colchicine in patients with FMF is derived from the published literature. Three randomized, placebo-controlled studies were identified. The three placebo-controlled studies randomized a total of 48 adult patients diagnosed with FMF and reported similar efficacy endpoints as well as inclusion and exclusion criteria.
- One of the studies randomized 15 patients with FMF to a 6-month crossover study during which 5 patients discontinued due to study non-compliance. The 10 patients completing the study experienced 5 attacks over the course of 90 days while treated with colchicine compared to 59 attacks over the course of 90 days while treated with placebo. Similarly, the second study randomized 22 patients with FMF to a 4-month crossover study during which 9 patients discontinued due to lack of efficacy while receiving placebo or study non-compliance. The 13 patients completing the study experienced 18 attacks over the course of 60 days while treated with colchicine compared to 68 attacks over the course of 60 days while treated with placebo. The third study was discontinued after an interim analysis of 6 of the 11 patients enrolled had completed the study; results could not be confirmed.
- Open-label experience with colchicine in adults and children with FMF is consistent with the randomized, controlled trial experience, and was utilized to support information on the safety profile of colchicine and for dosing recommendations.
# How Supplied
- COLCRYS® (colchicine, USP) tablets 0.6 mg, are purple, film-coated, capsule-shaped tablets, debossed with 'AR 374' on one side and scored on the other side.
- Store at 20° to 25°C (68° to 77°F).
- Protect from light.
- DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
## Storage
There is limited information regarding Colchicine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised to take COLCRYS as prescribed, even if they are feeling better. Patients should not alter the dose or discontinue treatment without consulting with their doctor. If a dose of COLCRYS is missed:
- For treatment of a gout flare when the patient is not being dosed for prophylaxis, take the missed dose as soon as possible.
- For treatment of a gout flare during prophylaxis, take the missed dose immediately, wait twelve hours, then resume the previous dosing schedule.
- For prophylaxis without treatment for a gout flare, or FMF, take the dose as soon as possible and then return to the normal dosing schedule. However, if a dose is skipped the patient should not double the next dose.
- Instruct patient that fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. COLCRYS should be kept out of the reach of children.
- Patients should be informed that bone marrow depression with agranulocytosis, aplastic anemia, and thrombocytopenia may occur with COLCRYS.
- Patients should be advised that many drugs or other substances may interact with COLCRYS and some interactions could be fatal. Therefore, patients should report to their healthcare provider all of the current medications they are taking, and check with their healthcare provider before starting any new medications, particularly antibiotics. Patients should also be advised to report the use of non-prescription medication or herbal products. Grapefruit and grapefruit juice may also interact and should not be consumed during COLCRYS treatment.
- Patients should be informed that muscle pain or weakness, tingling or numbness in fingers or toes may occur with COLCRYS alone or when it is used with certain other drugs. Patients developing any of these signs or symptoms must discontinue COLCRYS and seek medical evaluation immediately.
- COLCRYS® is a registered U.S. trademark of the URL Pharma, Inc. group of companies. © 2009 AR Holding Company, Inc., a URL Pharma, Inc. company
U.S. Patent Nos. 7,601,758; 7,619,004 and other patents pending,
# Precautions with Alcohol
- Alcohol-Colchicine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Colcrys®[2]
# Look-Alike Drug Names
- colchicine® — Cortrosyn®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Colchicine | |
86b228450900fe17192448d66faa9bdf3d6c6541 | wikidoc | Oral ulcer | Oral ulcer
# Overview
An oral ulcer (from Latin ulcus) is the name for the appearance of an open sore inside the mouth caused by a break in the mucous membrane or the epithelium on the lips or surrounding the mouth. The types of oral ulcers are diverse, with a multitude of associated causes including: physical or chemical trauma, infection from microorganisms or viruses, medical conditions or medications, cancerous and sometimes nonspecific processes. Once formed, the ulcer may be maintained by inflammation and/or secondary infection. Two common oral ulcer types are aphthous ulcers (canker sores) and cold sores, which are caused by the herpes simplex virus.
# Causes
## Common Causes
There are many processes which can lead to ulceration of the oral tissues. In some cases they are caused by an overreaction by the body's own immune system. Factors that appear to provoke them include stress, fatigue, illness, injury from accidental biting, hormonal changes, menstruation, sudden weight loss, food allergies and deficiencies in vitamin B12, iron and folic acid. Some drugs, such as nicorandil, have also been linked with oral ulcers. Some recreational drugs cause mouth ulcers. They may also be caused by eating too much sour food.
## Trauma
### Minor physical injuries
Trauma to the mouth is a common cause of oral ulcers. A sharp edge of a tooth, accidental biting (this can be particularly common with sharp canine teeth), sharp or abrasive food (particularly if left overnight), poorly fitting dentures, dental braces or trauma from a tooth brush may injure the mucosal lining of the mouth resulting in an ulcer. These ulcers usually heal at a moderate speed if the source of the injury is removed (for example, if poorly fitting dentures are removed or replaced).
### Chemical injuries
Chemicals such as Aspirin or alcohol that are held or that come in contact with the oral mucosa may cause tissues to become necrotic and slough off creating an ulcerated surface.
Sodium Lauryl Sulfate (SLS), one of the main ingredients in most toothpastes, has been implicated in increased incidence of oral ulcers.
## Infection
Viral, fungal and bacterial processes can lead to oral ulceration.
### Viral
The most common is Herpes simplex virus which causes recurrent herpetiform ulcerations preceded by usually painful multiple vesicles which burst. Herpes Zoster (shingles), Varicella Zoster (chicken pox), Coxsackie A virus and its associated subtype presentations, are some of the other viral processes that can lead to oral ulceration. HIV creates immunodeficiencies which allow opportunistic infections or neoplasms to proliferate.
### Bacterial
Bacterial processes leading to ulceration can be caused by Mycobacterium tuberculosis (tuberculosis) and Treponema pallidum (syphilis).
Opportunistic activity by combinations of otherwise normal bacterial fauna, such as aerobic streptococci, Neisseria, Actinomyces, spirochetes, and Bacteroides species can prolong the ulcerative process.
### Fungal
Coccidioides immitis (valley fever), Cryptococcus neoformans (cryptococcosis), Blastomyces dermatitidis ("North American Blastomycosis") are some of the fungal processes causing oral ulceration.
## Immune system
Many researchers view the causes of aphthous ulcers as a common end product of many different disease processes, each of which is mediated by the immune system.
Aphthous ulcers are thought to form when the body becomes aware of and attacks chemicals which it does not recognize. The presence of the unrecognized molecules garners a reaction by the lymphocytes, which trigger a reaction that causes the damage of an oral ulcer.
### Immunodeficiency
Repeat episodes of mouth ulcers can be indicative of an immunodeficiency, signaling low levels of immunoglobulin in the oral mucous membranes. Chemotherapy and HIV are both causes of immunodeficiency with which oral ulcers become a common manifestation.
### Autoimmunity
Autoimmunity is also a cause of oral ulceration. Mucous membrane pemphigoid, an autoimmune reaction to the epithelial basement membrane, causes desquamation/ulceration of the oral mucosa.
### Allergy
Contact with allergens can lead to ulcerations of the mucosa.
## Dietary
Vitamin C deficiencies may lead to scurvy which impairs wound healing, which can contribute to ulcer formation. Similarly deficiencies in vitamin B12, iron, zinc and folic acid have been linked to oral ulceration.
A common cause of ulcers is Coeliac disease, in which case consumption of wheat, rye, or barley can result in chronic oral ulcers. If gluten intolerance is the cause, prevention means taking most breads, pastas, cakes, pies, cookies, scones, biscuits, beers etc. out of the diet and substituting gluten-free varieties where available. Artificial sugars, such as those found in diet cola and sugarless gum, have been reported as causes of oral ulcers as well.
## Cancer
Oral cancers can lead to ulceration as the center of the lesion loses blood supply and necroses. Squamous cell carcinoma is just one of these.
## Causes Of Mouth Sores By Organ System
(By organ system)
## Causes of Mouth Sores In Alphabetical Order
# Diagnosis
## Symptoms
The symptoms preceding the ulcer may vary according to the cause of the ulcerative process.
Some oral ulcers may begin with a sharp stinging or burning sensation at the site of the future mouth ulcer. In a few days, they often progress to form a red spot or bump, followed by an open ulcer. Sometimes this takes a little bit longer, depending on the cause of the ulcer.
The oral ulcer appears as a white or yellow oval with an inflamed red border. Sometimes a white circle or halo around the lesion can be observed. The grey, white, or yellow coloured area within the red boundary is due to the formation of layers of fibrin, a protein involved in the clotting of blood. The ulcer, which itself is often extremely painful, especially when agitated, may be accompanied by a painful swelling of the lymph nodes below the jaw, which can be mistaken for toothache.
In some cases, the ulcer can cause other parts of the mouth to become slightly inflamed with patches of 'red bumps' which can feel rough to the tongue. It should be noted however, that any inflamed part of the mouth that remains there after 2 weeks should be seen by a doctor or dentist as soon as possible as this could be a warning sign of oral cancer.
# Treatment
The majority of the types of ulceration require treatment of the underlying cause of the oral ulceration for successful prevention; controlling imbalances in vitamins and minerals related to ulceration, managing or restricting the disease processes has shown to reduce the ulcerative process. For trauma related cases, avoiding the offending source will prevent ulceration, but since such trauma is usually accidental, this type of prevention is not usually practical.
Individuals who have a high incidence of opportunistic bacterial infections subsequent to an accidental oral injury (biting etc.) can prevent the injury from becoming infected by directly bathing the wound with an anti-bacterial mouthwash for one minute every 12 hours for 2 days; it is important to use a small vessel to contain the solution as most antibacterial mouth washes that remain in the mouth for a full minute will have detrimental effects such as a prolonged impairement to the sense of taste and the potential loss of otherwise desirable flora. Quantities around 1ml are more than sufficient. Ideally, the first treatment should occur within 3 hours. A subsequent rinse in accordance with the manufacturers directions can only be of benefit. | Oral ulcer
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Shankar Kumar, M.B.B.S. [4]
# Overview
An oral ulcer (from Latin ulcus) is the name for the appearance of an open sore inside the mouth caused by a break in the mucous membrane or the epithelium on the lips or surrounding the mouth. The types of oral ulcers are diverse, with a multitude of associated causes including: physical or chemical trauma, infection from microorganisms or viruses, medical conditions or medications, cancerous and sometimes nonspecific processes. Once formed, the ulcer may be maintained by inflammation and/or secondary infection. Two common oral ulcer types are aphthous ulcers (canker sores) and cold sores, which are caused by the herpes simplex virus.[1][2]
# Causes
## Common Causes
There are many processes which can lead to ulceration of the oral tissues. In some cases they are caused by an overreaction by the body's own immune system. Factors that appear to provoke them include stress, fatigue, illness, injury from accidental biting, hormonal changes, menstruation, sudden weight loss, food allergies and deficiencies in vitamin B12, iron and folic acid. Some drugs, such as nicorandil, have also been linked with oral ulcers. Some recreational drugs cause mouth ulcers. They may also be caused by eating too much sour food.
## Trauma
### Minor physical injuries
Trauma to the mouth is a common cause of oral ulcers. A sharp edge of a tooth, accidental biting (this can be particularly common with sharp canine teeth), sharp or abrasive food (particularly if left overnight), poorly fitting dentures, dental braces or trauma from a tooth brush may injure the mucosal lining of the mouth resulting in an ulcer. These ulcers usually heal at a moderate speed if the source of the injury is removed (for example, if poorly fitting dentures are removed or replaced).[1]
### Chemical injuries
Chemicals such as Aspirin or alcohol that are held or that come in contact with the oral mucosa may cause tissues to become necrotic and slough off creating an ulcerated surface.
Sodium Lauryl Sulfate (SLS), one of the main ingredients in most toothpastes, has been implicated in increased incidence of oral ulcers.
## Infection
Viral, fungal and bacterial processes can lead to oral ulceration.[1]
### Viral
The most common is Herpes simplex virus which causes recurrent herpetiform ulcerations preceded by usually painful multiple vesicles which burst. Herpes Zoster (shingles), Varicella Zoster (chicken pox), Coxsackie A virus and its associated subtype presentations, are some of the other viral processes that can lead to oral ulceration. HIV creates immunodeficiencies which allow opportunistic infections or neoplasms to proliferate.[2]
### Bacterial
Bacterial processes leading to ulceration can be caused by Mycobacterium tuberculosis (tuberculosis) and Treponema pallidum (syphilis).[2]
Opportunistic activity by combinations of otherwise normal bacterial fauna, such as aerobic streptococci, Neisseria, Actinomyces, spirochetes, and Bacteroides species can prolong the ulcerative process.[3]
### Fungal
Coccidioides immitis (valley fever), Cryptococcus neoformans (cryptococcosis), Blastomyces dermatitidis ("North American Blastomycosis") are some of the fungal processes causing oral ulceration.[2]
## Immune system
Many researchers view the causes of aphthous ulcers as a common end product of many different disease processes, each of which is mediated by the immune system.[2]
Aphthous ulcers are thought to form when the body becomes aware of and attacks chemicals which it does not recognize. The presence of the unrecognized molecules garners a reaction by the lymphocytes, which trigger a reaction that causes the damage of an oral ulcer.
### Immunodeficiency
Repeat episodes of mouth ulcers can be indicative of an immunodeficiency, signaling low levels of immunoglobulin in the oral mucous membranes. Chemotherapy and HIV are both causes of immunodeficiency with which oral ulcers become a common manifestation.
### Autoimmunity
Autoimmunity is also a cause of oral ulceration. Mucous membrane pemphigoid, an autoimmune reaction to the epithelial basement membrane, causes desquamation/ulceration of the oral mucosa.
### Allergy
Contact with allergens can lead to ulcerations of the mucosa.
## Dietary
Vitamin C deficiencies may lead to scurvy which impairs wound healing, which can contribute to ulcer formation.[2] Similarly deficiencies in vitamin B12, iron, zinc[4] and folic acid have been linked to oral ulceration.
A common cause of ulcers is Coeliac disease, in which case consumption of wheat, rye, or barley can result in chronic oral ulcers. If gluten intolerance is the cause, prevention means taking most breads, pastas, cakes, pies, cookies, scones, biscuits, beers etc. out of the diet and substituting gluten-free varieties where available. Artificial sugars, such as those found in diet cola and sugarless gum, have been reported as causes of oral ulcers as well.
## Cancer
Oral cancers can lead to ulceration as the center of the lesion loses blood supply and necroses. Squamous cell carcinoma is just one of these.
## Causes Of Mouth Sores By Organ System
(By organ system)
## Causes of Mouth Sores In Alphabetical Order
# Diagnosis
## Symptoms
The symptoms preceding the ulcer may vary according to the cause of the ulcerative process.
Some oral ulcers may begin with a sharp stinging or burning sensation at the site of the future mouth ulcer. In a few days, they often progress to form a red spot or bump, followed by an open ulcer. Sometimes this takes a little bit longer, depending on the cause of the ulcer.
The oral ulcer appears as a white or yellow oval with an inflamed red border. Sometimes a white circle or halo around the lesion can be observed. The grey, white, or yellow coloured area within the red boundary is due to the formation of layers of fibrin, a protein involved in the clotting of blood. The ulcer, which itself is often extremely painful, especially when agitated, may be accompanied by a painful swelling of the lymph nodes below the jaw, which can be mistaken for toothache.
In some cases, the ulcer can cause other parts of the mouth to become slightly inflamed with patches of 'red bumps' which can feel rough to the tongue. It should be noted however, that any inflamed part of the mouth that remains there after 2 weeks should be seen by a doctor or dentist as soon as possible as this could be a warning sign of oral cancer.
# Treatment
The majority of the types of ulceration require treatment of the underlying cause of the oral ulceration for successful prevention; controlling imbalances in vitamins and minerals related to ulceration, managing or restricting the disease processes has shown to reduce the ulcerative process. For trauma related cases, avoiding the offending source will prevent ulceration, but since such trauma is usually accidental, this type of prevention is not usually practical.
Individuals who have a high incidence of opportunistic bacterial infections subsequent to an accidental oral injury (biting etc.) can prevent the injury from becoming infected by directly bathing the wound with an anti-bacterial mouthwash for one minute every 12 hours for 2 days; it is important to use a small vessel to contain the solution as most antibacterial mouth washes that remain in the mouth for a full minute will have detrimental effects such as a prolonged impairement to the sense of taste and the potential loss of otherwise desirable flora. Quantities around 1ml are more than sufficient. Ideally, the first treatment should occur within 3 hours. A subsequent rinse in accordance with the manufacturers directions can only be of benefit. | https://www.wikidoc.org/index.php/Cold_sores | |
9e77d1de76f305a5aa875a22143a798352023aff | wikidoc | Colestipol | Colestipol
# 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
Colestipol is a bile acid sequestrant that is FDA approved for the treatment of primary hypercholesterolemia. Common adverse reactions include constipation and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Primary Hypercholesterolemia
- Tablet dosing information
- Initial dosage: 2 g PO qd or bid
- Dosage increases of 2 g PO qd or bid should occur at 1- or 2-month intervals.
- Recommended dosage: 2 to 16 g/day given once or in divided doses
- Appropriate use of lipid profiles as per NCEP guidelines including LDL-C and triglycerides, is advised so that optimal but not excessive doses are used to obtain the desired therapeutic effect on LDL-C level. If the desired therapeutic effect is not obtained at 2 to 16 grams/day with good compliance and acceptable side effects, combined therapy or alternate treatment should be considered.
- Colestipol tablets must be taken one at a time and be promptly swallowed whole, using plenty of water or other appropriate liquid. Do not cut, crush, or chew the tablets. Patients should take other drugs at least one hour before or four hours after colestipol tablets to minimize possible interference with their absorption.
- During Administration of Colestipol Tablets
- The patient should be carefully monitored clinically, including serum cholesterol and triglyceride levels. Periodic determinations of serum cholesterol levels as outlined in the NCEP guidelines should be done to confirm a favorable initial and long-term response.
- Failure of total or LDL-C to fall within the desired range should lead one to first examine dietary and drug compliance. If these are deemed acceptable, combined therapy or alternate treatment should be considered.
- Significant rise in triglyceride level should be considered as indication for dose reduction, drug discontinuation, or combined or alternate therapy.
- Suspension dosing information
- One dose (1 packet or 1 level scoopful) of colestipol HCl for oral suspension contains 5 gram of colestipol hydrochloride.
- Initial dosage: one dose PO qd or bid with an increment of one dose/day at one- or two-month intervals.
- Recommended daily adult dose: one to six doses given once or in divided doses. '
- Appropriate use of lipid profiles as per NCEP guidelines including LDL-cholesterol and triglycerides is advised so that optimal, but not excessive doses are used to obtain the desired therapeutic effect on LDL-cholesterol level. If the desired therapeutic effect is not obtained at one to six doses/day with good compliance and acceptable side effects, combined therapy or alternate treatment should be considered.
- To avoid accidental inhalation or esophageal distress, colestipol HCl for oral suspension should not be taken in its dry form. Colestipol HCl for oral suspension should always be mixed with water or other fluids before ingesting. Patients should take other drugs at least one hour before or four hours after colestipol HCl for oral suspension to minimize possible interference with their absorption.
- The scoop accompanying this product is not interchangeable with other scoops.
- Before Administration of Colestipol Tablets
- Define the type of hyperlipoproteinemia, as described in NCEP guidelines.
- Institute a trial of diet and weight reduction.
- Establish baseline serum total and LDL-C and triglyceride levels.
- Before Colestipol HCl for Oral Suspension Administration
- Define the type of hyperlipoproteinemia, as described in NCEP guidelines.
- Institute a trial of diet and weight reduction.
- Establish baseline serum total and LDL-cholesterol and triglyceride levels.
- During Colestipol HCl for Oral Suspension Administration
- The patient should be carefully monitored clinically, including serum cholesterol and triglyceride levels. Periodic determinations of serum cholesterol levels as outlined in the NCEP guidelines should be done to confirm a favorable initial and longer term response.
- Failure of total or LDL-cholesterol to fall within the desired range should lead one to first examine dietary and drug compliance. If these are deemed acceptable, combined therapy or alternate treatment should be considered.
- Significant rise in triglyceride level should be considered as indication for dose reduction, drug discontinuation, or combined or alternate therapy.
- Mixing and Administration Guide
- Colestipol HCl for oral suspension should always be mixed in a liquid such as water or the beverage of your choice. It may also be taken in soups or with cereals or pulpy fruits. Colestipol HCl for oral suspension should never be taken in its dry form.
- With Beverages
- Add the prescribed amount of colestipol HCl for oral suspension to a glassful (three ounces or more) of water or the beverage of your choice. A heavy or pulpy juice may minimize complaints relative to consistency.
- Stir the mixture until the medication is completely mixed. (Colestipol HCl for oral suspension will not dissolve in the liquid.) Colestipol HCl for oral suspension may also be mixed with carbonated beverages, slowly stirred in a large glass. However, this mixture may be associated with GI complaints.
- Rinse the glass with a small amount of additional beverage to make sure all the medication is taken.
- With cereals, soups, and fruits
- Colestipol HCl for oral suspension may be taken mixed with milk in hot or regular breakfast cereals, or even mixed in soups that have a high fluid content. It may also be added to fruits that are pulpy such as crushed pineapple, pears, peaches, or fruit cocktail.
### The NCEP guideline
- According to the NCEP guidelines, the goal of treatment is to lower LDL-C, and LDL-C is to be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy. The NCEP treatment guidelines are shown below.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Colestipol sandbox in adult patients.
### Non–Guideline-Supported Use
### Generalized Atherosclerosis
- Dosing information
- 10 g tid
- 30 g/day
- 10 g bid
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in the pediatric population have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information about Off-Label Guideline-Supported Use of Colestipol sandbox in pediatric patients.
### Non–Guideline-Supported Use
### Familial hypercholesterolemia
- Dosing information
- 10 g/day
- 10 g PO bid
- 0.125 g/kg bid
- 0.5 g/kg body weight bid for 8 weeks
- 5 g/day
# Contraindications
- Colestipol tablets are contraindicated in those individuals who have shown hypersensitivity to any of its components.
- Colestipol HCl for oral suspension is contraindicated in those individuals who have shown hypersensitivity to any of its components.
# Warnings
- To avoid accidental inhalation or esophageal distress, colestipol hcl for oral suspension should not be taken in its dry form. Always mix colestipol hcl for oral suspension with water or other fluids before ingesting.
## Precautions
- Prior to initiating therapy with colestipol tablets, secondary causes of hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism), should be excluded, and a lipid profile performed to assess total cholesterol, HDL-C, and triglycerides (TG). For individuals with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:
- LDL-C = Total cholesterol -
- For TG levels >400 mg/dL, this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases colestipol tablets may not be indicated.
- Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat absorption and, thus, may reduce absorption of folic acid and fat soluble vitamins such as A, D, and K.
- Chronic use of colestipol hydrochloride may be associated with an increased bleeding tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral administration of vitamin K1.
- Serum cholesterol and triglyceride levels should be determined periodically based on NCEP guidelines to confirm a favorable initial and adequate long-term response.
- Colestipol tablets may produce or severely worsen pre-existing constipation. The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction. In patients with pre-existing constipation, the starting dose should be 2 grams once or twice a day. Increased fluid and fiber intake should be encouraged to alleviate constipation and a stool softener may occasionally be indicated. If the initial dose is well tolerated, the dose may be increased by a further 2 to 4 grams/day (at monthly intervals) with periodic monitoring of serum lipoproteins. If constipation worsens or the desired therapeutic response is not achieved at 2 to 16 grams/day, combination therapy or alternate therapy should be considered. Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease. constipation associated with colestipol tablets may aggravate hemorrhoids.
- While there have been no reports of hypothyroidism induced in individuals with normal thyroid function, the theoretical possibility exists, particularly in patients with limited thyroid reserve.
- Since colestipol hydrochloride is a chloride form of an anion exchange resin, there is a possibility that prolonged use may lead to the development of hyperchloremic acidosis.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions are confined to the gastrointestinal tract. To achieve minimal GI disturbance with an optimal LDL-C lowering effect, a gradual increase of dosage starting with one dose/day is recommended. Constipation is the major single complaint and at times is severe. Most instances of constipation are mild, transient, and controlled with standard treatment. Increased fluid intake and inclusion of additional dietary fiber should be the first step; a stool softener may be added if needed. Some patients require decreased dosage or discontinuation of therapy. Hemorrhoids may be aggravated.
- Other, less frequent gastrointestinal complaints consist of abdominal discomfort (abdominal pain and cramping), intestinal gas, (bloating and flatulence), indigestion and heartburn, diarrhea and loose stools, and nausea and vomiting. Bleeding hemorrhoids and blood in the stool have been infrequently reported. Peptic ulceration, cholecystitis, and cholelithiasis have been rarely reported in patients receiving colestipol hydrochloride granules, and are not necessarily drug related.
- Difficulty swallowing and transient esophageal obstruction have been rarely reported in patients taking colestipol tablets.
- Transient and modest elevations of aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) and alkaline phosphatase were observed on one or more occasions in various patients treated with colestipol hydrochloride.
- The following non-gastrointestinal adverse reactions have been reported with generally equal frequency in patients receiving colestipol tablets, colestipol hydrochloride granules or placebo in clinical studies:
- Chest pain, angina, and tachycardia have been infrequently reported.
- Rash has been infrequently reported. Urticaria and dermatitis have been rarely noted in patients receiving colestipol hydrochloride granules.
- Musculoskeletal pain, aches and pains in the extremities, joint pains, arthritis, and backache have been reported.
- Headache, migraine headache and sinus headache have been reported. Other infrequently reported complaints include dizziness, light-headedness, and insomnia.
- Anorexia, fatigue, weakness, shortness of breath, and swelling of the hands or feet, have been infrequently reported.
## Postmarketing Experience
- FDA Package Insert for Abcixmab contains no information regarding Adverse Reactions.
# Drug Interactions
- Since colestipol hydrochloride is an anion exchange resin, it may have a strong affinity for anions other than the bile acids. In vitro studies have indicated that colestipol hydrochloride binds a number of drugs. Therefore, colestipol tablets may delay or reduce the absorption of concomitant oral medication. The interval between the administration of colestipol tablets and any other medication should be as long as possible. Patients should take other drugs at least one hour before or four hours after colestipol tablets to avoid impeding their absorption.
- Repeated doses of colestipol hydrochloride given prior to a single dose of propranolol in human trials have been reported to decrease propranolol absorption. However, in a follow-up study in normal subjects, single dose administration of colestipol hydrochloride and propranolol and twice-a-day administration for 5 days of both agents did not effect the extent of propranolol absorption, but had a small yet statistically significant effect on its rate of absorption; the time to reach maximum concentration was delayed 30 minutes. Effects on the absorption of other beta-blockers have not been determined. Therefore, patients on propranolol should be observed when colestipol tablets are either added or deleted from a therapeutic regimen.
- Studies in humans show that the absorption of chlorothiazide as reflected in urinary excretion is markedly decreased even when administered one hour before colestipol hydrochloride. The absorption of tetracycline, furosemide, penicillin G, hydrochlorothiazide, and gemfibrozil was significantly decreased when given simultaneously with colestipol hydrochloride; these drugs were not tested to determine the effect of administration one hour before colestipol hydrochloride.
- No depressant effect on blood levels in humans was noted when colestipol hydrochloride was administered with any of the following drugs: aspirin, clindamycin, clofibrate, methyldopa, nicotinic acid (niacin), tolbutamide, phenytoin or warfarin. Particular caution should be observed with digitalis preparations since there are conflicting results for the effect of colestipol hydrochloride on the availability of digoxin and digitoxin. The potential for binding of these drugs if given concomitantly is present. Discontinuing colestipol hydrochloride could pose a hazard to health if a potentially toxic drug that is significantly bound to the resin has been titrated to a maintenance level while the patient was taking colestipol hydrochloride.
- Bile acid binding resins may also interfere with the absorption of oral phosphate supplements and hydrocortisone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Since colestipol hydrochloride is essentially not absorbed systemically (less than 0.17% of the dose), it is not expected to cause fetal harm when administered during pregnancy in recommended dosages. There are no adequate and well controlled studies in pregnant women, and the known interference with absorption of fat soluble vitamins may be detrimental even in the presence of supplementation. The use of colestipol HCl for oral suspension in pregnancy or by women of childbearing potential requires that the potential benefits of drug therapy be weighed against possible hazards to the mother or child.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Colestipol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Colestipol during labor and delivery.
### Nursing Mothers
- Caution should be exercised when colestipol tablets are administered to a nursing mother. The possible lack of proper vitamin absorption described in the "pregnancy" section may have an effect on nursing infants.
### Pediatric Use
- Safety and effectiveness in the pediatric population have not been established.
### Geriatic Use
There is no FDA guidance on the use of Colestipol in geriatric settings.
### Gender
There is no FDA guidance on the use of Colestipol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Colestipol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Colestipol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Colestipol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Colestipol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Colestipol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Colestipol contains no information regarding drug monitoring.
# IV Compatibility
- FDA Package Insert for Colestipol contains no information regarding IV Compatibility.
# Overdosage
- Overdosage of colestipol tablets has not been reported. Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.
- Overdosage of colestipol HCl for oral suspension has not been reported. Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.
# Pharmacology
## Mechanism of Action
- Bile acid sequestrants are polymeric compounds which serve as ion exchange resins. Bile acid sequestrants exchange anions such as chloride ions for bile acids. By doing so, they bind bile acids and sequester them from enterohepatic circulation.
- Since bile acid sequestrants are large polymeric structures, they are not well-absorbed from the gut into the bloodstream. Thus, bile acid sequestrants, along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract.
## Structure
- The active ingredient in colestipol tablets is colestipol hydrochloride, which is a lipid lowering agent for oral use. Colestipol is an insoluble, high molecular weight basic anion-exchange copolymer of diethylenetriamine and 1-chloro-2, 3-epoxypropane, with approximately 1 out of 5 amine nitrogens protonated (chloride form). It is a light yellow water-insoluble resin which is hygroscopic and swells when suspended in water or aqueous fluids.
## Pharmacodynamics
- FDA Package Insert for colestipol contains no information regarding pharmacodynamics.
## Pharmacokinetics
- FDA Package Insert for colestipol contains no information regarding pharmacokinetics.
## Nonclinical Toxicology
- In studies conducted in rats in which cholestyramine resin (a bile acid sequestering agent similar to colestipol hydrochloride) was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin treated rats than in control rats.
- The relevance of this laboratory observation from studies in rats with cholestyramine resin to the clinical use of colestipol hydrochloride is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and non-fatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. Further follow-up of the LRC-CPPT participants by the sponsors of that study is planned for cause-specific mortality and cancer morbidity.
- When colestipol hydrochloride was administered in the diet to rats for 18 months, there was no evidence of any drug related intestinal tumor formation. In the Ames assay, colestipol hydrochloride was not mutagenic.
# Clinical Studies
- FDA Package Insert for Colestipol contains no information regarding Clinical Studies.
# How Supplied
### Tablet
- Colestipol hydrochloride tablets, 1 gram of colestipol hydrochloride, are off-white to pale yellow, film-coated, oval tablets, debossed with "G" on one side and plain on the other.
- Bottles of 120 NDC 0115-5211-16
- Bottles of 500 NDC 0115-5211-02
### Suspension
- Colestipol HCl for oral suspension USP is available as follows:
- Carton of 30 foil packets NDC 0115-5212-18
- Carton of 90 foil packets NDC 0115-5212-29
- Bottle of 500 grams with scoop NDC 0115-5213-02
## Storage
- Store at 20°C to 25°C (68°F to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Colestipol tablets may be larger than pills you have taken before. If you have had swallowing problems or choking with food, liquids or other tablets or capsules in the past, you should discuss this with your doctor before taking colestipol tablets.
- It is important that you take colestipol tablets correctly:
- Always take one tablet at a time and swallow promptly.
- Swallow each tablet whole. Do not cut, crush, or chew the tablets.
- Colestipol tablets must be taken with water or another liquid that you prefer. Swallowing the tablets will be easier if you drink plenty of liquid as you swallow each tablet.
- Difficulty swallowing and temporary obstruction of the esophagus (the tube between your mouth and stomach) have been rarely reported in patients taking colestipol tablets. If a tablet does get stuck after you swallow it, you may notice pressure or discomfort. If this happens to you, you should contact your doctor. Do not take colestipol tablets again without your doctor's advice.
- If you are taking other medications, you should take them at least one hour before or four hours after taking colestipol tablets.
# Precautions with Alcohol
- Alcohol-Colestipol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- COLESTID
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price | Colestipol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, 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
Colestipol is a bile acid sequestrant that is FDA approved for the treatment of primary hypercholesterolemia. Common adverse reactions include constipation and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Primary Hypercholesterolemia
- Tablet dosing information
- Initial dosage: 2 g PO qd or bid
- Dosage increases of 2 g PO qd or bid should occur at 1- or 2-month intervals.
- Recommended dosage: 2 to 16 g/day given once or in divided doses
- Appropriate use of lipid profiles as per NCEP guidelines including LDL-C and triglycerides, is advised so that optimal but not excessive doses are used to obtain the desired therapeutic effect on LDL-C level. If the desired therapeutic effect is not obtained at 2 to 16 grams/day with good compliance and acceptable side effects, combined therapy or alternate treatment should be considered.
- Colestipol tablets must be taken one at a time and be promptly swallowed whole, using plenty of water or other appropriate liquid. Do not cut, crush, or chew the tablets. Patients should take other drugs at least one hour before or four hours after colestipol tablets to minimize possible interference with their absorption.
- During Administration of Colestipol Tablets
- The patient should be carefully monitored clinically, including serum cholesterol and triglyceride levels. Periodic determinations of serum cholesterol levels as outlined in the NCEP guidelines should be done to confirm a favorable initial and long-term response.
- Failure of total or LDL-C to fall within the desired range should lead one to first examine dietary and drug compliance. If these are deemed acceptable, combined therapy or alternate treatment should be considered.
- Significant rise in triglyceride level should be considered as indication for dose reduction, drug discontinuation, or combined or alternate therapy.
- Suspension dosing information
- One dose (1 packet or 1 level scoopful) of colestipol HCl for oral suspension contains 5 gram of colestipol hydrochloride.
- Initial dosage: one dose PO qd or bid with an increment of one dose/day at one- or two-month intervals.
- Recommended daily adult dose: one to six doses given once or in divided doses. '
- Appropriate use of lipid profiles as per NCEP guidelines including LDL-cholesterol and triglycerides is advised so that optimal, but not excessive doses are used to obtain the desired therapeutic effect on LDL-cholesterol level. If the desired therapeutic effect is not obtained at one to six doses/day with good compliance and acceptable side effects, combined therapy or alternate treatment should be considered.
- To avoid accidental inhalation or esophageal distress, colestipol HCl for oral suspension should not be taken in its dry form. Colestipol HCl for oral suspension should always be mixed with water or other fluids before ingesting. Patients should take other drugs at least one hour before or four hours after colestipol HCl for oral suspension to minimize possible interference with their absorption.
- The scoop accompanying this product is not interchangeable with other scoops.
- Before Administration of Colestipol Tablets
- Define the type of hyperlipoproteinemia, as described in NCEP guidelines.
- Institute a trial of diet and weight reduction.
- Establish baseline serum total and LDL-C and triglyceride levels.
- Before Colestipol HCl for Oral Suspension Administration
- Define the type of hyperlipoproteinemia, as described in NCEP guidelines.
- Institute a trial of diet and weight reduction.
- Establish baseline serum total and LDL-cholesterol and triglyceride levels.
- During Colestipol HCl for Oral Suspension Administration
- The patient should be carefully monitored clinically, including serum cholesterol and triglyceride levels. Periodic determinations of serum cholesterol levels as outlined in the NCEP guidelines should be done to confirm a favorable initial and longer term response.
- Failure of total or LDL-cholesterol to fall within the desired range should lead one to first examine dietary and drug compliance. If these are deemed acceptable, combined therapy or alternate treatment should be considered.
- Significant rise in triglyceride level should be considered as indication for dose reduction, drug discontinuation, or combined or alternate therapy.
- Mixing and Administration Guide
- Colestipol HCl for oral suspension should always be mixed in a liquid such as water or the beverage of your choice. It may also be taken in soups or with cereals or pulpy fruits. Colestipol HCl for oral suspension should never be taken in its dry form.
- With Beverages
- Add the prescribed amount of colestipol HCl for oral suspension to a glassful (three ounces or more) of water or the beverage of your choice. A heavy or pulpy juice may minimize complaints relative to consistency.
- Stir the mixture until the medication is completely mixed. (Colestipol HCl for oral suspension will not dissolve in the liquid.) Colestipol HCl for oral suspension may also be mixed with carbonated beverages, slowly stirred in a large glass. However, this mixture may be associated with GI complaints.
- Rinse the glass with a small amount of additional beverage to make sure all the medication is taken.
- With cereals, soups, and fruits
- Colestipol HCl for oral suspension may be taken mixed with milk in hot or regular breakfast cereals, or even mixed in soups that have a high fluid content. It may also be added to fruits that are pulpy such as crushed pineapple, pears, peaches, or fruit cocktail.
### The NCEP guideline
- According to the NCEP guidelines, the goal of treatment is to lower LDL-C, and LDL-C is to be used to initiate and assess treatment response. Only if LDL-C levels are not available, should the Total-C be used to monitor therapy. The NCEP treatment guidelines are shown below.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Colestipol sandbox in adult patients.
### Non–Guideline-Supported Use
### Generalized Atherosclerosis
- Dosing information
- 10 g tid[1]
- 30 g/day[2]
- 10 g bid [3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness in the pediatric population have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information about Off-Label Guideline-Supported Use of Colestipol sandbox in pediatric patients.
### Non–Guideline-Supported Use
### Familial hypercholesterolemia
- Dosing information
- 10 g/day[4]
- 10 g PO bid[5]
- 0.125 g/kg bid[6]
- 0.5 g/kg body weight bid for 8 weeks[7]
- 5 g/day [8]
# Contraindications
- Colestipol tablets are contraindicated in those individuals who have shown hypersensitivity to any of its components.
- Colestipol HCl for oral suspension is contraindicated in those individuals who have shown hypersensitivity to any of its components.
# Warnings
- To avoid accidental inhalation or esophageal distress, colestipol hcl for oral suspension should not be taken in its dry form. Always mix colestipol hcl for oral suspension with water or other fluids before ingesting.
## Precautions
- Prior to initiating therapy with colestipol tablets, secondary causes of hypercholesterolemia (e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemias, obstructive liver disease, other drug therapy, alcoholism), should be excluded, and a lipid profile performed to assess total cholesterol, HDL-C, and triglycerides (TG). For individuals with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:
- LDL-C = Total cholesterol - [ (Triglycerides / 5)+HDL-C]
- For TG levels >400 mg/dL, this equation is less accurate and LDL-C concentrations should be determined by ultracentrifugation. In hypertriglyceridemic patients, LDL-C may be low or normal despite elevated Total-C. In such cases colestipol tablets may not be indicated.
- Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat absorption and, thus, may reduce absorption of folic acid and fat soluble vitamins such as A, D, and K.
- Chronic use of colestipol hydrochloride may be associated with an increased bleeding tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral administration of vitamin K1.
- Serum cholesterol and triglyceride levels should be determined periodically based on NCEP guidelines to confirm a favorable initial and adequate long-term response.
- Colestipol tablets may produce or severely worsen pre-existing constipation. The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction. In patients with pre-existing constipation, the starting dose should be 2 grams once or twice a day. Increased fluid and fiber intake should be encouraged to alleviate constipation and a stool softener may occasionally be indicated. If the initial dose is well tolerated, the dose may be increased by a further 2 to 4 grams/day (at monthly intervals) with periodic monitoring of serum lipoproteins. If constipation worsens or the desired therapeutic response is not achieved at 2 to 16 grams/day, combination therapy or alternate therapy should be considered. Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease. constipation associated with colestipol tablets may aggravate hemorrhoids.
- While there have been no reports of hypothyroidism induced in individuals with normal thyroid function, the theoretical possibility exists, particularly in patients with limited thyroid reserve.
- Since colestipol hydrochloride is a chloride form of an anion exchange resin, there is a possibility that prolonged use may lead to the development of hyperchloremic acidosis.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions are confined to the gastrointestinal tract. To achieve minimal GI disturbance with an optimal LDL-C lowering effect, a gradual increase of dosage starting with one dose/day is recommended. Constipation is the major single complaint and at times is severe. Most instances of constipation are mild, transient, and controlled with standard treatment. Increased fluid intake and inclusion of additional dietary fiber should be the first step; a stool softener may be added if needed. Some patients require decreased dosage or discontinuation of therapy. Hemorrhoids may be aggravated.
- Other, less frequent gastrointestinal complaints consist of abdominal discomfort (abdominal pain and cramping), intestinal gas, (bloating and flatulence), indigestion and heartburn, diarrhea and loose stools, and nausea and vomiting. Bleeding hemorrhoids and blood in the stool have been infrequently reported. Peptic ulceration, cholecystitis, and cholelithiasis have been rarely reported in patients receiving colestipol hydrochloride granules, and are not necessarily drug related.
- Difficulty swallowing and transient esophageal obstruction have been rarely reported in patients taking colestipol tablets.
- Transient and modest elevations of aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) and alkaline phosphatase were observed on one or more occasions in various patients treated with colestipol hydrochloride.
- The following non-gastrointestinal adverse reactions have been reported with generally equal frequency in patients receiving colestipol tablets, colestipol hydrochloride granules or placebo in clinical studies:
- Chest pain, angina, and tachycardia have been infrequently reported.
- Rash has been infrequently reported. Urticaria and dermatitis have been rarely noted in patients receiving colestipol hydrochloride granules.
- Musculoskeletal pain, aches and pains in the extremities, joint pains, arthritis, and backache have been reported.
- Headache, migraine headache and sinus headache have been reported. Other infrequently reported complaints include dizziness, light-headedness, and insomnia.
- Anorexia, fatigue, weakness, shortness of breath, and swelling of the hands or feet, have been infrequently reported.
## Postmarketing Experience
- FDA Package Insert for Abcixmab contains no information regarding Adverse Reactions.
# Drug Interactions
- Since colestipol hydrochloride is an anion exchange resin, it may have a strong affinity for anions other than the bile acids. In vitro studies have indicated that colestipol hydrochloride binds a number of drugs. Therefore, colestipol tablets may delay or reduce the absorption of concomitant oral medication. The interval between the administration of colestipol tablets and any other medication should be as long as possible. Patients should take other drugs at least one hour before or four hours after colestipol tablets to avoid impeding their absorption.
- Repeated doses of colestipol hydrochloride given prior to a single dose of propranolol in human trials have been reported to decrease propranolol absorption. However, in a follow-up study in normal subjects, single dose administration of colestipol hydrochloride and propranolol and twice-a-day administration for 5 days of both agents did not effect the extent of propranolol absorption, but had a small yet statistically significant effect on its rate of absorption; the time to reach maximum concentration was delayed 30 minutes. Effects on the absorption of other beta-blockers have not been determined. Therefore, patients on propranolol should be observed when colestipol tablets are either added or deleted from a therapeutic regimen.
- Studies in humans show that the absorption of chlorothiazide as reflected in urinary excretion is markedly decreased even when administered one hour before colestipol hydrochloride. The absorption of tetracycline, furosemide, penicillin G, hydrochlorothiazide, and gemfibrozil was significantly decreased when given simultaneously with colestipol hydrochloride; these drugs were not tested to determine the effect of administration one hour before colestipol hydrochloride.
- No depressant effect on blood levels in humans was noted when colestipol hydrochloride was administered with any of the following drugs: aspirin, clindamycin, clofibrate, methyldopa, nicotinic acid (niacin), tolbutamide, phenytoin or warfarin. Particular caution should be observed with digitalis preparations since there are conflicting results for the effect of colestipol hydrochloride on the availability of digoxin and digitoxin. The potential for binding of these drugs if given concomitantly is present. Discontinuing colestipol hydrochloride could pose a hazard to health if a potentially toxic drug that is significantly bound to the resin has been titrated to a maintenance level while the patient was taking colestipol hydrochloride.
- Bile acid binding resins may also interfere with the absorption of oral phosphate supplements and hydrocortisone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Since colestipol hydrochloride is essentially not absorbed systemically (less than 0.17% of the dose), it is not expected to cause fetal harm when administered during pregnancy in recommended dosages. There are no adequate and well controlled studies in pregnant women, and the known interference with absorption of fat soluble vitamins may be detrimental even in the presence of supplementation. The use of colestipol HCl for oral suspension in pregnancy or by women of childbearing potential requires that the potential benefits of drug therapy be weighed against possible hazards to the mother or child.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Colestipol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Colestipol during labor and delivery.
### Nursing Mothers
- Caution should be exercised when colestipol tablets are administered to a nursing mother. The possible lack of proper vitamin absorption described in the "pregnancy" section may have an effect on nursing infants.
### Pediatric Use
- Safety and effectiveness in the pediatric population have not been established.
### Geriatic Use
There is no FDA guidance on the use of Colestipol in geriatric settings.
### Gender
There is no FDA guidance on the use of Colestipol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Colestipol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Colestipol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Colestipol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Colestipol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Colestipol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Colestipol contains no information regarding drug monitoring.
# IV Compatibility
- FDA Package Insert for Colestipol contains no information regarding IV Compatibility.
# Overdosage
- Overdosage of colestipol tablets has not been reported. Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.
- Overdosage of colestipol HCl for oral suspension has not been reported. Should overdosage occur, however, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction and the presence or absence of normal gut motility would determine treatment.
# Pharmacology
## Mechanism of Action
- Bile acid sequestrants are polymeric compounds which serve as ion exchange resins. Bile acid sequestrants exchange anions such as chloride ions for bile acids. By doing so, they bind bile acids and sequester them from enterohepatic circulation.
- Since bile acid sequestrants are large polymeric structures, they are not well-absorbed from the gut into the bloodstream. Thus, bile acid sequestrants, along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract.[9]
## Structure
- The active ingredient in colestipol tablets is colestipol hydrochloride, which is a lipid lowering agent for oral use. Colestipol is an insoluble, high molecular weight basic anion-exchange copolymer of diethylenetriamine and 1-chloro-2, 3-epoxypropane, with approximately 1 out of 5 amine nitrogens protonated (chloride form). It is a light yellow water-insoluble resin which is hygroscopic and swells when suspended in water or aqueous fluids.
## Pharmacodynamics
- FDA Package Insert for colestipol contains no information regarding pharmacodynamics.
## Pharmacokinetics
- FDA Package Insert for colestipol contains no information regarding pharmacokinetics.
## Nonclinical Toxicology
- In studies conducted in rats in which cholestyramine resin (a bile acid sequestering agent similar to colestipol hydrochloride) was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin treated rats than in control rats.
- The relevance of this laboratory observation from studies in rats with cholestyramine resin to the clinical use of colestipol hydrochloride is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and non-fatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. Further follow-up of the LRC-CPPT participants by the sponsors of that study is planned for cause-specific mortality and cancer morbidity.
- When colestipol hydrochloride was administered in the diet to rats for 18 months, there was no evidence of any drug related intestinal tumor formation. In the Ames assay, colestipol hydrochloride was not mutagenic.
# Clinical Studies
- FDA Package Insert for Colestipol contains no information regarding Clinical Studies.
# How Supplied
### Tablet
- Colestipol hydrochloride tablets, 1 gram of colestipol hydrochloride, are off-white to pale yellow, film-coated, oval tablets, debossed with "G" on one side and plain on the other.
- Bottles of 120 NDC 0115-5211-16
- Bottles of 500 NDC 0115-5211-02
### Suspension
- Colestipol HCl for oral suspension USP is available as follows:
- Carton of 30 foil packets NDC 0115-5212-18
- Carton of 90 foil packets NDC 0115-5212-29
- Bottle of 500 grams with scoop NDC 0115-5213-02
## Storage
- Store at 20°C to 25°C (68°F to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Colestipol tablets may be larger than pills you have taken before. If you have had swallowing problems or choking with food, liquids or other tablets or capsules in the past, you should discuss this with your doctor before taking colestipol tablets.
- It is important that you take colestipol tablets correctly:
- Always take one tablet at a time and swallow promptly.
- Swallow each tablet whole. Do not cut, crush, or chew the tablets.
- Colestipol tablets must be taken with water or another liquid that you prefer. Swallowing the tablets will be easier if you drink plenty of liquid as you swallow each tablet.
- Difficulty swallowing and temporary obstruction of the esophagus (the tube between your mouth and stomach) have been rarely reported in patients taking colestipol tablets. If a tablet does get stuck after you swallow it, you may notice pressure or discomfort. If this happens to you, you should contact your doctor. Do not take colestipol tablets again without your doctor's advice.
- If you are taking other medications, you should take them at least one hour before or four hours after taking colestipol tablets.
# Precautions with Alcohol
- Alcohol-Colestipol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- COLESTID
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Colestid | |
9efe301e41d3f27290dc900e074045ccc56f70d1 | wikidoc | Colestilan | Colestilan
# Overview
Colestilan (INN, trade name BindRen) is a medication that acts as a phosphate binder and bile acid sequestrant.
# Clinical Use
Colestilan is used for the treatment of hyperphosphataemia (too high phosphate concentrations in the blood serum) in patients undergoing dialysis, including peritoneal dialysis.
# Contraindications
Colestilan is contraindicated in patients with bowel obstruction.
# Interactions
The substance can inhibit the resorption of other drugs, as well as fat soluble vitamins (A, D, E, K) and folate, from the gut. Resulting lower blood levels can be clinically problematic with immunosuppressant and antiepileptic drugs.
# Adverse Effects
Adverse effects include gastrointestinal problems such as constipation, as well as vitamin and calcium deficiency. Vitamin K deficiency sometimes causes gastrointestinal bleeding.
# Chemistry and Mechanism of Action
Colestilan is a cross-linked copolymer of 2-methylimidazole and epichlorohydrin and works as an anion exchanger resin with affinity to phosphate, bile acid anions and urate. It binds these anions in the gut and removes them from the enterohepatic circulation. Colestilan is not absorbed from the gut, but is excreted together with the bound anions. | Colestilan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Colestilan (INN, trade name BindRen) is a medication that acts as a phosphate binder[1] and bile acid sequestrant.
# Clinical Use
Colestilan is used for the treatment of hyperphosphataemia (too high phosphate concentrations in the blood serum) in patients undergoing dialysis, including peritoneal dialysis.[1][2]
# Contraindications
Colestilan is contraindicated in patients with bowel obstruction.[2]
# Interactions
The substance can inhibit the resorption of other drugs, as well as fat soluble vitamins (A, D, E, K) and folate, from the gut.[1] Resulting lower blood levels can be clinically problematic with immunosuppressant and antiepileptic drugs.[2]
# Adverse Effects
Adverse effects include gastrointestinal problems such as constipation, as well as vitamin and calcium deficiency. Vitamin K deficiency sometimes causes gastrointestinal bleeding.[1][2]
# Chemistry and Mechanism of Action
Colestilan is a cross-linked copolymer of 2-methylimidazole and epichlorohydrin and works as an anion exchanger resin with affinity to phosphate, bile acid anions and urate. It binds these anions in the gut and removes them from the enterohepatic circulation. Colestilan is not absorbed from the gut, but is excreted together with the bound anions. | https://www.wikidoc.org/index.php/Colestilan | |
d73c1e45fc743d55e60e173f1c6af0f93175dd04 | wikidoc | Flank pain | Flank pain
# Overview
Flank pain is defined as a discomfort or distress felt posteriorly or in the midaxillary line below the rib and above the ilium. The pain is triggered by renal capsule distention which results in stimulation of specialized nerve endings. Flank pain originating from urinary tract pathology may be due to underlying obstruction, inflammation, or mass. Urologic etiologies such as renal calculus disease or acute pyelonephritis are considered as the most common causes; however, cardiac, intraabdominal, musculoskeletal, and psychological causes should be considered on a probable list. The kidney and its capsule are innervated by sensory fibers traveling to the T10-L1 spinal cord; hence, pain originating from it is often felt just lateral to the sacrospinalis muscle beneath the 12th rib posteriorly. The pain often radiates anteriorly and referred to the inguinal, labial, penile, or testicular areas. The quality and severity of the pain may aid in making the probable diagnosis as the severity of the pain generally correlates inversely with the duration of the problem. A dull and steady pain indicates the infectious etiology such as acute pyelonephritis; whereas pain that is due to an acutely obstructing calculus can be intense and sharp. Mild to moderate flank pain is usually reported in the cases such as slowly enlarging ureteral tumor because it results in chronic gradual but possibly severe distention of the renal collecting system and capsule over a long period of time. Conversely, the acute flank pain due to an obstructing renal calculus termed as renal colic is often severe and sharp as it results in sudden distention of the renal collecting system and capsule. It is important to determine if the pain represents an emergency condition or can be managed in the outpatient setting. When flank pain is associated with fever, dehydration, nausea, vomiting or other comorbid medical conditions, such as diabetes, immunocompromised state, or pregnancy; hospital admission may be necessary to prevent possible complications such as pyelonephritis, urosepsis or even renal failure.
# Pathophysiology
- Characteristics of pain: Flank pain originating in the urinary system is caused by distention of the ureter, renal pelvis or renal capsule. The severity of the pain is directly related to the rapidity or acuteness of the obstruction irrespective of the degree of distention.
Acute onset: These patient will have extremely severe pain with mild dilation of the ureter and no irreversible renal damage. Hence, as stone passes through the ureter and suddenly becomes lodged in one position causes extremely severe pain and subsequently, causing multiple episodes of pain with a stone becoming lodged in a new and more distal position in the ureter.
Chronic onset: They might have no pain or mild pain because the ureteral dilation has developed over a long period of time resulting in a severe ureteral obstruction and irreversible renal damage.
- Acute onset: These patient will have extremely severe pain with mild dilation of the ureter and no irreversible renal damage. Hence, as stone passes through the ureter and suddenly becomes lodged in one position causes extremely severe pain and subsequently, causing multiple episodes of pain with a stone becoming lodged in a new and more distal position in the ureter.
- Chronic onset: They might have no pain or mild pain because the ureteral dilation has developed over a long period of time resulting in a severe ureteral obstruction and irreversible renal damage.
- Course of pain in ureteral obstruction: The location of pain can help to predict the level of obstruction in the urinary tract.
Proximal ureteral or renal pelvic obstruction: Flank pain originating in the posterior part of the flank and radiating to the ipsilateral testicle of the male or the labia of the female is usually due to the common innervation of the testicle and the renal pelvis (T11–12).
Middle third of the ureter: Gradually, the pain becomes lower and more anterior in the flank.
Ureterovesical junction obstruction: The pain is lower and radiates to the scrotal skin rather than the testicle, and is associated with voiding symptoms such as urinary frequency and urgency.
- Proximal ureteral or renal pelvic obstruction: Flank pain originating in the posterior part of the flank and radiating to the ipsilateral testicle of the male or the labia of the female is usually due to the common innervation of the testicle and the renal pelvis (T11–12).
- Middle third of the ureter: Gradually, the pain becomes lower and more anterior in the flank.
- Ureterovesical junction obstruction: The pain is lower and radiates to the scrotal skin rather than the testicle, and is associated with voiding symptoms such as urinary frequency and urgency.
- Renal stone formation: It involves two processes namely urine supersaturation and physicochemical changes.
Urine supersaturation: Patients with low urine volumes (usually less than 1 liter per day) increase the concentration of solutes (indicated by urine with an osmolarity greater than 600 mOsm/kg) and promote urinary stasis, which can cause supersaturation of solutes and lead to stone formation. In the setting of supersaturation, solutes precipitate in the urine leading to nucleation and crystal concretions. In respect to nephrolithiasis, supersaturation of stone-forming constituents like calcium, phosphorus, uric acid, oxalate, cystine, and low urine volume are risk factors for crystallization.
Physicochemical changes: PH and specific concentrations of excess substances influence the transformation of a liquid to a solid. Most urinary stones start as Randall's plaque at the junction of the nephron's collecting tubule and the renal pelvis in the papilla. These plaques start suburothelial and then gradually grow until they break through into the renal pelvis. Once in continuous contact with urine, layers of calcium oxalate typically start to form on the calcium phosphate nidus (all Randall's plaques are composed of calcium phosphate). Calcium oxalate stones tend to form when the urinary pH is under 7.2, while calcium phosphate will form in the more alkaline urine. Hyperparathyroidism and similar metabolic disturbances like renal tubular acidosis typically form stones that are primarily or significantly composed of calcium phosphate. Overly acidic urine is the primary cause of uric acid stones (not hyperuricosuria).
- Urine supersaturation: Patients with low urine volumes (usually less than 1 liter per day) increase the concentration of solutes (indicated by urine with an osmolarity greater than 600 mOsm/kg) and promote urinary stasis, which can cause supersaturation of solutes and lead to stone formation. In the setting of supersaturation, solutes precipitate in the urine leading to nucleation and crystal concretions. In respect to nephrolithiasis, supersaturation of stone-forming constituents like calcium, phosphorus, uric acid, oxalate, cystine, and low urine volume are risk factors for crystallization.
- Physicochemical changes: PH and specific concentrations of excess substances influence the transformation of a liquid to a solid. Most urinary stones start as Randall's plaque at the junction of the nephron's collecting tubule and the renal pelvis in the papilla. These plaques start suburothelial and then gradually grow until they break through into the renal pelvis. Once in continuous contact with urine, layers of calcium oxalate typically start to form on the calcium phosphate nidus (all Randall's plaques are composed of calcium phosphate). Calcium oxalate stones tend to form when the urinary pH is under 7.2, while calcium phosphate will form in the more alkaline urine. Hyperparathyroidism and similar metabolic disturbances like renal tubular acidosis typically form stones that are primarily or significantly composed of calcium phosphate. Overly acidic urine is the primary cause of uric acid stones (not hyperuricosuria).
- Acute pyelonephritis: E. coli is the most common bacteria due to its unique ability to adhere to and colonize the urinary tract and kidneys. E.coli has adhesive molecules called P-fimbriae which interact with receptors on the surface of uroepithelial cells. Kidneys infected with E. coli can lead to an acute inflammatory response which can cause scarring of the renal parenchyma. Though the mechanism in which renal scarring occurs is still poorly understood, it has been hypothesized that the adhesion of bacteria to the renal cells disrupts the protective barriers resulting in the localized infection, hypoxia, ischemia, and clotting in an attempt to contain the infection. Inflammatory cytokines, bacterial toxins, and other reactive processes further lead to complete pyelonephritis and in many cases systemic symptoms of sepsis and shock.
# Causes
- The etiology of flank pain is multifactorial which ranges from local, systemic, metabolic to underlying genetic factors. Depending upon the etiology in association with other comorbidities, it is determined to treat the patients in an outpatient or hospital setting; as life-threatening causes may result in death or permanent renal disability within 24 hours if left untreated.
Table 1: List the most common and life threatening causes of flank pain
Table 2: System wise causative factors of flank pain
Table 3: Alphabetical presentation of the causative factors of flank pain
# Epidemiology and Demographics
- Renal colic: Nephrolithiasis affects approximately 5% to 15% of the population, and out of those, 50% will have a recurrent stone within 5-7 years of the initial presentation if preventive measures are not practiced. Over 70% of stones occur in people 20 to 50 years old, and they are more common in men than women by a factor of about 2:1.
- Acute pyelonephritis: It is reported at a rate of 15 to 17 cases per 10,000 females and 3 to 4 cases per 10,000 males annually in the United States. Extreme age groups such as the elderly and infants are at increased risk due to abnormalities in anatomy and changes in hormones. Sexually active young women and pregnant females can also be at higher risk, and usually 20% to 30% will develop acute pyelonephritis during the second and early third trimester. Acute pyelonephritis has no racial predisposition.
- Renal infarction: Renal artery thrombosis is usually seen at the age of 30-50’s. There seems to be no gender predominance or domination of the right over the left artery. Renal infarctions are rare, numbers vary according to different studies (0.007%), and reported incidence is 0.01% in Europe and Asia. It can be missed on patient work-up, and hence, makes its documented incidence falsely lower than the true incidence.
- Urinary tract infection: They are very frequent bacterial infection in women and usually occur between the ages of 16-35 years, with 10% of women getting an infection yearly and more than 40% to 60% having an infection at least once in their lives. Recurrences are common, with nearly half getting a second infection within a year. They occur four times more frequently in females than males.
# Risk Factors
- Risk factor consists of primary factors which are mainly related to urinary system, and secondary conditions arising from extra-urinary pathologies which predisposes the patients to the flank pain.
Table 4: List the risk factors for flank pain
# Screening
- Prenatal renal ultrasound: Its objective is to describe the type of renal anomaly, to exclude associated malformations, and to screen for parameters predictive of deranged renal function postnatally; hence, allowing for a needful multidisciplinary perinatal approach.
It can detect several conditions such as unilateral renal agenesis or aplasia, ectopic kidneys, fetal hyperechoic kidneys resulting from obstructive dysplasia, bilateral multicystic kidney disease (both autosomal recessive and dominant), nephroblastomatosis, renal vein thrombosis, ischemia, infectious and metabolic diseases, nephrotic syndrome and aneuploidy; obstructive cystic dysplasia and antenatal hydronephrosis.
These conditions can present with flank pain at any age depending upon the severity of the underlying disorder. Therefore, knowledge about the specific conditions will help with prenatal counseling, determination of the need for therapeutic intervention in utero versus early delivery, and the postnatal evaluation and management of these condition.
- It can detect several conditions such as unilateral renal agenesis or aplasia, ectopic kidneys, fetal hyperechoic kidneys resulting from obstructive dysplasia, bilateral multicystic kidney disease (both autosomal recessive and dominant), nephroblastomatosis, renal vein thrombosis, ischemia, infectious and metabolic diseases, nephrotic syndrome and aneuploidy; obstructive cystic dysplasia and antenatal hydronephrosis.
- These conditions can present with flank pain at any age depending upon the severity of the underlying disorder. Therefore, knowledge about the specific conditions will help with prenatal counseling, determination of the need for therapeutic intervention in utero versus early delivery, and the postnatal evaluation and management of these condition.
# Prognosis
- Nephrolithiasis: The prognosis for most patients with kidney stones is good as most of them passes within four weeks, but stones larger than 8 mm may require some intervention before they can get excreted. The recurrence of kidney stones is common as 30-50% of individuals have a recurrent stone within 10 years after a first stone episode; therefore, the patient should be educated on adequate fluid intake and avoidance of certain foods.
- Acute pyelonephritis: Overall mortality has been reported around 10% to 20% in some studies with a recent study from Hong Kong stating a mortality rate closer to 7.4%. It further reported that the old age (older than 65 years), male gender, impaired renal function, or presence of disseminated intravascular coagulation were associated with increased mortality. However, with the timely detection of the underlying etiology and prompt intervention with adequate treatment, even patients with severe pyelonephritis generally have a good outcome.
- Urinary tract infection: The majority of women have an excellent outcome as the mortality after a UTI is close to zero. The duration of symptoms is usually 2 to 4 days following treatment with an antibiotic; however, nearly 30% of women will have a recurrent episode. Morbidity is usually seen in older debilitated patients, and those with renal calculi, diabetes, underlying malignancy, chemotherapy and chronic catheterization of the bladder.
# Complications
- Acute pyelonephritis: Renal or perinephric abscess formation, sepsis, renal vein thrombosis, papillary necrosis, acute renal failure, emphysematous pyelonephritis.
- Urinary tract infection: pyelonephritis and/or pyonephrosis.
- Renal infarction: Declining renal function and/or renal failure.
- Renal calculi: Abscess, Urosepsis, Ureteral scarring/perforation, Urine extravasation, Kidney atrophy in chronic cases
# Flank pain in reproductive aged and pregnant females
- In females of reproductive age, the gynecologic and obstetric causes of flank pain such as ectopic pregnancy, ovarian cyst, ovarian torsion, and pelvic inflammatory disease are important considerations in addition to the diagnoses commonly found in the general population.
- Before ordering diagnostic work-up in premenopausal women, it is mandatory to obtain a beta human chorionic gonadotropin (β-hCG) measurement to narrow the differential diagnosis and to limit the possibility of exposing an embryo or fetus to ionizing radiation.
- Transvaginal or transabdominal ultrasonography (USG) of the pelvis is the recommended imaging study for reproductive-aged females in whom a gynecologic etiology is suspected or a β-hCG test result is positive.
- In pregnant patients with acute flank pain, USG and MRI are typically the imaging studies of choice because they lack ionizing radiation.
- MRI has been shown to have excellent sensitivity and specificity for the evaluation of the etiologies of the flank pain in females.
- If USG and MRI are unavailable or inconclusive and if serious pathology remains a concern, CT can be used. The risk of a negative outcome for a developing embryo or fetus exposed to a single CT of the abdomen and pelvis is very low.
- The American College of Radiology (ACR) practice parameter regarding the use of imaging with ionizing radiation in pregnant patients outlines the specific risks based on gestational age and emphasizes the importance of obtaining informed consent from the patient before imaging is performed.
- Physiologic hydronephrosis of pregnancy occurs in >80% of pregnant women, more commonly occurs on the right than the left, and is generally seen beginning in the second trimester.
- However, the differential diagnosis of hydronephrosis in the pregnant patient is confounded by physiologic hydronephrosis of pregnancy which is thought to be caused by compression of the ureters between the gravid uterus and the linea terminalis.
# Diagnosis
## History and Symptoms
- The history is the most important and initial source of the evaluation of the patient presenting with flank pain.
- Onset and severity:
Acute and severe pain most commonly results from an acute obstruction of the urinary tract due to a calculus and often termed as a renal colic.
Chronic and dull pain is more typical of an underlying infectious, malignant, or congenital anomalies.
- Acute and severe pain most commonly results from an acute obstruction of the urinary tract due to a calculus and often termed as a renal colic.
- Chronic and dull pain is more typical of an underlying infectious, malignant, or congenital anomalies.
- Nausea and Vomiting: These symptoms are due to irritation of the peritoneum and distention of the renal capsule; and are most severe when the flank pain is acute and severe originating from a renal calculi.
- Urinary frequency and urgency: It is due to the referred pain to the bladder area.
- Gross hematuria: It mandates a complete urological evaluation to rule out a malignancy of the urinary tract such as a renal carcinoma, bladder carcinoma, or ureteral tumor. The diagnostic work-up should include imaging of the upper urinary tract with ultrasound or CT scan and evaluation of the bladder with cystoscopy.
- Fever: It is an ominous sign indicating an infectious etiology. The source of the fever typically is infected urine that remains undrained behind the source of obstruction such as a calculi, stricture, or tumor. However, in the cases where the patient complains of flank pain and fever with no underlying obstruction of the urinary tract collecting system; acute pyelonephritis should be most likely suspected as the renal tissue itself is infected.
- Comorbid conditions: They might predispose an individual to urosepsis.
- Tobacco use: Its use should be ruled out as it increases the risk for developing a transitional cell carcinoma. The tumor or a blood clot formation from gross hematuria can cause obstruction resulting in the flank pain similar to produced by a renal calculi.
- Cardiac arrhythmias: It can presents with acutely severe flank pain due to underlying possible thromboembolic event. In such scenarios, a cardiac thrombus suddenly is dislodged and obstructs the main renal artery or one of its branches. The resulting pain is identical to that produced by a renal calculi; hence, a history of cardiac arrhythmia is essential for establishing the diagnosis. A functional imaging study such as an IVP, contrast-enhanced CT, or renal angiogram demonstrates absence of renal blood flow and confirms the obstruction of the renal artery.
## Physical Examination
- A complete physical examination helps to determine the etiology and the severity of the problem in order to avoid the focus on the urinary tract or flank area exclusively.
- Vital signs: They are taken to determine the association with dehydration, infection, or urosepsis.
Urosepsis: It is suggested in patients with fever, rapid pulse rate, respiratory rate and labile blood pressure. The patients should be hospitalized in all suspected cases of urosepsis to prevent septic shock by providing intravenous antibiotics, aggressive fluid replacement and urologic relief of any hydronephrosis situation.
Urinary tract infection: A low grade fever may indicate a lower urinary tract infection (bladder) and high spiking temperatures suggest upper tract infection (kidney). However, it is not always correct to localize the site of the infection by the severity of the temperature. In other words, a high temperature necessarily does not indicate upper urinary tract infection and vice versa especially in children.
- Urosepsis: It is suggested in patients with fever, rapid pulse rate, respiratory rate and labile blood pressure. The patients should be hospitalized in all suspected cases of urosepsis to prevent septic shock by providing intravenous antibiotics, aggressive fluid replacement and urologic relief of any hydronephrosis situation.
- Urinary tract infection: A low grade fever may indicate a lower urinary tract infection (bladder) and high spiking temperatures suggest upper tract infection (kidney). However, it is not always correct to localize the site of the infection by the severity of the temperature. In other words, a high temperature necessarily does not indicate upper urinary tract infection and vice versa especially in children.
- Carotid arteries: They should be auscultated for bruits to evaluate for a possible cardiac etiology of the flank pain such as a renal artery disease or embolus.
- Heart auscultation: Heart rate, rhythm, and murmurs should be listened for underlying renal artery embolism which usually occurs in patients with atrial fibrillation.
- Abdomen: It should be examined for bruits, tenderness, and masses. If the pain is more severe during the abdominal examination, consider intraabdominal etiologies for the flank pain.
- Rectal examination: It should be done with stool for guaiac test to exclude a possible intraabdominal cause for the flank pain.
- Genital examination: It should be done in both males and females since referred pain is common. The bladder sometimes is able to be palpated just above the pubic symphysis. A distended bladder suggests a possible urological etiology for the pain. In females, it is essential to determine if the patient is pregnant with a urine or serum b-human chorionic gonadotropin (b-HCG) test. If the patient is pregnant, x-rays should be avoided, and ultrasound should be used for the evaluation.
- Flank area: It should be examined for asymmetry, mass, and percussion tenderness. It is uncommon to discover a palpable flank mass unless a large underlying renal tumor is present. Patients with acute pyelonephritis or obstructing renal calculi complain of severe pain when the flank is percussed indicating costovertebral tenderness.
- Lower extremities: The lower extremities should be examined for motor and sensory function to rule out a musculoskeletal etiology for the flank pain.
## Laboratory Findings
- Urinalysis:
Initial diagnostic test.
Parameters to be considered: pH, WBCs, RBCs, bacteria, casts, and crystals
Alkaline pH: Infected urine secondary to urea splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and coagulase-negative Staphylococcus
Acidic pH: An acidic urine predisposes the patients to uric acid stones formation.
WBC: The presence of WBCs signifies infection and stone induced inflammation; while WBC casts strongly suggests urinary tract infection or acute pyelonephritis.
RBC: Tumors of the urinary tract usually result in urinary RBCs and gives grossly bloody appearance to the urine. Similarly, a stone can result in RBCs in the urine; so it is important to repeat a urinalysis in patients after they have passed the stone to exclude an underlying urologic cancer. If the patient has RBCs in the urine after the stone has passed, urologic evaluation is necessary.
Gram stain: It can be done in the emergency room or clinic to determine if infection is present. A negative Gram stain suggests sterile urine. Finding bacteria on an unspun specimen suggests infection. Most urinary tract infections are caused by gram-negative bacteria such as E. coli; however, gram-positive organisms can cause them as well. If urinary calculi are present within the urinary tract; it is not uncommon to find crystals in the urine analysis along with RBCs and WBCs.
Crystals: The shape of the crystal can be used by the laboratory technician to help identify its composition.
The urinalysis may be normal if the etiology of the flank pain is due to cardiac, intraabdominal, musculoskeletal, or psychological etiologies.
- Initial diagnostic test.
- Parameters to be considered: pH, WBCs, RBCs, bacteria, casts, and crystals
Alkaline pH: Infected urine secondary to urea splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and coagulase-negative Staphylococcus
Acidic pH: An acidic urine predisposes the patients to uric acid stones formation.
WBC: The presence of WBCs signifies infection and stone induced inflammation; while WBC casts strongly suggests urinary tract infection or acute pyelonephritis.
RBC: Tumors of the urinary tract usually result in urinary RBCs and gives grossly bloody appearance to the urine. Similarly, a stone can result in RBCs in the urine; so it is important to repeat a urinalysis in patients after they have passed the stone to exclude an underlying urologic cancer. If the patient has RBCs in the urine after the stone has passed, urologic evaluation is necessary.
Gram stain: It can be done in the emergency room or clinic to determine if infection is present. A negative Gram stain suggests sterile urine. Finding bacteria on an unspun specimen suggests infection. Most urinary tract infections are caused by gram-negative bacteria such as E. coli; however, gram-positive organisms can cause them as well. If urinary calculi are present within the urinary tract; it is not uncommon to find crystals in the urine analysis along with RBCs and WBCs.
Crystals: The shape of the crystal can be used by the laboratory technician to help identify its composition.
- Alkaline pH: Infected urine secondary to urea splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and coagulase-negative Staphylococcus
- Acidic pH: An acidic urine predisposes the patients to uric acid stones formation.
- WBC: The presence of WBCs signifies infection and stone induced inflammation; while WBC casts strongly suggests urinary tract infection or acute pyelonephritis.
- RBC: Tumors of the urinary tract usually result in urinary RBCs and gives grossly bloody appearance to the urine. Similarly, a stone can result in RBCs in the urine; so it is important to repeat a urinalysis in patients after they have passed the stone to exclude an underlying urologic cancer. If the patient has RBCs in the urine after the stone has passed, urologic evaluation is necessary.
- Gram stain: It can be done in the emergency room or clinic to determine if infection is present. A negative Gram stain suggests sterile urine. Finding bacteria on an unspun specimen suggests infection. Most urinary tract infections are caused by gram-negative bacteria such as E. coli; however, gram-positive organisms can cause them as well. If urinary calculi are present within the urinary tract; it is not uncommon to find crystals in the urine analysis along with RBCs and WBCs.
- Crystals: The shape of the crystal can be used by the laboratory technician to help identify its composition.
- The urinalysis may be normal if the etiology of the flank pain is due to cardiac, intraabdominal, musculoskeletal, or psychological etiologies.
- Complete Blood Count:
Leucocytosis suspects infectious etiology.
Anemia and a low or high platelet count might be seen in the presence of bleeding urologic tumors.
An abnormally high hematocrit can be seen in a dehydrated state.
- Leucocytosis suspects infectious etiology.
- Anemia and a low or high platelet count might be seen in the presence of bleeding urologic tumors.
- An abnormally high hematocrit can be seen in a dehydrated state.
- Serum blood urea nitrogen (BUN):
An elevated BUN can be due to renal disease or dehydration.
BUN greater than 10 times the serum creatinine level indicates dehydration.
BUN to serum creatinine ratio 10 or less, suggests renal pathology.
- An elevated BUN can be due to renal disease or dehydration.
- BUN greater than 10 times the serum creatinine level indicates dehydration.
- BUN to serum creatinine ratio 10 or less, suggests renal pathology.
- Serum creatinine:
Its level directly reflects renal function as an elevated creatinine indicates impaired renal function regardless of the BUN value.
Deranged levels: Dehydration, obstruction, tumor, infarct, bilateral renal disease, or solitary kidney disease.
- Its level directly reflects renal function as an elevated creatinine indicates impaired renal function regardless of the BUN value.
- Deranged levels: Dehydration, obstruction, tumor, infarct, bilateral renal disease, or solitary kidney disease.
- Serum sodium: Hyponatremia results from volume overload and can cause nausea, vomiting, and seizures.
- Serum potassium: Hyperkalemia could result in cardiac arrhythmias.
- Serum bicarbonate: Its level falls in long-standing renal compromise along with hyperkalemia.
- Serum uric acid level and Serum calcium level: The levels are measured in suspected urinary calculus cases.
- Beta hCG test: It is done to confirm or rule out a pregnancy in reproductive age group females.
- Blood and Urine culture: Positive urine culture shows growth of ≥100,000 colony-forming units/mL of urine. Positive blood culture is found in 15-30 percent of cases.
- Peripheral blood film: It show leukocytosis with or without left shift.
- Coagulation profile: In cases where surgical intervention can be planned.
- Miscellaneous: Anti nuclear antibody, perinuclear anti neutrophil and cytoplasmic anti neutrophilic antibody, protein C and protein S levels, Factor V Leiden mutation, anticardiolipine antibody IgM and IgG, antithrombine 3 activity, B12 vitamin, folic acid, homocysteine levels are done to rule out other differential conditions, hypercoaguable states and thromboembolic events.
## Radiographs (X-Ray)
- A plain abdominal film can help to identify urinary calculi. It is called a KUB since it visualizes the kidney, ureter, and bladder.
- The entire film should be viewed for intestinal gas pattern, gallstones, bony structure and free air which may provide insight into the etiology of the pain.
- Renal cell carcinomas are osteolytic tumors which can be seen radiographically in metastatic stage.
- An abnormal intestinal gas pattern, gallstones, or free air suggest intraabdominal pathology.
- Aortic calcifications and aneurysms should be determined to evaluate renal artery disease as the etiology of the flank pain.
- Urinary calculi are seen as calcifications overlying the kidney shadow or along the course of the ureter. Small stones 1 to 2mm in size can cause severe flank pain if they obstruct urinary flow into the bladder. Stones typically become obstructive where the ureter meets the renal pelvis , where the ureter crosses over the pelvic brim, and where the ureter enters the bladder . Small stones tend to lodge at the UVJ, whereas bigger stones lodge higher in the urinary tract. It should be noted that the uric acid calculi are radiolucent and are not seen on a plain film of the abdomen, but they can be seen on ultrasound or CT scan.
## Intravenous pyelogram (IVP)
- The IVP is a relatively inexpensive functional study that diagnoses most urologic, infectious, and cardiac causes of flank pain.
- Indication: A renal ultrasound and noncontrast CT scan do not assess renal function. In cases, where a renal ultrasound and noncontrast CT scan shows no abnormalities and likelihood of possible renal infarct secondary to an arterial embolus is high; however, kidney is no longer functioning due to the recent infarct. Hence, to assess function, either an IVP or intravenous contrast enhanced CT scan could be done.
- Contraindications: Renal insufficiency, dehydration, past reaction to iodinated contrast agents, and pregnancy.
- Adverse effects: It requires the administration of iodine-based intravenous contrast medium; therefore, an allergic reaction to the contrast is possible. Additionally, it may take several hours for excretion to occur in the presence of acute obstruction, in which case IVU is more time-consuming than the alternative techniques. Moreover, these reactions can be severe and results in hemodynamic and respiratory collapse. To avoid contrast reactions, an ultrasound or noncontrast CT can be used instead of an IVP. Source: Case courtesy of Dr Aditya Shetty, Radiopaedia.org, rID: 27633
## Ultrasonography (USG)
- USG is a primary imaging modality in patients with acute flank pain since it is a safe, rapid, inexpensive and repeatable technique allowing the identification of stones located in the renal pelvis and calyces, detect renal pelvic dilation, and other renal pathologies.
- Advantages: No ionizing radiation exposure and ability to demonstrate some stones.
- Disadvantages: A need for skilled personnel, its inability to accurately measure the size of the stone, the need to observe the ureteral jet phenomenon at the ureterovesical junction (UVJ), and its inability to differentiate dilatation without obstruction from true obstruction.
- Ultrasonographic findings in Renal stones:
Renal stones on USG are hyperechoic and show posterior acoustic shadowing depending on their size and the transducer frequency.
USG is highly effective at showing large stones (>5 mm) with nearly 100% sensitivity; but poor at visualizing stones smaller than 3 mm. It may be hard to distinguish small stones from vascular calcifications.
USG is very useful in demonstrating ureteral stones and the secondary sign of hydronephrosis. Although USG can detect renal stones located at the upper ureter or distally at the UVJ that cause hydronephrosis; most ureteral stones are typically obscured by overlying bowel gas. USG had a sensitivity of only 37% for direct ureteral stone detection; but when hydronephrosis was included as a positive sign for a ureteral stone, the sensitivity increased to 74%. Additionally, KUB plain abdomen radiography or CT increased the sensitivity for ureteric stones to 100%. Source: Case courtesy of Brendan Cullinane, Radiopaedia.org, rID: 12932
Twinkling artifact: It shows secondary findings of renal stones or hydronephrosis include the twinkling artifact and the absence of a urine jet on the affected side. The twinkling artifact is a rapid alternation of color immediately behind a stone that may be observed on color Doppler imaging, just like gallbladder stones. The twinkling artifact is mainly observed on rough, hyperechoic and irregular surfaces with multiple cracks which cause a strong reflection of incident ultrasound waves. It appears as a discrete focus of alternating colors with or without an associated color comet-tail artifact. The appearance of the twinkling artifact is highly dependent on the machine settings; and in order to observe it clearly, it is recommended to use a low pulse repetition frequency and high color priority. Urine jets occur from the periodic contraction of the ureters and are easily visible on color Doppler imaging. Obstruction manifests as either the complete absence of the urine jet on the affected side or continuous low-level flow on the affected side depending on the severity of the obstruction.
- Renal stones on USG are hyperechoic and show posterior acoustic shadowing depending on their size and the transducer frequency.
- USG is highly effective at showing large stones (>5 mm) with nearly 100% sensitivity; but poor at visualizing stones smaller than 3 mm. It may be hard to distinguish small stones from vascular calcifications.
- USG is very useful in demonstrating ureteral stones and the secondary sign of hydronephrosis. Although USG can detect renal stones located at the upper ureter or distally at the UVJ that cause hydronephrosis; most ureteral stones are typically obscured by overlying bowel gas. USG had a sensitivity of only 37% for direct ureteral stone detection; but when hydronephrosis was included as a positive sign for a ureteral stone, the sensitivity increased to 74%. Additionally, KUB plain abdomen radiography or CT increased the sensitivity for ureteric stones to 100%. Source: Case courtesy of Brendan Cullinane, Radiopaedia.org, rID: 12932
- Twinkling artifact: It shows secondary findings of renal stones or hydronephrosis include the twinkling artifact and the absence of a urine jet on the affected side. The twinkling artifact is a rapid alternation of color immediately behind a stone that may be observed on color Doppler imaging, just like gallbladder stones. The twinkling artifact is mainly observed on rough, hyperechoic and irregular surfaces with multiple cracks which cause a strong reflection of incident ultrasound waves. It appears as a discrete focus of alternating colors with or without an associated color comet-tail artifact. The appearance of the twinkling artifact is highly dependent on the machine settings; and in order to observe it clearly, it is recommended to use a low pulse repetition frequency and high color priority. Urine jets occur from the periodic contraction of the ureters and are easily visible on color Doppler imaging. Obstruction manifests as either the complete absence of the urine jet on the affected side or continuous low-level flow on the affected side depending on the severity of the obstruction.
- Ultrasonographic findings in Acute Pyelonephritis (APN): Source: Case courtesy of Dr Ayush Goel, Radiopaedia.org, rID: 26161
The most common sonographic finding of APN is normal echogenicity. In other words, most patients with clinically suspected APN (up to 80%) have negative USG results.
When positive findings of APN are suspected on USG, they can include hypoechogenicity due to parenchymal edema and hyperechogenicity in cases of hemorrhage, swelling, a perfusion defect on power Doppler images, loss of corticomedullary differentiation, wall thickening of the renal pelvis, or abscess formation.
Despite the presence of several ancillary findings for the diagnosis of APN, it can be very difficult to differentiate between artifacts and true positive findings if the sonic window is poor (due to bowel gas, bony thorax, or thick subcutaneous fat tissue) or if the patient’s respiration is irregular (due to conditions such as tachypnea). Thus, CT is considered to be the modality of choice for evaluating acute bacterial pyelonephritis.
- The most common sonographic finding of APN is normal echogenicity. In other words, most patients with clinically suspected APN (up to 80%) have negative USG results.
- When positive findings of APN are suspected on USG, they can include hypoechogenicity due to parenchymal edema and hyperechogenicity in cases of hemorrhage, swelling, a perfusion defect on power Doppler images, loss of corticomedullary differentiation, wall thickening of the renal pelvis, or abscess formation.
- Despite the presence of several ancillary findings for the diagnosis of APN, it can be very difficult to differentiate between artifacts and true positive findings if the sonic window is poor (due to bowel gas, bony thorax, or thick subcutaneous fat tissue) or if the patient’s respiration is irregular (due to conditions such as tachypnea). Thus, CT is considered to be the modality of choice for evaluating acute bacterial pyelonephritis.
## Computed Tomography (CT)
- Since its introduction by Smith et al in 1995, unenhanced helical CT has revolutionized the imaging evaluation of acute flank pain.
- Advantages: Unlike excretory urography, CT is fast (less than 5 minutes), has very low interobserver variability, usually does not require the intravenous administration of contrast material, and requires no patient bowel preparation; hence, making it particularly effective in the emergent setting. Additionally, it may detect extrarenal causes of abdominal pain including appendicitis, diverticulitis, biliary tract disease, leaking aortic aneurysm, and gynecologic disease.
- The sensitivity and specificity of CT for diagnosing kidney stones have been reported as 95% to 96% and 98% to 100% respectively, with overall accuracy of 98%.
- CT in Renal stones:
It is now considered to be the investigation of choice for the diagnosis of renal colic since it can be rapidly performed and can detect nearly all types of renal calculi.
The only stones that CT typically does not detect are completely radiolucent stones such as stones secondary to indinavir therapy, an antiretroviral agent.
CT can determine both the size and location of stones, the primary predictors of whether a ureteral stone will pass primarily without intervention. Ureteral stones that are 5 mm or smaller in maximum diameter and/or distally located are much more likely to pass.
However, CT measurement of the maximum stone diameter does not always correlate well with the actual stone size, often overestimating the maximum diameter by 1 mm or more. Source: Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 9233
- It is now considered to be the investigation of choice for the diagnosis of renal colic since it can be rapidly performed and can detect nearly all types of renal calculi.
- The only stones that CT typically does not detect are completely radiolucent stones such as stones secondary to indinavir therapy, an antiretroviral agent.
- CT can determine both the size and location of stones, the primary predictors of whether a ureteral stone will pass primarily without intervention. Ureteral stones that are 5 mm or smaller in maximum diameter and/or distally located are much more likely to pass.
- However, CT measurement of the maximum stone diameter does not always correlate well with the actual stone size, often overestimating the maximum diameter by 1 mm or more. Source: Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 9233
- CT in Renal embolism or infarct:
CT scan of the kidney with intravenous contrast media is fast becoming the diagnostic technique of choice for renal embolism.
Renal infarcts are most easily identified on post contrast images, preferably in the cortical/arterial phase.
One or more focal and wedge-shaped parenchymal defects involving both the cortex and medulla which extend to the capsular surface are demonstrated.
The entire kidney fails to enhance in cases of occluded main renal artery.
Cortical rim sign: ~50% of cases have enhanced a thin rim of cortex due to collateral capsular perfusion. However, it is not usually present immediately after infarction, but can be seen as early as 8 hours after occlusion (typically best seen several days later).
Flip-flop enhancement: It can be seen where a region of hypoenhancement on early phases becomes hyperattenuating on delayed imaging.
- CT scan of the kidney with intravenous contrast media is fast becoming the diagnostic technique of choice for renal embolism.
- Renal infarcts are most easily identified on post contrast images, preferably in the cortical/arterial phase.
- One or more focal and wedge-shaped parenchymal defects involving both the cortex and medulla which extend to the capsular surface are demonstrated.
- The entire kidney fails to enhance in cases of occluded main renal artery.
- Cortical rim sign: ~50% of cases have enhanced a thin rim of cortex due to collateral capsular perfusion. However, it is not usually present immediately after infarction, but can be seen as early as 8 hours after occlusion (typically best seen several days later).
- Flip-flop enhancement: It can be seen where a region of hypoenhancement on early phases becomes hyperattenuating on delayed imaging.
- Disadvantages: An exposure to ionizing radiation, high cost and cannot easily detect renal artery thromboembolism without intravenous contrast. An incidental findings on CT may be helpful at times; however, it may frequently lead to further testing and intervention that may be unnecessary and result in increased risk and cost.
## Magnetic Resonance Imaging (MRI)
- MRI can be considered as an alternative to low-dose non contrast CT in certain group of patients such as pregnant women (noncontrast MRI), young individuals, and individuals who have undergone multiple prior CT examinations.
- MRI is considered highly accurate for the diagnosis of hydronephrosis and perinephric edema but is less accurate in directly visualizing stones as compared to NCCT.
- The sensitivity of MRI(82%) is higher than that of USG and KUB radiography but less than that of CT, as stones are less easily visible when using MRI than CT.
- Diffusion-weighted imaging has also been shown to detect changes in renal perfusion and diffusion in the setting of acute ureteral obstruction.
- A major benefit of MRI is the ability to provide 3D imaging without radiation. However, MRI costs about three times more than a CT scan and has lower accuracy and much longer image acquisition times. Hence, this prevent its widespread use in stone imaging.
## Other Diagnostic Studies
- CT renal angiography, CT angiography, and DMSA radioisotope scan can be used to diagnose renal infarction.
- In renal infarction patients, the CT angiography is the initial tool of choice, but definite diagnosis is made by renal angiography. The classic finding is of a wedge-shaped zone of peripheral diminished density without enhancement.
- Renal doppler: Doppler evaluation of renal arterial and venous blood flow should be able to detect global or major segmental renal infarction by demonstrating the absence of blood flow. However, segmental renal infarction has more risk to be missed by Doppler than global renal infarction.
- ECG, Echocardiography and Holter monitoring: They are done to rule out other underlying systemic conditions such as atrial fibrillation, infective endocarditis, previous infarction, and valvular or ischemic heart disease resulting in renal infarction.
## Tips to remember
- NCCT is the most accurate technique for evaluating flank pain.
- Low-dose NCCT should be performed when evaluating for renal or ureteral stones.
- If there is uncertainty about whether a calcific density represents a ureteral stone or a phlebolith, intravenous contrast material can be administered and excretory-phase images obtained for definitive diagnosis.
- USG is the best initial study for pregnant patients with flank pain.
- Abdominal radiography combined with USG may be able to diagnose most clinically significant stones; and should be considered in young patients and those with known stone disease.
- MRI could be considered to evaluate for hydronephrosis though is less accurate for the direct visualization of renal and ureteral stones.
# Treatment
- Treatment can be provided as an either outpatient or inpatient. Inpatient treatment is usually required in elderly, immunocompromised, very young, pregnant females, poorly controlled diabetic patients, renal transplant patients, patients with urinary tract structural anomalies, or those who cannot tolerate oral intake.
- The mainstay of treatment is analgesics, antipyretics, and antibiotics. Optimal timing of intervention for renal colic depends on the underlying etiology. For an obstructing stone, an intervention is suggested even in asymptomatic patients after 30 days due to the increased risk of scarring and other complications.
- NSIADS: Immediate intervention with analgesia and antiemetics. NSAIDs and opiates are first-line therapies for analgesia. NSAIDs work in two ways in renal colic. First, NSAIDs decrease the production of arachidonic acid metabolites which mediate pain receptors and alleviates the pain caused by distension of the renal capsule. Additionally, they cause contraction of the efferent arterioles to the glomerulus causing a reduction in glomerular filtration, and subsequently reduces hydrostatic pressure across the glomerulus. As patients are frequently unable to tolerate oral medications due to nauseous sensation, parenteral NSAIDs such as ketorolac (15 mg to 30 mg intravenously (IV) or intramuscularly (IM)) or diclofenac (37.5 mg IV) are most commonly used.
- LIDOCAINE: Successful use of intravenous lidocaine for renal colic has been reported. The protocol is to inject lidocaine 120 mg in 100 mL normal saline intravenously over 10 minutes for pain management. It has been quite effective for intractable renal colic unresponsive to standard therapy and typically starts to work in 3-5 minutes. No adverse events have been reported.
- OPIATES: Opiate pain medication such as morphine sulfate (0.1 mg/kg IV or IM) or hydromorphone (0.02 mg/kg IV or IM) can also be used effectively for analgesia especially when other measures have failed. However, opiates are associated with respiratory depression, sedation and a risk of dependence associated with prolonged opiate use. Anti-emetic agents may be given along with the narcotics as nausea and emesis may occur with stone passage and commonly complicate narcotic use.
- FLUIDS: Although there is no evidence to support that empiric fluid will help “flush out” a stone; however, many patients are dehydrated secondary to decreased oral intake or vomiting and can benefit from hydration.
- MEDICAL EXPLUSIVE THERAPY: Alpha 1 adrenergic receptors exist in increasing concentration in the distal ureter. The use of alpha blockade medications (for example: tamsulosin, nifedipine, alfuzosin or doxazosin) is theorized to facilitate stone passage by decreasing intra-ureteral pressure and dilating the distal ureter. However, data from randomized control trials stated them useful in passing smaller stones lodged in the lower or distal ureter; and of little help in larger stones in the proximal ureter.
- CONSERVATIVE VS SURGICAL MANAGEMENT: A stone’s size is an important factor together with symptom severity, degree of obstruction, presence or absence of infection, intractable pain, and level of renal function in deciding whether to manage the stone initially by observation, awaiting spontaneous passage, or to intervene by urological consultation with a surgical procedure. Stones vary from less than 2 mm to greater than 2 cm in diameter.
≤4 mm width: Small stones tend to pass spontaneously in most cases.
5 mm width: 50% chance of spontaneous passage if in the proximal ureter and a better chance if in the distal ureter. Overall, for stones ≤5 mm, approximately 68% will pass spontaneously.
5 mm and ≤10 mm: An approximately 47% will pass spontaneously. One study found that stones >9mm had only a 25% chance of spontaneous passage. Distal stones are more likely to clear than proximal stones (proximal ureter 48%, mid-ureter 60%, distal ureter 75% passage rate).
Thus, symptomatic management and close follow-up with the anticipation of stone passage is a reasonable treatment of choice.
- ≤4 mm width: Small stones tend to pass spontaneously in most cases.
- 5 mm width: 50% chance of spontaneous passage if in the proximal ureter and a better chance if in the distal ureter. Overall, for stones ≤5 mm, approximately 68% will pass spontaneously.
- >5 mm and ≤10 mm: An approximately 47% will pass spontaneously. One study found that stones >9mm had only a 25% chance of spontaneous passage. Distal stones are more likely to clear than proximal stones (proximal ureter 48%, mid-ureter 60%, distal ureter 75% passage rate).
- Thus, symptomatic management and close follow-up with the anticipation of stone passage is a reasonable treatment of choice.
- SURGICAL OPTIONS: It is a definitive management of impacted stones. There are several invasive methods to improve stone passage.
Shock wave lithotripsy: A high energy shock waves are used to fragment stones
Ureteroscopy with either laser or electrohydraulic stone fragmentation
Double J stent or percutaneous nephrostomy: It is used in the presence of infection to help with urinary drainage of the affected renal unit with definitive stone therapy postponed until the patient is stable
Open surgery
- Shock wave lithotripsy: A high energy shock waves are used to fragment stones
- Ureteroscopy with either laser or electrohydraulic stone fragmentation
- Double J stent or percutaneous nephrostomy: It is used in the presence of infection to help with urinary drainage of the affected renal unit with definitive stone therapy postponed until the patient is stable
- Open surgery
- NERVE BLOCK: It can often be helpful especially in chronic cases of flank pain. An anesthetic injection is typically injected proximal to the area of the 11th or 12th intercostal nerve. Good efficacy of a nerve block suggests a musculoskeletal or neuropathic etiology. Paraveterbral, splanchnic, and intercostal nerve blocks have all shown varying degrees of efficacy in relief from flank pain.
- ANTIBIOTICS in UTI:
Trimethoprim/Sulfamethoxazole: It is given for 3 days as a mini-dose therapy, but resistance rates are high in many areas.
First-generation cephalosporins: They are good choices for mini-dose therapy.
Nitrofurantoin: It is a good choice for uncomplicated UTI; but it is bacteriostatic, not bacteriocidal, and must be used for 5 to 7 days.
Fluoroquinolones: It has a high resistance but are a favorite of urologists for some reason. Recent precautions from the FDA about fluoroquinolone side effects should be heeded. Recently the FDA approved fosfomycin as a single-dose therapy for uncomplicated UTI caused by E coli. Adjunctive therapy with phenazopyridine for several days may help provide symptom relief.
Even without treatment, the UTI will spontaneously resolve in about 20% of women. The likelihood that a female will develop acute pyelonephritis is very small. Asymptomatic bacteriuria is quite common and requires no treatment except in pregnant women, those who are immunosuppressed, have undergone a transplant or a urological procedure.
- Trimethoprim/Sulfamethoxazole: It is given for 3 days as a mini-dose therapy, but resistance rates are high in many areas.
- First-generation cephalosporins: They are good choices for mini-dose therapy.
- Nitrofurantoin: It is a good choice for uncomplicated UTI; but it is bacteriostatic, not bacteriocidal, and must be used for 5 to 7 days.
- Fluoroquinolones: It has a high resistance but are a favorite of urologists for some reason. Recent precautions from the FDA about fluoroquinolone side effects should be heeded. Recently the FDA approved fosfomycin as a single-dose therapy for uncomplicated UTI caused by E coli. Adjunctive therapy with phenazopyridine for several days may help provide symptom relief.
- Even without treatment, the UTI will spontaneously resolve in about 20% of women. The likelihood that a female will develop acute pyelonephritis is very small. Asymptomatic bacteriuria is quite common and requires no treatment except in pregnant women, those who are immunosuppressed, have undergone a transplant or a urological procedure.
- ANTIBIOTICS in Pyelonephritis: The initial selection of antibiotics will be empiric and should be based on the local antibiotic resistance. Antibiotic therapy should then be adjusted based on the results of the urine culture. Most uncomplicated cases of acute pyelonephritis will be caused by E. coli for which patients can be treated with oral cephalosporins or TMP-SMX for 14 days. Complicated cases of acute pyelonephritis require intravenous (IV) antibiotic treatment such as piperacillin-tazobactam, fluoroquinolones, meropenem, and cefepime until there are clinical improvements. Vancomycin can be used in patients allergic to penicillin.
# Preventive measures
- Nephrolithiasis and Urolithiasis:
Fluid intake: Increase it to optimize urine output to 2-2.5ltr/daily.
Calcium stones and high urine calcium: Patients should limit sodium intake and maintain a goal of moderate calcium intake of 1-1.2 kg dietary calcium daily.
A healthy lifestyle including weight loss if overweight/obese is encouraged.
Hyperuricosuric calcium stone: Those with calcium stones and low urinary citrate or those with uric acid stones and high urinary uric acid should increase intake of fruits and vegetables and decrease non-dairy animal protein. They may benefit from potassium citrate supplementation and prophylactic allopurinol.
Recurrent calcium stones and high urinary calcium: Thiazide diuretics are indicated to reduce the amount of urinary calcium.
Hyperoxaluria: Patients should be encouraged to lower their oxalate intake (spinach, nuts, chocolate, green leafy vegetables).
Avoidance of fish oil and vitamin C has also been shown to reduce the risk of stone formation.
Intake of citric acid (lemon juice, orange juice, melon juice) has also been shown to be beneficial in stone prevention.
Despite common belief, a diet with higher calcium intake (milk, tofu, orange juice, almonds), has been shown to reduce the risk of stone formation because calcium will bind with oxalate in the gut, reducing the amount of urinary oxalate available to precipitate into a stone.
- Fluid intake: Increase it to optimize urine output to 2-2.5ltr/daily.
- Calcium stones and high urine calcium: Patients should limit sodium intake and maintain a goal of moderate calcium intake of 1-1.2 kg dietary calcium daily.
- A healthy lifestyle including weight loss if overweight/obese is encouraged.
- Hyperuricosuric calcium stone: Those with calcium stones and low urinary citrate or those with uric acid stones and high urinary uric acid should increase intake of fruits and vegetables and decrease non-dairy animal protein. They may benefit from potassium citrate supplementation and prophylactic allopurinol.
- Recurrent calcium stones and high urinary calcium: Thiazide diuretics are indicated to reduce the amount of urinary calcium.
- Hyperoxaluria: Patients should be encouraged to lower their oxalate intake (spinach, nuts, chocolate, green leafy vegetables).
- Avoidance of fish oil and vitamin C has also been shown to reduce the risk of stone formation.
- Intake of citric acid (lemon juice, orange juice, melon juice) has also been shown to be beneficial in stone prevention.
- Despite common belief, a diet with higher calcium intake (milk, tofu, orange juice, almonds), has been shown to reduce the risk of stone formation because calcium will bind with oxalate in the gut, reducing the amount of urinary oxalate available to precipitate into a stone.
- Urinary tract infection and Pyelonephritis:
The key to prevent recurrent episodes is the patient education.
Fluid intake: It should be increased to maintain vigorous urine flow and avoid dehydration to prevent acute pyelonephritis and improves kidney function.
Sexually active women: They should try to void right after sexual intercourse as this can help flush the bacteria out of the bladder because bacteria in the bladder can increase by ten-fold after intercourse. After urination, women should wipe from front to back, not from the anal area forward, which seems to drag pathogenic organisms nearer to the urethra.
Recurrent UTIs: Prophylactic antibiotics should be used.
Non-medical remedies: The use of cranberry juice and probiotics may help to reduce the severity and frequency of UTI in some women.
- The key to prevent recurrent episodes is the patient education.
- Fluid intake: It should be increased to maintain vigorous urine flow and avoid dehydration to prevent acute pyelonephritis and improves kidney function.
- Sexually active women: They should try to void right after sexual intercourse as this can help flush the bacteria out of the bladder because bacteria in the bladder can increase by ten-fold after intercourse. After urination, women should wipe from front to back, not from the anal area forward, which seems to drag pathogenic organisms nearer to the urethra.
- Recurrent UTIs: Prophylactic antibiotics should be used.
- Non-medical remedies: The use of cranberry juice and probiotics may help to reduce the severity and frequency of UTI in some women. | Flank pain
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1],Associate Editor(s)-in-Chief: Jaspinder Kaur, MBBS[2]
# Overview
Flank pain is defined as a discomfort or distress felt posteriorly or in the midaxillary line below the rib and above the ilium. The pain is triggered by renal capsule distention which results in stimulation of specialized nerve endings. Flank pain originating from urinary tract pathology may be due to underlying obstruction, inflammation, or mass. Urologic etiologies such as renal calculus disease or acute pyelonephritis are considered as the most common causes; however, cardiac, intraabdominal, musculoskeletal, and psychological causes should be considered on a probable list. The kidney and its capsule are innervated by sensory fibers traveling to the T10-L1 spinal cord; hence, pain originating from it is often felt just lateral to the sacrospinalis muscle beneath the 12th rib posteriorly. The pain often radiates anteriorly and referred to the inguinal, labial, penile, or testicular areas. The quality and severity of the pain may aid in making the probable diagnosis as the severity of the pain generally correlates inversely with the duration of the problem. A dull and steady pain indicates the infectious etiology such as acute pyelonephritis; whereas pain that is due to an acutely obstructing calculus can be intense and sharp. Mild to moderate flank pain is usually reported in the cases such as slowly enlarging ureteral tumor because it results in chronic gradual but possibly severe distention of the renal collecting system and capsule over a long period of time. Conversely, the acute flank pain due to an obstructing renal calculus termed as renal colic is often severe and sharp as it results in sudden distention of the renal collecting system and capsule. It is important to determine if the pain represents an emergency condition or can be managed in the outpatient setting. When flank pain is associated with fever, dehydration, nausea, vomiting or other comorbid medical conditions, such as diabetes, immunocompromised state, or pregnancy; hospital admission may be necessary to prevent possible complications such as pyelonephritis, urosepsis or even renal failure.
# Pathophysiology
- Characteristics of pain: Flank pain originating in the urinary system is caused by distention of the ureter, renal pelvis or renal capsule. The severity of the pain is directly related to the rapidity or acuteness of the obstruction irrespective of the degree of distention. [1]
Acute onset: These patient will have extremely severe pain with mild dilation of the ureter and no irreversible renal damage. Hence, as stone passes through the ureter and suddenly becomes lodged in one position causes extremely severe pain and subsequently, causing multiple episodes of pain with a stone becoming lodged in a new and more distal position in the ureter.
Chronic onset: They might have no pain or mild pain because the ureteral dilation has developed over a long period of time resulting in a severe ureteral obstruction and irreversible renal damage.
- Acute onset: These patient will have extremely severe pain with mild dilation of the ureter and no irreversible renal damage. Hence, as stone passes through the ureter and suddenly becomes lodged in one position causes extremely severe pain and subsequently, causing multiple episodes of pain with a stone becoming lodged in a new and more distal position in the ureter.
- Chronic onset: They might have no pain or mild pain because the ureteral dilation has developed over a long period of time resulting in a severe ureteral obstruction and irreversible renal damage.
- Course of pain in ureteral obstruction: The location of pain can help to predict the level of obstruction in the urinary tract.[1]
Proximal ureteral or renal pelvic obstruction: Flank pain originating in the posterior part of the flank and radiating to the ipsilateral testicle of the male or the labia of the female is usually due to the common innervation of the testicle and the renal pelvis (T11–12).
Middle third of the ureter: Gradually, the pain becomes lower and more anterior in the flank.
Ureterovesical junction obstruction: The pain is lower and radiates to the scrotal skin rather than the testicle, and is associated with voiding symptoms such as urinary frequency and urgency.
- Proximal ureteral or renal pelvic obstruction: Flank pain originating in the posterior part of the flank and radiating to the ipsilateral testicle of the male or the labia of the female is usually due to the common innervation of the testicle and the renal pelvis (T11–12).
- Middle third of the ureter: Gradually, the pain becomes lower and more anterior in the flank.
- Ureterovesical junction obstruction: The pain is lower and radiates to the scrotal skin rather than the testicle, and is associated with voiding symptoms such as urinary frequency and urgency.
- Renal stone formation: It involves two processes namely urine supersaturation and physicochemical changes.
Urine supersaturation: Patients with low urine volumes (usually less than 1 liter per day) increase the concentration of solutes (indicated by urine with an osmolarity greater than 600 mOsm/kg) and promote urinary stasis, which can cause supersaturation of solutes and lead to stone formation. In the setting of supersaturation, solutes precipitate in the urine leading to nucleation and crystal concretions. In respect to nephrolithiasis, supersaturation of stone-forming constituents like calcium, phosphorus, uric acid, oxalate, cystine, and low urine volume are risk factors for crystallization.[2]
Physicochemical changes: PH and specific concentrations of excess substances influence the transformation of a liquid to a solid. Most urinary stones start as Randall's plaque at the junction of the nephron's collecting tubule and the renal pelvis in the papilla. These plaques start suburothelial and then gradually grow until they break through into the renal pelvis. Once in continuous contact with urine, layers of calcium oxalate typically start to form on the calcium phosphate nidus (all Randall's plaques are composed of calcium phosphate). Calcium oxalate stones tend to form when the urinary pH is under 7.2, while calcium phosphate will form in the more alkaline urine. Hyperparathyroidism and similar metabolic disturbances like renal tubular acidosis typically form stones that are primarily or significantly composed of calcium phosphate. Overly acidic urine is the primary cause of uric acid stones (not hyperuricosuria). [3]
- Urine supersaturation: Patients with low urine volumes (usually less than 1 liter per day) increase the concentration of solutes (indicated by urine with an osmolarity greater than 600 mOsm/kg) and promote urinary stasis, which can cause supersaturation of solutes and lead to stone formation. In the setting of supersaturation, solutes precipitate in the urine leading to nucleation and crystal concretions. In respect to nephrolithiasis, supersaturation of stone-forming constituents like calcium, phosphorus, uric acid, oxalate, cystine, and low urine volume are risk factors for crystallization.[2]
- Physicochemical changes: PH and specific concentrations of excess substances influence the transformation of a liquid to a solid. Most urinary stones start as Randall's plaque at the junction of the nephron's collecting tubule and the renal pelvis in the papilla. These plaques start suburothelial and then gradually grow until they break through into the renal pelvis. Once in continuous contact with urine, layers of calcium oxalate typically start to form on the calcium phosphate nidus (all Randall's plaques are composed of calcium phosphate). Calcium oxalate stones tend to form when the urinary pH is under 7.2, while calcium phosphate will form in the more alkaline urine. Hyperparathyroidism and similar metabolic disturbances like renal tubular acidosis typically form stones that are primarily or significantly composed of calcium phosphate. Overly acidic urine is the primary cause of uric acid stones (not hyperuricosuria). [3]
- Acute pyelonephritis: E. coli is the most common bacteria due to its unique ability to adhere to and colonize the urinary tract and kidneys. E.coli has adhesive molecules called P-fimbriae which interact with receptors on the surface of uroepithelial cells. Kidneys infected with E. coli can lead to an acute inflammatory response which can cause scarring of the renal parenchyma. Though the mechanism in which renal scarring occurs is still poorly understood, it has been hypothesized that the adhesion of bacteria to the renal cells disrupts the protective barriers resulting in the localized infection, hypoxia, ischemia, and clotting in an attempt to contain the infection. Inflammatory cytokines, bacterial toxins, and other reactive processes further lead to complete pyelonephritis and in many cases systemic symptoms of sepsis and shock. [4]
# Causes
- The etiology of flank pain is multifactorial which ranges from local, systemic, metabolic to underlying genetic factors. Depending upon the etiology in association with other comorbidities, it is determined to treat the patients in an outpatient or hospital setting; as life-threatening causes may result in death or permanent renal disability within 24 hours if left untreated. [1] [5] [6]
Table 1: List the most common and life threatening causes of flank pain
Table 2: System wise causative factors of flank pain
Table 3: Alphabetical presentation of the causative factors of flank pain
# Epidemiology and Demographics
- Renal colic: Nephrolithiasis affects approximately 5% to 15% of the population, and out of those, 50% will have a recurrent stone within 5-7 years of the initial presentation if preventive measures are not practiced. Over 70% of stones occur in people 20 to 50 years old, and they are more common in men than women by a factor of about 2:1. [7] [8]
- Acute pyelonephritis: It is reported at a rate of 15 to 17 cases per 10,000 females and 3 to 4 cases per 10,000 males annually in the United States. Extreme age groups such as the elderly and infants are at increased risk due to abnormalities in anatomy and changes in hormones. Sexually active young women and pregnant females can also be at higher risk, and usually 20% to 30% will develop acute pyelonephritis during the second and early third trimester. Acute pyelonephritis has no racial predisposition. [9]
- Renal infarction: Renal artery thrombosis is usually seen at the age of 30-50’s. There seems to be no gender predominance or domination of the right over the left artery. Renal infarctions are rare, numbers vary according to different studies (0.007%), and reported incidence is 0.01% in Europe and Asia. It can be missed on patient work-up, and hence, makes its documented incidence falsely lower than the true incidence. [10] [11]
- Urinary tract infection: They are very frequent bacterial infection in women and usually occur between the ages of 16-35 years, with 10% of women getting an infection yearly and more than 40% to 60% having an infection at least once in their lives. Recurrences are common, with nearly half getting a second infection within a year. They occur four times more frequently in females than males. [12] [13]
# Risk Factors
- Risk factor consists of primary factors which are mainly related to urinary system, and secondary conditions arising from extra-urinary pathologies which predisposes the patients to the flank pain.
Table 4: List the risk factors for flank pain[14]
# Screening
- Prenatal renal ultrasound: Its objective is to describe the type of renal anomaly, to exclude associated malformations, and to screen for parameters predictive of deranged renal function postnatally; hence, allowing for a needful multidisciplinary perinatal approach.[15]
It can detect several conditions such as unilateral renal agenesis or aplasia, ectopic kidneys, fetal hyperechoic kidneys resulting from obstructive dysplasia, bilateral multicystic kidney disease (both autosomal recessive and dominant), nephroblastomatosis, renal vein thrombosis, ischemia, infectious and metabolic diseases, nephrotic syndrome and aneuploidy; obstructive cystic dysplasia and antenatal hydronephrosis.
These conditions can present with flank pain at any age depending upon the severity of the underlying disorder. Therefore, knowledge about the specific conditions will help with prenatal counseling, determination of the need for therapeutic intervention in utero versus early delivery, and the postnatal evaluation and management of these condition.
- It can detect several conditions such as unilateral renal agenesis or aplasia, ectopic kidneys, fetal hyperechoic kidneys resulting from obstructive dysplasia, bilateral multicystic kidney disease (both autosomal recessive and dominant), nephroblastomatosis, renal vein thrombosis, ischemia, infectious and metabolic diseases, nephrotic syndrome and aneuploidy; obstructive cystic dysplasia and antenatal hydronephrosis.
- These conditions can present with flank pain at any age depending upon the severity of the underlying disorder. Therefore, knowledge about the specific conditions will help with prenatal counseling, determination of the need for therapeutic intervention in utero versus early delivery, and the postnatal evaluation and management of these condition.
# Prognosis
- Nephrolithiasis: The prognosis for most patients with kidney stones is good as most of them passes within four weeks, but stones larger than 8 mm may require some intervention before they can get excreted. The recurrence of kidney stones is common as 30-50% of individuals have a recurrent stone within 10 years after a first stone episode; therefore, the patient should be educated on adequate fluid intake and avoidance of certain foods. [7]
- Acute pyelonephritis: Overall mortality has been reported around 10% to 20% in some studies with a recent study from Hong Kong stating a mortality rate closer to 7.4%. It further reported that the old age (older than 65 years), male gender, impaired renal function, or presence of disseminated intravascular coagulation were associated with increased mortality. However, with the timely detection of the underlying etiology and prompt intervention with adequate treatment, even patients with severe pyelonephritis generally have a good outcome. [16]
- Urinary tract infection: The majority of women have an excellent outcome as the mortality after a UTI is close to zero. The duration of symptoms is usually 2 to 4 days following treatment with an antibiotic; however, nearly 30% of women will have a recurrent episode. Morbidity is usually seen in older debilitated patients, and those with renal calculi, diabetes, underlying malignancy, chemotherapy and chronic catheterization of the bladder. [17]
# Complications
- Acute pyelonephritis: Renal or perinephric abscess formation, sepsis, renal vein thrombosis, papillary necrosis, acute renal failure, emphysematous pyelonephritis. [18]
- Urinary tract infection: pyelonephritis and/or pyonephrosis. [19]
- Renal infarction: Declining renal function and/or renal failure. [20]
- Renal calculi: Abscess, Urosepsis, Ureteral scarring/perforation, Urine extravasation, Kidney atrophy in chronic cases [7]
# Flank pain in reproductive aged and pregnant females
- In females of reproductive age, the gynecologic and obstetric causes of flank pain such as ectopic pregnancy, ovarian cyst, ovarian torsion, and pelvic inflammatory disease are important considerations in addition to the diagnoses commonly found in the general population.
- Before ordering diagnostic work-up in premenopausal women, it is mandatory to obtain a beta human chorionic gonadotropin (β-hCG) measurement to narrow the differential diagnosis and to limit the possibility of exposing an embryo or fetus to ionizing radiation.
- Transvaginal or transabdominal ultrasonography (USG) of the pelvis is the recommended imaging study for reproductive-aged females in whom a gynecologic etiology is suspected or a β-hCG test result is positive. [21]
- In pregnant patients with acute flank pain, USG and MRI are typically the imaging studies of choice because they lack ionizing radiation.
- MRI has been shown to have excellent sensitivity and specificity for the evaluation of the etiologies of the flank pain in females.
- If USG and MRI are unavailable or inconclusive and if serious pathology remains a concern, CT can be used. The risk of a negative outcome for a developing embryo or fetus exposed to a single CT of the abdomen and pelvis is very low.
- The American College of Radiology (ACR) practice parameter regarding the use of imaging with ionizing radiation in pregnant patients outlines the specific risks based on gestational age and emphasizes the importance of obtaining informed consent from the patient before imaging is performed. [22]
- Physiologic hydronephrosis of pregnancy occurs in >80% of pregnant women, more commonly occurs on the right than the left, and is generally seen beginning in the second trimester.
- However, the differential diagnosis of hydronephrosis in the pregnant patient is confounded by physiologic hydronephrosis of pregnancy which is thought to be caused by compression of the ureters between the gravid uterus and the linea terminalis. [23]
# Diagnosis
## History and Symptoms[14]
- The history is the most important and initial source of the evaluation of the patient presenting with flank pain.
- Onset and severity:
Acute and severe pain most commonly results from an acute obstruction of the urinary tract due to a calculus and often termed as a renal colic. [7]
Chronic and dull pain is more typical of an underlying infectious, malignant, or congenital anomalies.
- Acute and severe pain most commonly results from an acute obstruction of the urinary tract due to a calculus and often termed as a renal colic. [7]
- Chronic and dull pain is more typical of an underlying infectious, malignant, or congenital anomalies.
- Nausea and Vomiting: These symptoms are due to irritation of the peritoneum and distention of the renal capsule; and are most severe when the flank pain is acute and severe originating from a renal calculi. [7]
- Urinary frequency and urgency: It is due to the referred pain to the bladder area.
- Gross hematuria: It mandates a complete urological evaluation to rule out a malignancy of the urinary tract such as a renal carcinoma, bladder carcinoma, or ureteral tumor. The diagnostic work-up should include imaging of the upper urinary tract with ultrasound or CT scan and evaluation of the bladder with cystoscopy.
- Fever: It is an ominous sign indicating an infectious etiology. The source of the fever typically is infected urine that remains undrained behind the source of obstruction such as a calculi, stricture, or tumor. However, in the cases where the patient complains of flank pain and fever with no underlying obstruction of the urinary tract collecting system; acute pyelonephritis should be most likely suspected as the renal tissue itself is infected. [4]
- Comorbid conditions: They might predispose an individual to urosepsis.
- Tobacco use: Its use should be ruled out as it increases the risk for developing a transitional cell carcinoma. The tumor or a blood clot formation from gross hematuria can cause obstruction resulting in the flank pain similar to produced by a renal calculi.
- Cardiac arrhythmias: It can presents with acutely severe flank pain due to underlying possible thromboembolic event. In such scenarios, a cardiac thrombus suddenly is dislodged and obstructs the main renal artery or one of its branches. The resulting pain is identical to that produced by a renal calculi; hence, a history of cardiac arrhythmia is essential for establishing the diagnosis. A functional imaging study such as an IVP, contrast-enhanced CT, or renal angiogram demonstrates absence of renal blood flow and confirms the obstruction of the renal artery.
## Physical Examination[14]
- A complete physical examination helps to determine the etiology and the severity of the problem in order to avoid the focus on the urinary tract or flank area exclusively.
- Vital signs: They are taken to determine the association with dehydration, infection, or urosepsis.
Urosepsis: It is suggested in patients with fever, rapid pulse rate, respiratory rate and labile blood pressure. The patients should be hospitalized in all suspected cases of urosepsis to prevent septic shock by providing intravenous antibiotics, aggressive fluid replacement and urologic relief of any hydronephrosis situation.[4]
Urinary tract infection: A low grade fever may indicate a lower urinary tract infection (bladder) and high spiking temperatures suggest upper tract infection (kidney). However, it is not always correct to localize the site of the infection by the severity of the temperature. In other words, a high temperature necessarily does not indicate upper urinary tract infection and vice versa especially in children. [19]
- Urosepsis: It is suggested in patients with fever, rapid pulse rate, respiratory rate and labile blood pressure. The patients should be hospitalized in all suspected cases of urosepsis to prevent septic shock by providing intravenous antibiotics, aggressive fluid replacement and urologic relief of any hydronephrosis situation.[4]
- Urinary tract infection: A low grade fever may indicate a lower urinary tract infection (bladder) and high spiking temperatures suggest upper tract infection (kidney). However, it is not always correct to localize the site of the infection by the severity of the temperature. In other words, a high temperature necessarily does not indicate upper urinary tract infection and vice versa especially in children. [19]
- Carotid arteries: They should be auscultated for bruits to evaluate for a possible cardiac etiology of the flank pain such as a renal artery disease or embolus.
- Heart auscultation: Heart rate, rhythm, and murmurs should be listened for underlying renal artery embolism which usually occurs in patients with atrial fibrillation.
- Abdomen: It should be examined for bruits, tenderness, and masses. If the pain is more severe during the abdominal examination, consider intraabdominal etiologies for the flank pain.
- Rectal examination: It should be done with stool for guaiac test to exclude a possible intraabdominal cause for the flank pain.
- Genital examination: It should be done in both males and females since referred pain is common. The bladder sometimes is able to be palpated just above the pubic symphysis. A distended bladder suggests a possible urological etiology for the pain. In females, it is essential to determine if the patient is pregnant with a urine or serum b-human chorionic gonadotropin (b-HCG) test. If the patient is pregnant, x-rays should be avoided, and ultrasound should be used for the evaluation.
- Flank area: It should be examined for asymmetry, mass, and percussion tenderness. It is uncommon to discover a palpable flank mass unless a large underlying renal tumor is present. Patients with acute pyelonephritis or obstructing renal calculi complain of severe pain when the flank is percussed indicating costovertebral tenderness. [4]
- Lower extremities: The lower extremities should be examined for motor and sensory function to rule out a musculoskeletal etiology for the flank pain.
## Laboratory Findings[14] [24]
- Urinalysis:
Initial diagnostic test.
Parameters to be considered: pH, WBCs, RBCs, bacteria, casts, and crystals
Alkaline pH: Infected urine secondary to urea splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and coagulase-negative Staphylococcus
Acidic pH: An acidic urine predisposes the patients to uric acid stones formation.
WBC: The presence of WBCs signifies infection and stone induced inflammation; while WBC casts strongly suggests urinary tract infection or acute pyelonephritis.
RBC: Tumors of the urinary tract usually result in urinary RBCs and gives grossly bloody appearance to the urine. Similarly, a stone can result in RBCs in the urine; so it is important to repeat a urinalysis in patients after they have passed the stone to exclude an underlying urologic cancer. If the patient has RBCs in the urine after the stone has passed, urologic evaluation is necessary.
Gram stain: It can be done in the emergency room or clinic to determine if infection is present. A negative Gram stain suggests sterile urine. Finding bacteria on an unspun specimen suggests infection. Most urinary tract infections are caused by gram-negative bacteria such as E. coli; however, gram-positive organisms can cause them as well. If urinary calculi are present within the urinary tract; it is not uncommon to find crystals in the urine analysis along with RBCs and WBCs.
Crystals: The shape of the crystal can be used by the laboratory technician to help identify its composition.
The urinalysis may be normal if the etiology of the flank pain is due to cardiac, intraabdominal, musculoskeletal, or psychological etiologies.
- Initial diagnostic test.
- Parameters to be considered: pH, WBCs, RBCs, bacteria, casts, and crystals
Alkaline pH: Infected urine secondary to urea splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and coagulase-negative Staphylococcus
Acidic pH: An acidic urine predisposes the patients to uric acid stones formation.
WBC: The presence of WBCs signifies infection and stone induced inflammation; while WBC casts strongly suggests urinary tract infection or acute pyelonephritis.
RBC: Tumors of the urinary tract usually result in urinary RBCs and gives grossly bloody appearance to the urine. Similarly, a stone can result in RBCs in the urine; so it is important to repeat a urinalysis in patients after they have passed the stone to exclude an underlying urologic cancer. If the patient has RBCs in the urine after the stone has passed, urologic evaluation is necessary.
Gram stain: It can be done in the emergency room or clinic to determine if infection is present. A negative Gram stain suggests sterile urine. Finding bacteria on an unspun specimen suggests infection. Most urinary tract infections are caused by gram-negative bacteria such as E. coli; however, gram-positive organisms can cause them as well. If urinary calculi are present within the urinary tract; it is not uncommon to find crystals in the urine analysis along with RBCs and WBCs.
Crystals: The shape of the crystal can be used by the laboratory technician to help identify its composition.
- Alkaline pH: Infected urine secondary to urea splitting bacteria such as Proteus, Klebsiella, Pseudomonas, and coagulase-negative Staphylococcus
- Acidic pH: An acidic urine predisposes the patients to uric acid stones formation.
- WBC: The presence of WBCs signifies infection and stone induced inflammation; while WBC casts strongly suggests urinary tract infection or acute pyelonephritis.
- RBC: Tumors of the urinary tract usually result in urinary RBCs and gives grossly bloody appearance to the urine. Similarly, a stone can result in RBCs in the urine; so it is important to repeat a urinalysis in patients after they have passed the stone to exclude an underlying urologic cancer. If the patient has RBCs in the urine after the stone has passed, urologic evaluation is necessary.
- Gram stain: It can be done in the emergency room or clinic to determine if infection is present. A negative Gram stain suggests sterile urine. Finding bacteria on an unspun specimen suggests infection. Most urinary tract infections are caused by gram-negative bacteria such as E. coli; however, gram-positive organisms can cause them as well. If urinary calculi are present within the urinary tract; it is not uncommon to find crystals in the urine analysis along with RBCs and WBCs.
- Crystals: The shape of the crystal can be used by the laboratory technician to help identify its composition.
- The urinalysis may be normal if the etiology of the flank pain is due to cardiac, intraabdominal, musculoskeletal, or psychological etiologies.
- Complete Blood Count:
Leucocytosis suspects infectious etiology.
Anemia and a low or high platelet count might be seen in the presence of bleeding urologic tumors.
An abnormally high hematocrit can be seen in a dehydrated state.
- Leucocytosis suspects infectious etiology.
- Anemia and a low or high platelet count might be seen in the presence of bleeding urologic tumors.
- An abnormally high hematocrit can be seen in a dehydrated state.
- Serum blood urea nitrogen (BUN):
An elevated BUN can be due to renal disease or dehydration.
BUN greater than 10 times the serum creatinine level indicates dehydration.
BUN to serum creatinine ratio 10 or less, suggests renal pathology.
- An elevated BUN can be due to renal disease or dehydration.
- BUN greater than 10 times the serum creatinine level indicates dehydration.
- BUN to serum creatinine ratio 10 or less, suggests renal pathology.
- Serum creatinine:
Its level directly reflects renal function as an elevated creatinine indicates impaired renal function regardless of the BUN value.
Deranged levels: Dehydration, obstruction, tumor, infarct, bilateral renal disease, or solitary kidney disease.
- Its level directly reflects renal function as an elevated creatinine indicates impaired renal function regardless of the BUN value.
- Deranged levels: Dehydration, obstruction, tumor, infarct, bilateral renal disease, or solitary kidney disease.
- Serum sodium: Hyponatremia results from volume overload and can cause nausea, vomiting, and seizures.
- Serum potassium: Hyperkalemia could result in cardiac arrhythmias.
- Serum bicarbonate: Its level falls in long-standing renal compromise along with hyperkalemia.
- Serum uric acid level and Serum calcium level: The levels are measured in suspected urinary calculus cases.
- Beta hCG test: It is done to confirm or rule out a pregnancy in reproductive age group females.
- Blood and Urine culture: Positive urine culture shows growth of ≥100,000 colony-forming units/mL of urine. Positive blood culture is found in 15-30 percent of cases.
- Peripheral blood film: It show leukocytosis with or without left shift.
- Coagulation profile: In cases where surgical intervention can be planned.
- Miscellaneous: Anti nuclear antibody, perinuclear anti neutrophil and cytoplasmic anti neutrophilic antibody, protein C and protein S levels, Factor V Leiden mutation, anticardiolipine antibody IgM and IgG, antithrombine 3 activity, B12 vitamin, folic acid, homocysteine levels are done to rule out other differential conditions, hypercoaguable states and thromboembolic events.[20]
## Radiographs (X-Ray)[7][14]
- A plain abdominal film can help to identify urinary calculi. It is called a KUB since it visualizes the kidney, ureter, and bladder.
- The entire film should be viewed for intestinal gas pattern, gallstones, bony structure and free air which may provide insight into the etiology of the pain.
- Renal cell carcinomas are osteolytic tumors which can be seen radiographically in metastatic stage.
- An abnormal intestinal gas pattern, gallstones, or free air suggest intraabdominal pathology.
- Aortic calcifications and aneurysms should be determined to evaluate renal artery disease as the etiology of the flank pain.
- Urinary calculi are seen as calcifications overlying the kidney shadow or along the course of the ureter. Small stones 1 to 2mm in size can cause severe flank pain if they obstruct urinary flow into the bladder. Stones typically become obstructive where the ureter meets the renal pelvis [ureteropelvic junction (UPJ)], where the ureter crosses over the pelvic brim, and where the ureter enters the bladder [ureterovesical junction (UVJ)]. Small stones tend to lodge at the UVJ, whereas bigger stones lodge higher in the urinary tract. It should be noted that the uric acid calculi are radiolucent and are not seen on a plain film of the abdomen, but they can be seen on ultrasound or CT scan.
## Intravenous pyelogram (IVP)[14] [25]
- The IVP is a relatively inexpensive functional study that diagnoses most urologic, infectious, and cardiac causes of flank pain.
- Indication: A renal ultrasound and noncontrast CT scan do not assess renal function. In cases, where a renal ultrasound and noncontrast CT scan shows no abnormalities and likelihood of possible renal infarct secondary to an arterial embolus is high; however, kidney is no longer functioning due to the recent infarct. Hence, to assess function, either an IVP or intravenous contrast enhanced CT scan could be done.
- Contraindications: Renal insufficiency, dehydration, past reaction to iodinated contrast agents, and pregnancy.
- Adverse effects: It requires the administration of iodine-based intravenous contrast medium; therefore, an allergic reaction to the contrast is possible. Additionally, it may take several hours for excretion to occur in the presence of acute obstruction, in which case IVU is more time-consuming than the alternative techniques. Moreover, these reactions can be severe and results in hemodynamic and respiratory collapse. To avoid contrast reactions, an ultrasound or noncontrast CT can be used instead of an IVP. Source: Case courtesy of Dr Aditya Shetty, Radiopaedia.org, rID: 27633
## Ultrasonography (USG)
- USG is a primary imaging modality in patients with acute flank pain since it is a safe, rapid, inexpensive and repeatable technique allowing the identification of stones located in the renal pelvis and calyces, detect renal pelvic dilation, and other renal pathologies.
- Advantages: No ionizing radiation exposure and ability to demonstrate some stones.
- Disadvantages: A need for skilled personnel, its inability to accurately measure the size of the stone, the need to observe the ureteral jet phenomenon at the ureterovesical junction (UVJ), and its inability to differentiate dilatation without obstruction from true obstruction. [25]
- Ultrasonographic findings in Renal stones:
Renal stones on USG are hyperechoic and show posterior acoustic shadowing depending on their size and the transducer frequency.
USG is highly effective at showing large stones (>5 mm) with nearly 100% sensitivity; but poor at visualizing stones smaller than 3 mm. It may be hard to distinguish small stones from vascular calcifications.
USG is very useful in demonstrating ureteral stones and the secondary sign of hydronephrosis. Although USG can detect renal stones located at the upper ureter or distally at the UVJ that cause hydronephrosis; most ureteral stones are typically obscured by overlying bowel gas. USG had a sensitivity of only 37% for direct ureteral stone detection; but when hydronephrosis was included as a positive sign for a ureteral stone, the sensitivity increased to 74%. Additionally, KUB plain abdomen radiography or CT increased the sensitivity for ureteric stones to 100%. Source: Case courtesy of Brendan Cullinane, Radiopaedia.org, rID: 12932 [26]
Twinkling artifact: It shows secondary findings of renal stones or hydronephrosis include the twinkling artifact and the absence of a urine jet on the affected side. The twinkling artifact is a rapid alternation of color immediately behind a stone that may be observed on color Doppler imaging, just like gallbladder stones. The twinkling artifact is mainly observed on rough, hyperechoic and irregular surfaces with multiple cracks which cause a strong reflection of incident ultrasound waves. It appears as a discrete focus of alternating colors with or without an associated color comet-tail artifact. The appearance of the twinkling artifact is highly dependent on the machine settings; and in order to observe it clearly, it is recommended to use a low pulse repetition frequency and high color priority. Urine jets occur from the periodic contraction of the ureters and are easily visible on color Doppler imaging. Obstruction manifests as either the complete absence of the urine jet on the affected side or continuous low-level flow on the affected side depending on the severity of the obstruction. [27]
- Renal stones on USG are hyperechoic and show posterior acoustic shadowing depending on their size and the transducer frequency.
- USG is highly effective at showing large stones (>5 mm) with nearly 100% sensitivity; but poor at visualizing stones smaller than 3 mm. It may be hard to distinguish small stones from vascular calcifications.
- USG is very useful in demonstrating ureteral stones and the secondary sign of hydronephrosis. Although USG can detect renal stones located at the upper ureter or distally at the UVJ that cause hydronephrosis; most ureteral stones are typically obscured by overlying bowel gas. USG had a sensitivity of only 37% for direct ureteral stone detection; but when hydronephrosis was included as a positive sign for a ureteral stone, the sensitivity increased to 74%. Additionally, KUB plain abdomen radiography or CT increased the sensitivity for ureteric stones to 100%. Source: Case courtesy of Brendan Cullinane, Radiopaedia.org, rID: 12932 [26]
- Twinkling artifact: It shows secondary findings of renal stones or hydronephrosis include the twinkling artifact and the absence of a urine jet on the affected side. The twinkling artifact is a rapid alternation of color immediately behind a stone that may be observed on color Doppler imaging, just like gallbladder stones. The twinkling artifact is mainly observed on rough, hyperechoic and irregular surfaces with multiple cracks which cause a strong reflection of incident ultrasound waves. It appears as a discrete focus of alternating colors with or without an associated color comet-tail artifact. The appearance of the twinkling artifact is highly dependent on the machine settings; and in order to observe it clearly, it is recommended to use a low pulse repetition frequency and high color priority. Urine jets occur from the periodic contraction of the ureters and are easily visible on color Doppler imaging. Obstruction manifests as either the complete absence of the urine jet on the affected side or continuous low-level flow on the affected side depending on the severity of the obstruction. [27]
- Ultrasonographic findings in Acute Pyelonephritis (APN): Source: Case courtesy of Dr Ayush Goel, Radiopaedia.org, rID: 26161
The most common sonographic finding of APN is normal echogenicity. In other words, most patients with clinically suspected APN (up to 80%) have negative USG results.
When positive findings of APN are suspected on USG, they can include hypoechogenicity due to parenchymal edema and hyperechogenicity in cases of hemorrhage, swelling, a perfusion defect on power Doppler images, loss of corticomedullary differentiation, wall thickening of the renal pelvis, or abscess formation.
Despite the presence of several ancillary findings for the diagnosis of APN, it can be very difficult to differentiate between artifacts and true positive findings if the sonic window is poor (due to bowel gas, bony thorax, or thick subcutaneous fat tissue) or if the patient’s respiration is irregular (due to conditions such as tachypnea). Thus, CT is considered to be the modality of choice for evaluating acute bacterial pyelonephritis. [28]
- The most common sonographic finding of APN is normal echogenicity. In other words, most patients with clinically suspected APN (up to 80%) have negative USG results.
- When positive findings of APN are suspected on USG, they can include hypoechogenicity due to parenchymal edema and hyperechogenicity in cases of hemorrhage, swelling, a perfusion defect on power Doppler images, loss of corticomedullary differentiation, wall thickening of the renal pelvis, or abscess formation.
- Despite the presence of several ancillary findings for the diagnosis of APN, it can be very difficult to differentiate between artifacts and true positive findings if the sonic window is poor (due to bowel gas, bony thorax, or thick subcutaneous fat tissue) or if the patient’s respiration is irregular (due to conditions such as tachypnea). Thus, CT is considered to be the modality of choice for evaluating acute bacterial pyelonephritis. [28]
## Computed Tomography (CT)
- Since its introduction by Smith et al in 1995, unenhanced helical CT has revolutionized the imaging evaluation of acute flank pain.[29]
- Advantages: Unlike excretory urography, CT is fast (less than 5 minutes), has very low interobserver variability, usually does not require the intravenous administration of contrast material, and requires no patient bowel preparation; hence, making it particularly effective in the emergent setting. Additionally, it may detect extrarenal causes of abdominal pain including appendicitis, diverticulitis, biliary tract disease, leaking aortic aneurysm, and gynecologic disease. [30]
- The sensitivity and specificity of CT for diagnosing kidney stones have been reported as 95% to 96% and 98% to 100% respectively, with overall accuracy of 98%. [31]
- CT in Renal stones:
It is now considered to be the investigation of choice for the diagnosis of renal colic since it can be rapidly performed and can detect nearly all types of renal calculi.
The only stones that CT typically does not detect are completely radiolucent stones such as stones secondary to indinavir therapy, an antiretroviral agent.
CT can determine both the size and location of stones, the primary predictors of whether a ureteral stone will pass primarily without intervention. Ureteral stones that are 5 mm or smaller in maximum diameter and/or distally located are much more likely to pass. [32]
However, CT measurement of the maximum stone diameter does not always correlate well with the actual stone size, often overestimating the maximum diameter by 1 mm or more.[33] Source: Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 9233
- It is now considered to be the investigation of choice for the diagnosis of renal colic since it can be rapidly performed and can detect nearly all types of renal calculi.
- The only stones that CT typically does not detect are completely radiolucent stones such as stones secondary to indinavir therapy, an antiretroviral agent.
- CT can determine both the size and location of stones, the primary predictors of whether a ureteral stone will pass primarily without intervention. Ureteral stones that are 5 mm or smaller in maximum diameter and/or distally located are much more likely to pass. [32]
- However, CT measurement of the maximum stone diameter does not always correlate well with the actual stone size, often overestimating the maximum diameter by 1 mm or more.[33] Source: Case courtesy of Assoc Prof Frank Gaillard, Radiopaedia.org, rID: 9233
- CT in Renal embolism or infarct:
CT scan of the kidney with intravenous contrast media is fast becoming the diagnostic technique of choice for renal embolism.
Renal infarcts are most easily identified on post contrast images, preferably in the cortical/arterial phase.
One or more focal and wedge-shaped parenchymal defects involving both the cortex and medulla which extend to the capsular surface are demonstrated.[33]
The entire kidney fails to enhance in cases of occluded main renal artery.
Cortical rim sign: ~50% of cases have enhanced a thin rim of cortex due to collateral capsular perfusion. However, it is not usually present immediately after infarction, but can be seen as early as 8 hours after occlusion (typically best seen several days later). [34]
Flip-flop enhancement: It can be seen where a region of hypoenhancement on early phases becomes hyperattenuating on delayed imaging. [35]
- CT scan of the kidney with intravenous contrast media is fast becoming the diagnostic technique of choice for renal embolism.
- Renal infarcts are most easily identified on post contrast images, preferably in the cortical/arterial phase.
- One or more focal and wedge-shaped parenchymal defects involving both the cortex and medulla which extend to the capsular surface are demonstrated.[33]
- The entire kidney fails to enhance in cases of occluded main renal artery.
- Cortical rim sign: ~50% of cases have enhanced a thin rim of cortex due to collateral capsular perfusion. However, it is not usually present immediately after infarction, but can be seen as early as 8 hours after occlusion (typically best seen several days later). [34]
- Flip-flop enhancement: It can be seen where a region of hypoenhancement on early phases becomes hyperattenuating on delayed imaging. [35]
- Disadvantages: An exposure to ionizing radiation, high cost and cannot easily detect renal artery thromboembolism without intravenous contrast. An incidental findings on CT may be helpful at times; however, it may frequently lead to further testing and intervention that may be unnecessary and result in increased risk and cost.
## Magnetic Resonance Imaging (MRI)
- MRI can be considered as an alternative to low-dose non contrast CT in certain group of patients such as pregnant women (noncontrast MRI), young individuals, and individuals who have undergone multiple prior CT examinations. [36]
- MRI is considered highly accurate for the diagnosis of hydronephrosis and perinephric edema but is less accurate in directly visualizing stones as compared to NCCT. [37]
- The sensitivity of MRI(82%) is higher than that of USG and KUB radiography but less than that of CT, as stones are less easily visible when using MRI than CT.
- Diffusion-weighted imaging has also been shown to detect changes in renal perfusion and diffusion in the setting of acute ureteral obstruction.
- A major benefit of MRI is the ability to provide 3D imaging without radiation. However, MRI costs about three times more than a CT scan and has lower accuracy and much longer image acquisition times. Hence, this prevent its widespread use in stone imaging. [38]
## Other Diagnostic Studies
- CT renal angiography, CT angiography, and DMSA radioisotope scan can be used to diagnose renal infarction. [20]
- In renal infarction patients, the CT angiography is the initial tool of choice, but definite diagnosis is made by renal angiography. The classic finding is of a wedge-shaped zone of peripheral diminished density without enhancement. [30]
- Renal doppler: Doppler evaluation of renal arterial and venous blood flow should be able to detect global or major segmental renal infarction by demonstrating the absence of blood flow. However, segmental renal infarction has more risk to be missed by Doppler than global renal infarction.[39]
- ECG, Echocardiography and Holter monitoring: They are done to rule out other underlying systemic conditions such as atrial fibrillation, infective endocarditis, previous infarction, and valvular or ischemic heart disease resulting in renal infarction.[20]
## Tips to remember[25]
- NCCT is the most accurate technique for evaluating flank pain.
- Low-dose NCCT should be performed when evaluating for renal or ureteral stones.
- If there is uncertainty about whether a calcific density represents a ureteral stone or a phlebolith, intravenous contrast material can be administered and excretory-phase images obtained for definitive diagnosis.
- USG is the best initial study for pregnant patients with flank pain.
- Abdominal radiography combined with USG may be able to diagnose most clinically significant stones; and should be considered in young patients and those with known stone disease.
- MRI could be considered to evaluate for hydronephrosis though is less accurate for the direct visualization of renal and ureteral stones.
# Treatment
- Treatment can be provided as an either outpatient or inpatient. Inpatient treatment is usually required in elderly, immunocompromised, very young, pregnant females, poorly controlled diabetic patients, renal transplant patients, patients with urinary tract structural anomalies, or those who cannot tolerate oral intake.
- The mainstay of treatment is analgesics, antipyretics, and antibiotics. Optimal timing of intervention for renal colic depends on the underlying etiology. For an obstructing stone, an intervention is suggested even in asymptomatic patients after 30 days due to the increased risk of scarring and other complications. [7]
- NSIADS: Immediate intervention with analgesia and antiemetics. NSAIDs and opiates are first-line therapies for analgesia. NSAIDs work in two ways in renal colic. First, NSAIDs decrease the production of arachidonic acid metabolites which mediate pain receptors and alleviates the pain caused by distension of the renal capsule. Additionally, they cause contraction of the efferent arterioles to the glomerulus causing a reduction in glomerular filtration, and subsequently reduces hydrostatic pressure across the glomerulus. As patients are frequently unable to tolerate oral medications due to nauseous sensation, parenteral NSAIDs such as ketorolac (15 mg to 30 mg intravenously (IV) or intramuscularly (IM)) or diclofenac (37.5 mg IV) are most commonly used. [40]
- LIDOCAINE: Successful use of intravenous lidocaine for renal colic has been reported. The protocol is to inject lidocaine 120 mg in 100 mL normal saline intravenously over 10 minutes for pain management. It has been quite effective for intractable renal colic unresponsive to standard therapy and typically starts to work in 3-5 minutes. No adverse events have been reported.[41]
- OPIATES: Opiate pain medication such as morphine sulfate (0.1 mg/kg IV or IM) or hydromorphone (0.02 mg/kg IV or IM) can also be used effectively for analgesia especially when other measures have failed. However, opiates are associated with respiratory depression, sedation and a risk of dependence associated with prolonged opiate use. Anti-emetic agents may be given along with the narcotics as nausea and emesis may occur with stone passage and commonly complicate narcotic use. [7]
- FLUIDS: Although there is no evidence to support that empiric fluid will help “flush out” a stone; however, many patients are dehydrated secondary to decreased oral intake or vomiting and can benefit from hydration.[7]
- MEDICAL EXPLUSIVE THERAPY: Alpha 1 adrenergic receptors exist in increasing concentration in the distal ureter. The use of alpha blockade medications (for example: tamsulosin, nifedipine, alfuzosin or doxazosin) is theorized to facilitate stone passage by decreasing intra-ureteral pressure and dilating the distal ureter. However, data from randomized control trials stated them useful in passing smaller stones lodged in the lower or distal ureter; and of little help in larger stones in the proximal ureter.[42]
- CONSERVATIVE VS SURGICAL MANAGEMENT: A stone’s size is an important factor together with symptom severity, degree of obstruction, presence or absence of infection, intractable pain, and level of renal function in deciding whether to manage the stone initially by observation, awaiting spontaneous passage, or to intervene by urological consultation with a surgical procedure. Stones vary from less than 2 mm to greater than 2 cm in diameter. [24]
≤4 mm width: Small stones tend to pass spontaneously in most cases.
5 mm width: 50% chance of spontaneous passage if in the proximal ureter and a better chance if in the distal ureter. Overall, for stones ≤5 mm, approximately 68% will pass spontaneously.
>5 mm and ≤10 mm: An approximately 47% will pass spontaneously. One study found that stones >9mm had only a 25% chance of spontaneous passage. Distal stones are more likely to clear than proximal stones (proximal ureter 48%, mid-ureter 60%, distal ureter 75% passage rate).
Thus, symptomatic management and close follow-up with the anticipation of stone passage is a reasonable treatment of choice.
- ≤4 mm width: Small stones tend to pass spontaneously in most cases.
- 5 mm width: 50% chance of spontaneous passage if in the proximal ureter and a better chance if in the distal ureter. Overall, for stones ≤5 mm, approximately 68% will pass spontaneously.
- >5 mm and ≤10 mm: An approximately 47% will pass spontaneously. One study found that stones >9mm had only a 25% chance of spontaneous passage. Distal stones are more likely to clear than proximal stones (proximal ureter 48%, mid-ureter 60%, distal ureter 75% passage rate).
- Thus, symptomatic management and close follow-up with the anticipation of stone passage is a reasonable treatment of choice.
- SURGICAL OPTIONS: It is a definitive management of impacted stones. There are several invasive methods to improve stone passage. [43][44]
Shock wave lithotripsy: A high energy shock waves are used to fragment stones
Ureteroscopy with either laser or electrohydraulic stone fragmentation
Double J stent or percutaneous nephrostomy: It is used in the presence of infection to help with urinary drainage of the affected renal unit with definitive stone therapy postponed until the patient is stable
Open surgery
- Shock wave lithotripsy: A high energy shock waves are used to fragment stones
- Ureteroscopy with either laser or electrohydraulic stone fragmentation
- Double J stent or percutaneous nephrostomy: It is used in the presence of infection to help with urinary drainage of the affected renal unit with definitive stone therapy postponed until the patient is stable
- Open surgery
- NERVE BLOCK: It can often be helpful especially in chronic cases of flank pain. An anesthetic injection is typically injected proximal to the area of the 11th or 12th intercostal nerve. Good efficacy of a nerve block suggests a musculoskeletal or neuropathic etiology. Paraveterbral, splanchnic, and intercostal nerve blocks have all shown varying degrees of efficacy in relief from flank pain. [45] [46] [47]
- ANTIBIOTICS in UTI: [48] [49]
Trimethoprim/Sulfamethoxazole: It is given for 3 days as a mini-dose therapy, but resistance rates are high in many areas.
First-generation cephalosporins: They are good choices for mini-dose therapy.
Nitrofurantoin: It is a good choice for uncomplicated UTI; but it is bacteriostatic, not bacteriocidal, and must be used for 5 to 7 days.
Fluoroquinolones: It has a high resistance but are a favorite of urologists for some reason. Recent precautions from the FDA about fluoroquinolone side effects should be heeded. Recently the FDA approved fosfomycin as a single-dose therapy for uncomplicated UTI caused by E coli. Adjunctive therapy with phenazopyridine for several days may help provide symptom relief.
Even without treatment, the UTI will spontaneously resolve in about 20% of women. The likelihood that a female will develop acute pyelonephritis is very small. Asymptomatic bacteriuria is quite common and requires no treatment except in pregnant women, those who are immunosuppressed, have undergone a transplant or a urological procedure.
- Trimethoprim/Sulfamethoxazole: It is given for 3 days as a mini-dose therapy, but resistance rates are high in many areas.
- First-generation cephalosporins: They are good choices for mini-dose therapy.
- Nitrofurantoin: It is a good choice for uncomplicated UTI; but it is bacteriostatic, not bacteriocidal, and must be used for 5 to 7 days.
- Fluoroquinolones: It has a high resistance but are a favorite of urologists for some reason. Recent precautions from the FDA about fluoroquinolone side effects should be heeded. Recently the FDA approved fosfomycin as a single-dose therapy for uncomplicated UTI caused by E coli. Adjunctive therapy with phenazopyridine for several days may help provide symptom relief.
- Even without treatment, the UTI will spontaneously resolve in about 20% of women. The likelihood that a female will develop acute pyelonephritis is very small. Asymptomatic bacteriuria is quite common and requires no treatment except in pregnant women, those who are immunosuppressed, have undergone a transplant or a urological procedure.
- ANTIBIOTICS in Pyelonephritis: The initial selection of antibiotics will be empiric and should be based on the local antibiotic resistance. Antibiotic therapy should then be adjusted based on the results of the urine culture. Most uncomplicated cases of acute pyelonephritis will be caused by E. coli for which patients can be treated with oral cephalosporins or TMP-SMX for 14 days. Complicated cases of acute pyelonephritis require intravenous (IV) antibiotic treatment such as piperacillin-tazobactam, fluoroquinolones, meropenem, and cefepime until there are clinical improvements. Vancomycin can be used in patients allergic to penicillin. [4]
# Preventive measures
- Nephrolithiasis and Urolithiasis:[50]
Fluid intake: Increase it to optimize urine output to 2-2.5ltr/daily.
Calcium stones and high urine calcium: Patients should limit sodium intake and maintain a goal of moderate calcium intake of 1-1.2 kg dietary calcium daily.
A healthy lifestyle including weight loss if overweight/obese is encouraged.
Hyperuricosuric calcium stone: Those with calcium stones and low urinary citrate or those with uric acid stones and high urinary uric acid should increase intake of fruits and vegetables and decrease non-dairy animal protein. They may benefit from potassium citrate supplementation and prophylactic allopurinol.
Recurrent calcium stones and high urinary calcium: Thiazide diuretics are indicated to reduce the amount of urinary calcium.
Hyperoxaluria: Patients should be encouraged to lower their oxalate intake (spinach, nuts, chocolate, green leafy vegetables).
Avoidance of fish oil and vitamin C has also been shown to reduce the risk of stone formation.
Intake of citric acid (lemon juice, orange juice, melon juice) has also been shown to be beneficial in stone prevention.
Despite common belief, a diet with higher calcium intake (milk, tofu, orange juice, almonds), has been shown to reduce the risk of stone formation because calcium will bind with oxalate in the gut, reducing the amount of urinary oxalate available to precipitate into a stone.
- Fluid intake: Increase it to optimize urine output to 2-2.5ltr/daily.
- Calcium stones and high urine calcium: Patients should limit sodium intake and maintain a goal of moderate calcium intake of 1-1.2 kg dietary calcium daily.
- A healthy lifestyle including weight loss if overweight/obese is encouraged.
- Hyperuricosuric calcium stone: Those with calcium stones and low urinary citrate or those with uric acid stones and high urinary uric acid should increase intake of fruits and vegetables and decrease non-dairy animal protein. They may benefit from potassium citrate supplementation and prophylactic allopurinol.
- Recurrent calcium stones and high urinary calcium: Thiazide diuretics are indicated to reduce the amount of urinary calcium.
- Hyperoxaluria: Patients should be encouraged to lower their oxalate intake (spinach, nuts, chocolate, green leafy vegetables).
- Avoidance of fish oil and vitamin C has also been shown to reduce the risk of stone formation.
- Intake of citric acid (lemon juice, orange juice, melon juice) has also been shown to be beneficial in stone prevention.
- Despite common belief, a diet with higher calcium intake (milk, tofu, orange juice, almonds), has been shown to reduce the risk of stone formation because calcium will bind with oxalate in the gut, reducing the amount of urinary oxalate available to precipitate into a stone.
- Urinary tract infection and Pyelonephritis: [51]
The key to prevent recurrent episodes is the patient education.
Fluid intake: It should be increased to maintain vigorous urine flow and avoid dehydration to prevent acute pyelonephritis and improves kidney function.
Sexually active women: They should try to void right after sexual intercourse as this can help flush the bacteria out of the bladder because bacteria in the bladder can increase by ten-fold after intercourse. After urination, women should wipe from front to back, not from the anal area forward, which seems to drag pathogenic organisms nearer to the urethra.
Recurrent UTIs: Prophylactic antibiotics should be used.
Non-medical remedies: The use of cranberry juice and probiotics may help to reduce the severity and frequency of UTI in some women.
- The key to prevent recurrent episodes is the patient education.
- Fluid intake: It should be increased to maintain vigorous urine flow and avoid dehydration to prevent acute pyelonephritis and improves kidney function.
- Sexually active women: They should try to void right after sexual intercourse as this can help flush the bacteria out of the bladder because bacteria in the bladder can increase by ten-fold after intercourse. After urination, women should wipe from front to back, not from the anal area forward, which seems to drag pathogenic organisms nearer to the urethra.
- Recurrent UTIs: Prophylactic antibiotics should be used.
- Non-medical remedies: The use of cranberry juice and probiotics may help to reduce the severity and frequency of UTI in some women. | https://www.wikidoc.org/index.php/Colicky_flank_pain | |
2dcb5a46788be30ba20152a0db92b2ebcc74d69b | wikidoc | Colposcopy | Colposcopy
# Overview
Colposcopy or colcoscopy is a medical diagnostic procedure to examine an illuminated, magnified view of the cervix and the tissues of the vagina and vulva. Many premalignant lesions and malignant lesions in these areas have discernible characteristics which can be detected thorough the examination. It is done using a colposcope, which provides an enlarged view of the areas, allowing the colposcopist to visually distinguish normal from abnormal appearing tissue and take directed biopsies for further pathological examination. The main goal of colposcopy is to prevent cervical cancer by detecting precancerous lesions early and treating them. The procedure was developed in 1925 by the German physician Hans Hinselmann.
# Indications for colposcopy
Most women undergo a colposcopic examination to further investigate a cytological abnormality on their pap smears. Other indications for a woman to have a colposcopy include:
- assessment of diethylstilbestrol (DES) exposure in utero,
- immunosuppression such as HIV infection, or
- an abnormal appearance of the cervix as noted by a physician.
Many physicians base their current evaluation and treatment decisions on the report "Guidelines for the Management of Cytological Abnormalities and Cervical Cancer Precursors", created by the American Society for Colposcopy and Cervical Pathology, during a September 2001 conference.
# The procedure
During the initial evaluation, a medical history is obtained, including gravidity (number of prior pregnancies), parity (number of prior deliveries), last menstrual period, contraception use, prior abnormal pap smear results, allergies, significant past medical history, other medications, prior cervical procedures, and smoking history. In some cases, a pregnancy test may be performed before the procedure. The procedure is fully described to the patient, questions are asked and answered, and she then signs a consent form.
A colposcope is used to identify visible clues suggestive of abnormal tissue. It functions as a lighted binocular microscope to magnify the view of the cervix, vagina, and vulvar surface. Low power (2× to 6×) may be used to obtain a general impression of the surface architecture. Medium (8× to 15×) and high (15× to 25×) powers are utilized to evaluate the vagina and cervix. The higher powers are often necessary to identify certain vascular patterns that may indicate the presence of more advanced precancerous or cancerous lesions. Various light filters are available to highlight different aspects of the surface of the cervix. Acetic acid solution and iodine solution (Lugol's or Schiller's) are applied to the surface to improve visualization of abnormal areas.
Colposcopy is performed with the woman on her back, legs in stirrups, and buttocks close to the lower edge of the table (a position known as the dorsal lithotomy position). A speculum is placed in the vagina after the vulva is examined for any suspicious lesions.
Three percent acetic acid is applied to the cervix using cotton swabs. The transformation zone is a critical area on the cervix where many precancerous and cancerous lesions most often arise. The ability to see the transformation zone and the entire extent of any lesion visualized determines whether an adequate colposcopic examination is attainable.
Areas of the cervix which turn white after the application of acetic acid or have an abnormal vascular pattern are often considered for biopsy. If no lesions are visible, an iodine solution may be applied to the cervix to help highlight areas of abnormality.
After a complete examination, the colposcopist determines the areas with the highest degree of visible abnormality and obtains biopsies from these areas using a long biopsy instrument. Some doctors consider anesthesia unnecessary, however, many colposcopists now recommend and use a topical anesthetic such as lidocaine or a cervical block to diminish patient discomfort, particularly if many biopsy samples are taken.
Following any biopsies, an endocervical curettage (ECC) is often done. The ECC utilizes a long straight curette to scrape the inside of the cervical canal. The ECC should never be done on a pregnant woman. Monsel's solution is applied with large cotton swabs to the surface of the cervix to control bleeding. This solution looks like mustard and becomes black in color when exposed to blood. After the procedure this material will be expelled naturally: women can expect to have a thin coffee-ground like discharge for up to several days after the procedure.
# Complications
Significant complications from a colposcopy are not common, but may include bleeding, infection at the biopsy site or endometrium, and failure to identify the lesion. Monsel's solution and silver nitrate interfere with interpretation of biopsy specimen, so these substances should not be applied until all biopsies have been taken. Most patients experience some degree of pain during the curettage, and almost all experience pain during the biopsy.
# Follow up
Adequate follow-up is critical to the success of this procedure. Human Papilloma Virus (HPV) is a common infection and the underlying cause for most cervical dysplasia. Women should be counseled on the benefits of safe sex for reducing their risks of contracting and spreading the HPV virus.
A new vaccination against HPV (Gardasil) was approved June 8, 2006 by the US Food and Drug Administration after being tested for five years on 20,541 girls from age 16 to 26. The vaccine is indicated for prevention of cervical cancer, precancerous and dysplastic lesions and genital warts caused by HPV types 6, 11, 16 and 18. Adequate widespread vaccination may reduce the need for colposcopic examinations in the future.
Smoking predisposes women to developing cervical abnormalities. A smoking cessation program should be part of the treatment plan for women who smoke.
Without proper treatment, minor abnormalities may develop into cancerous lesions. Various treatments exist for significant lesions, most commonly cryotherapy, loop electrical excision procedure (LEEP), and laser ablation.
# Future technologies
Colposcopy is the "gold standard" tool in the United States for diagnosing cervical abnormalities after an abnormal pap smear. The procedure requires many resources and can be expensive to perform, making it a less-than-ideal screening tool.
Newer visualization techniques on the horizon utilize broad-band light (e.g., direct visualization, speculoscopy, cervicography, and colposcopy) and electronic detection methods (e.g., Polarprobe and in-vivo Spectroscopy). These techniques are less expensive and can be performed with significantly less training. At this point, these newer techniques have not been validated by large-scale trials and are not in general use. | Colposcopy
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Colposcopy or colcoscopy is a medical diagnostic procedure to examine an illuminated, magnified view of the cervix and the tissues of the vagina and vulva. Many premalignant lesions and malignant lesions in these areas have discernible characteristics which can be detected thorough the examination. It is done using a colposcope, which provides an enlarged view of the areas, allowing the colposcopist to visually distinguish normal from abnormal appearing tissue and take directed biopsies for further pathological examination. The main goal of colposcopy is to prevent cervical cancer by detecting precancerous lesions early and treating them. The procedure was developed in 1925 by the German physician Hans Hinselmann.
# Indications for colposcopy
Most women undergo a colposcopic examination to further investigate a cytological abnormality on their pap smears. Other indications for a woman to have a colposcopy include:
- assessment of diethylstilbestrol (DES) exposure in utero,
- immunosuppression such as HIV infection, or
- an abnormal appearance of the cervix as noted by a physician.
Many physicians base their current evaluation and treatment decisions on the report "Guidelines for the Management of Cytological Abnormalities and Cervical Cancer Precursors", created by the American Society for Colposcopy and Cervical Pathology, during a September 2001 conference. [1]
# The procedure
During the initial evaluation, a medical history is obtained, including gravidity (number of prior pregnancies), parity (number of prior deliveries), last menstrual period, contraception use, prior abnormal pap smear results, allergies, significant past medical history, other medications, prior cervical procedures, and smoking history. In some cases, a pregnancy test may be performed before the procedure. The procedure is fully described to the patient, questions are asked and answered, and she then signs a consent form.
A colposcope is used to identify visible clues suggestive of abnormal tissue. It functions as a lighted binocular microscope to magnify the view of the cervix, vagina, and vulvar surface. Low power (2× to 6×) may be used to obtain a general impression of the surface architecture. Medium (8× to 15×) and high (15× to 25×) powers are utilized to evaluate the vagina and cervix. The higher powers are often necessary to identify certain vascular patterns that may indicate the presence of more advanced precancerous or cancerous lesions. Various light filters are available to highlight different aspects of the surface of the cervix. Acetic acid solution and iodine solution (Lugol's or Schiller's) are applied to the surface to improve visualization of abnormal areas.
Colposcopy is performed with the woman on her back, legs in stirrups, and buttocks close to the lower edge of the table (a position known as the dorsal lithotomy position). A speculum is placed in the vagina after the vulva is examined for any suspicious lesions.
Three percent acetic acid is applied to the cervix using cotton swabs. The transformation zone is a critical area on the cervix where many precancerous and cancerous lesions most often arise. The ability to see the transformation zone and the entire extent of any lesion visualized determines whether an adequate colposcopic examination is attainable.
Areas of the cervix which turn white after the application of acetic acid or have an abnormal vascular pattern are often considered for biopsy. If no lesions are visible, an iodine solution may be applied to the cervix to help highlight areas of abnormality.
After a complete examination, the colposcopist determines the areas with the highest degree of visible abnormality and obtains biopsies from these areas using a long biopsy instrument. Some doctors consider anesthesia unnecessary, however, many colposcopists now recommend and use a topical anesthetic such as lidocaine or a cervical block to diminish patient discomfort, particularly if many biopsy samples are taken.
Following any biopsies, an endocervical curettage (ECC) is often done. The ECC utilizes a long straight curette to scrape the inside of the cervical canal. The ECC should never be done on a pregnant woman. Monsel's solution is applied with large cotton swabs to the surface of the cervix to control bleeding. This solution looks like mustard and becomes black in color when exposed to blood. After the procedure this material will be expelled naturally: women can expect to have a thin coffee-ground like discharge for up to several days after the procedure.
# Complications
Significant complications from a colposcopy are not common, but may include bleeding, infection at the biopsy site or endometrium, and failure to identify the lesion. Monsel's solution and silver nitrate interfere with interpretation of biopsy specimen, so these substances should not be applied until all biopsies have been taken. Most patients experience some degree of pain during the curettage, and almost all experience pain during the biopsy.
# Follow up
Adequate follow-up is critical to the success of this procedure. Human Papilloma Virus (HPV) is a common infection and the underlying cause for most cervical dysplasia. Women should be counseled on the benefits of safe sex for reducing their risks of contracting and spreading the HPV virus.[2]
A new vaccination against HPV (Gardasil) was approved June 8, 2006 by the US Food and Drug Administration after being tested for five years on 20,541 girls from age 16 to 26. The vaccine is indicated for prevention of cervical cancer, precancerous and dysplastic lesions and genital warts caused by HPV types 6, 11, 16 and 18. Adequate widespread vaccination may reduce the need for colposcopic examinations in the future.
Smoking predisposes women to developing cervical abnormalities. A smoking cessation program should be part of the treatment plan for women who smoke.
Without proper treatment, minor abnormalities may develop into cancerous lesions. Various treatments exist for significant lesions, most commonly cryotherapy, loop electrical excision procedure (LEEP), and laser ablation.
# Future technologies
Colposcopy is the "gold standard" tool in the United States for diagnosing cervical abnormalities after an abnormal pap smear. The procedure requires many resources and can be expensive to perform, making it a less-than-ideal screening tool.
Newer visualization techniques on the horizon utilize broad-band light (e.g., direct visualization, speculoscopy, cervicography, and colposcopy) and electronic detection methods (e.g., Polarprobe and in-vivo Spectroscopy). These techniques are less expensive and can be performed with significantly less training. At this point, these newer techniques have not been validated by large-scale trials and are not in general use. | https://www.wikidoc.org/index.php/Colposcope | |
dab3adb7f20d1defe770db448b010e7f156e599e | wikidoc | Combustion | Combustion
Combustion or burning is a complex sequence of exothermic chemical reactions between a fuel and an oxidant accompanied by the production of heat or both heat and light in the form of either a glow or flames.
Direct combustion by atmospheric oxygen is a reaction mediated by radical intermediates. The conditions for radical production are naturally produced by thermal runaway, where the heat generated by combustion is necessary to maintain the high temperature necessary for radical production.
In a complete combustion reaction, a compound reacts with an oxidizing element, such as oxygen or fluorine, and the products are compounds of each element in the fuel with the oxidizing element. For example:
A simpler example can be seen in the combustion of hydrogen and oxygen, which is a commonly used reaction in rocket engines:
The result is simply water vapor.
In the large majority of the real world uses of combustion, the oxygen (O2) oxidant is obtained from the ambient air and the resultant flue gas from the combustion will contain nitrogen:
As can be seen, when air is the source of the oxygen, nitrogen is by far the largest part of the resultant flue gas.
In reality, combustion processes are never perfect or complete. In flue gases from combustion of carbon (as in coal combustion) or carbon compounds (as in combustion of hydrocarbons, wood etc.) both unburned carbon (as soot) and carbon compounds (CO and others) will be present. Also, when air is the oxidant, some nitrogen will be oxidized to various nitrogen oxides (NOx).
# Types
## Rapid
Rapid combustion is a form of combustion in which large amounts of heat and light energy are released, which often results in a fire. This is used in a form of machinery such as internal combustion engines and in thermobaric weapons. Sometimes, a large volume of gas is liberated in combustion besides the production of heat and light.The sudden evolution of large quantities of gas creates excessive pressure that produces a loud noise.Such a combustion is known as an explosion.
## Slow
Slow combustion is a form of combustion which takes place at low temperatures. Cellular respiration is an example of slow combustion.
## Complete
In complete combustion, the reactant will burn in oxygen, producing a limited number of products. When a hydrocarbon burns in oxygen, the reaction will only yield carbon dioxide and water. When a hydrocarbon or any fuel burns in air, the combustion products will also include nitrogen. When elements such as carbon, nitrogen, sulfur, and iron are burned, they will yield the most common oxides. Carbon will yield carbon dioxide. Nitrogen will yield nitrogen dioxide. Sulfur will yield sulfur dioxide. Iron will yield iron(III) oxide. It should be noted that complete combustion is almost impossible to achieve. In reality, as actual combustion reactions come to equilibrium, a wide variety of major and minor species will be present. For example, the combustion of methane in air will yield, in addition to the major products of carbon dioxide and water, the minor product carbon monoxide and nitrogen oxides, which are products of a side reaction (oxidation of nitrogen).
## Turbulent
Turbulent combustion is a combustion characterized by turbulent flows. It is the most used for industrial application (e.g. gas turbines, diesel engines, etc.) because the turbulence helps the mixing process between the fuel and oxidizer.
## Microgravity
Nearly every Flame behaves differently in the Microgravity environment. Microgravity combustion research contributes to understanding of spacecraft fire safety and diverse aspects of combustion physics.
## Incomplete
Incomplete combustion occurs when there isn't enough oxygen to allow the fuel (usually a hydrocarbon) to react completely with the oxygen to produce carbon dioxide and water, also when the combustion is quenched by a heat sink such as a solid surface or flame trap. When a hydrocarbon burns in air, the reaction will yield carbon dioxide, water, carbon monoxide, pure carbon (soot or ash) and various other compounds such as nitrogen oxides.
The quality of combustion can be improved by design of combustion devices, such as burners and internal combustion engines. Further improvements are achievable by catalytic after-burning devices (such as catalytic converters) or by the simple partial return of the exhaust gases into the combustion process. Such devices are required by environmental legislation for cars in most countries, and may be necessary in large combustion devices, such as thermal power plants, to reach legal emission standards.
## Smouldering
Smouldering combustion is a flameless form of combustion, deriving its heat from heterogeneous reactions occurring on the surface of a solid fuel when heated in an oxidizing environment. The fundamental difference between smouldering and flaming combustion is that in smouldering, the oxidation of the reactant species occurs on the surface of the solid rather than in the gas phase. The characteristic temperature and heat released during smouldering are low compared to those in the flaming combustion of a solid. Typical values in smouldering are around 600 °C for the peak temperature and 5 kJ/g-O2 for the heat released; typical values during flaming are around 1500 °C and 13 kJ/g-O2 respectively. These characteristics cause smoulder to propagate at low velocities, typically around 0.1 mm/s, which is about two orders of magnitude lower than the velocity of flame spread over a solid. In spite of its weak combustion characteristics, smouldering is a significant fire hazard.
# Combustion with other oxidants
Oxygen can be assumed as the oxidant when talking about combustion, but other oxidants exist. Nitrous oxide is used in rockets and in motorsport; it produces oxygen at over 1300 C. Fluorine, another oxidizing element, can produce a combustion reaction, to produce fluorinated products (rather than oxides). For example, mixtures of gaseous fluorine and methane are explosive, just like mixtures of oxygen and methane. Chlorine trifluoride is a strong fluorinating agent that ignites fuels more readily than oxygen.
# Chemical equation
Generally, the chemical equation for stoichiometric burning of hydrocarbon in oxygen is as follows:
For example, the burning of propane is:
The simple word equation for the combustion of a hydrocarbon in oxygen is:
If the combustion takes place using air as the oxygen source, the nitrogen can be added to the equation, although it does not react, to show the composition of the flue gas:
For example, the burning of propane is:
The simple word equation for the combustion of a hydrocarbon in air is:
Nitrogen may also oxidize when there is an excess of oxygen. The reaction is thermodynamically favored only at high temperatures. Diesel engines are run with an excess of oxygen to combust small particles that tend to form with only a stoichiometric amount of oxygen, necessarily producing nitrogen oxide emissions. Both the United States and European Union are planning to impose limits to nitrogen oxide emissions, which necessitate the use of a special catalytic converter or treatment of the exhaust with urea.
# Fuels
## Liquid fuels
Combustion of a liquid fuel in an oxidizing atmosphere actually happens in the gas phase. It is the vapour that burns, not the liquid. Therefore, a liquid will normally catch fire only above a certain temperature, its flash point. The flash point of a liquid fuel is the lowest temperature at which it can form an ignitable mix with air. It is also the minimum temperature at which there is enough evaporated fuel in the air to start combustion.
## Solid fuels
The act of combustion consists of three relatively distinct but overlapping phases:
- Preheating phase, when the unburned fuel is heated up to its flash point and then fire point. Flammable gases start being evolved in a process similar to dry distillation.
- Distillation phase or gaseous phase, when the mix of evolved flammable gases with oxygen is ignited. Energy is produced in the form of heat and light. Flames are often visible. Heat transfer from the combustion to the solid maintains the evolution of flammable vapours.
- Charcoal phase or solid phase, when the output of flammable gases from the material is too low for persistent presence of flame and the charred fuel does not burn rapidly anymore but just glows and later only smoulders.
# Reaction mechanism
Combustion in oxygen is a radical chain reaction where many distinct radical intermediates participate.
The high energy required for initiation is explained by the unusual structure of the dioxygen molecule. The lowest-energy configuration of the dioxygen molecule is a stable, relatively unreactive diradical in a triplet spin state. Bonding can be described with three bonding electron pairs and two antibonding electrons, whose spins are aligned, such that the molecule has nonzero total angular momentum. Most fuels, on the other hand, are in a singlet state, with paired spins and zero total angular momentum. Interaction between the two is quantum mechanically a "forbidden transition", i.e. possible with a very low probability. To initiate combustion, energy is required to force dioxygen into a spin-paired state, or singlet oxygen. This intermediate is extremely reactive. The energy is supplied as heat. The reaction produces heat, which keeps it going.
Combustion of hydrocarbons is thought to be initiated by the abstraction of a hydride radical (H) from the fuel to oxygen, to give a hydroperoxide radical (HOO). This reacts further to give hydroperoxides, which break up to give hydroxyl radicals. There are a great variety of these processes that produce fuel radicals and oxidizing radicals. Oxidizing species include singlet oxygen, hydroperoxide, hydroxyl, monatomic oxygen, and hydroperoxyl (OH2). Such intermediates are short-lived and cannot be isolated. However, non-radical intermediates are stable and are produced in incomplete combustion. An example is acetaldehyde produced in the combustion of ethanol. An intermediate in the combustion of carbon and hydrocarbons, carbon monoxide, is of special importance because it is a poisonous gas.
Solid fuels also undergo a great number of pyrolysis reactions that give more easily oxidized, gaseous fuels. These reactions are endothermic and require constant energy input from the combustion reactions. A lack of oxygen or other poorly designed conditions result in these noxious and carcinogenic pyrolysis products being emitted as thick, black smoke.
# Temperature
Assuming perfect combustion conditions, such as complete combustion under adiabatic conditions (i.e., no heat loss or gain), the adiabatic combustion temperature can be determined. The formula that yields this temperature is based on the first law of thermodynamics and takes note of the fact that the heat of combustion is used entirely for heating the fuel, the combustion air or oxygen, and the combustion product gases (commonly referred to as the flue gas).
In the case of fossil fuels burnt in air, the combustion temperature depends on
- the heating value
- the stoichiometric air to fuel ratio {\lambda}
- the specific heat capacity of fuel and air
- the air and fuel inlet temperatures
The adiabatic combustion temperature (also known as the adiabatic flame temperature) increases for higher heating values and inlet air and fuel temperatures and for stoichiometric air ratios approaching one.
Most commonly, the adiabatic combustion temperatures for coals are around 2200 °C (for inlet air and fuel at ambient temperatures and for \lambda = 1.0), around 2150 °C for oil and 2000 °C for natural gas.
In industrial fired heaters, power plant steam generators, and large gas-fired turbines, the more common way of expressing the usage of more than the stoichiometric combustion air is percent excess combustion air. For example, excess combustion air of 15 percent means that 15 percent more than the required stoichiometric air is being used.
# Combustion analysis
This section provides a combustion analysis for a few typical fuels (carbon, hydrogen, sulfur, coal, oil and gas) when the fuel reacts with air at stoichiometric conditions. For this analysis, both fuel and air are taken to be at inlet combustion conditions of 298 K and 1 atm of absolute pressure, and combustion is taken to be complete and with no heat loss.
The analysis also requires knowing the physical properties for the reactants and combustion products, as well as knowing the composition of both the fuel and oxidant compositions.
For solid and liquid type fuels, the fuel compositions is given on weight fraction basis. In this analysis, CH4 is the only gas fuel considered. In order to keep the combustion analysis simple and straightforward, the CH4 composition is also provided on the weight fraction basis. Oxidant composition is usually given on the mole or volume basis.
Table 1 provides some fuel compositions on a weight fraction basis:
Table 2 provides the composition of air:
Again, in this combustion analysis, only the stoichiometric combustion is analyzed. Results of such analysis are provided, including the composition of the combustion gas products on a weight and mole/volume basis, the adiabatic flame temperature, the stoichiometric ratio and the fuel's higher heating value (HHV).
Table 3 provides the composition of the combustion gas products on a weight fraction basis:
Table 4 provides the composition of the combustion gas products on a mole fraction basis (which is the same as a volume basis):
When considering coal, oil and gas as the fuel, coal has the largest amount of CO2 in the combustion gas products on both a weight and mole basis.
Table 5 provides the combustion adiabatic flame temperature, stoichiometric ratio and the fuel's higher heating value:
# Instabilities
Combustion instabilities are typically violent pressure oscillations in a combustion chamber. These pressure oscillations can be as high as 180dB, and long term exposure to these cyclic pressure and thermal loads reduces the life of engine components. In rockets, such as the F1 used in the Saturn V program, instabilities led to massive damage of the combustion chamber and surrounding components. This problem was solved by re-designing the fuel injector. In liquid jet engines the droplet size and distribution can be used to attenuate the instabilities. Combustion instabilities are a major concern in ground-based gas turbine engines because of NOx emissions. The tendency is to run lean, an equivalence ratio less than 1, to reduce the combustion temperature and thus reduce the NOx emissions; however, running the combustor lean makes it very susceptible to combustion instabilities.
The Rayleigh Criterion is the basis for analysis of thermoacoustic combustion instabilities and is evaluated using the Rayleigh Index over one cycle of instability.
When the heat release oscillations are in phase with the pressure oscillations the Rayleigh Index is positive and the magnitude of the thermoacoustic instability increases. Consecutively if the Rayleigh Index is negative then thermoacoustic damping occurs. The Rayleigh Criterion implies that a thermoacoustic instability can be optimally controlled by having heat release oscillations 180 degrees out of phase with pressure oscillations at the same frequency. This minimizes the Rayleigh Index. | Combustion
Combustion or burning is a complex sequence of exothermic chemical reactions between a fuel and an oxidant accompanied by the production of heat or both heat and light in the form of either a glow or flames.
Direct combustion by atmospheric oxygen is a reaction mediated by radical intermediates. The conditions for radical production are naturally produced by thermal runaway, where the heat generated by combustion is necessary to maintain the high temperature necessary for radical production.
In a complete combustion reaction, a compound reacts with an oxidizing element, such as oxygen or fluorine, and the products are compounds of each element in the fuel with the oxidizing element. For example:
A simpler example can be seen in the combustion of hydrogen and oxygen, which is a commonly used reaction in rocket engines:
The result is simply water vapor.
In the large majority of the real world uses of combustion, the oxygen (O2) oxidant is obtained from the ambient air and the resultant flue gas from the combustion will contain nitrogen:
As can be seen, when air is the source of the oxygen, nitrogen is by far the largest part of the resultant flue gas.
In reality, combustion processes are never perfect or complete. In flue gases from combustion of carbon (as in coal combustion) or carbon compounds (as in combustion of hydrocarbons, wood etc.) both unburned carbon (as soot) and carbon compounds (CO and others) will be present. Also, when air is the oxidant, some nitrogen will be oxidized to various nitrogen oxides (NOx).
# Types
## Rapid
Rapid combustion is a form of combustion in which large amounts of heat and light energy are released, which often results in a fire. This is used in a form of machinery such as internal combustion engines and in thermobaric weapons. Sometimes, a large volume of gas is liberated in combustion besides the production of heat and light.The sudden evolution of large quantities of gas creates excessive pressure that produces a loud noise.Such a combustion is known as an explosion.
## Slow
Slow combustion is a form of combustion which takes place at low temperatures. Cellular respiration is an example of slow combustion.
## Complete
In complete combustion, the reactant will burn in oxygen, producing a limited number of products. When a hydrocarbon burns in oxygen, the reaction will only yield carbon dioxide and water. When a hydrocarbon or any fuel burns in air, the combustion products will also include nitrogen. When elements such as carbon, nitrogen, sulfur, and iron are burned, they will yield the most common oxides. Carbon will yield carbon dioxide. Nitrogen will yield nitrogen dioxide. Sulfur will yield sulfur dioxide. Iron will yield iron(III) oxide. It should be noted that complete combustion is almost impossible to achieve. In reality, as actual combustion reactions come to equilibrium, a wide variety of major and minor species will be present. For example, the combustion of methane in air will yield, in addition to the major products of carbon dioxide and water, the minor product carbon monoxide and nitrogen oxides, which are products of a side reaction (oxidation of nitrogen).
## Turbulent
Turbulent combustion is a combustion characterized by turbulent flows. It is the most used for industrial application (e.g. gas turbines, diesel engines, etc.) because the turbulence helps the mixing process between the fuel and oxidizer.
## Microgravity
Nearly every Flame behaves differently in the Microgravity environment. Microgravity combustion research contributes to understanding of spacecraft fire safety and diverse aspects of combustion physics.
## Incomplete
Incomplete combustion occurs when there isn't enough oxygen to allow the fuel (usually a hydrocarbon) to react completely with the oxygen to produce carbon dioxide and water, also when the combustion is quenched by a heat sink such as a solid surface or flame trap. When a hydrocarbon burns in air, the reaction will yield carbon dioxide, water, carbon monoxide, pure carbon (soot or ash) and various other compounds such as nitrogen oxides.
The quality of combustion can be improved by design of combustion devices, such as burners and internal combustion engines. Further improvements are achievable by catalytic after-burning devices (such as catalytic converters) or by the simple partial return of the exhaust gases into the combustion process. Such devices are required by environmental legislation for cars in most countries, and may be necessary in large combustion devices, such as thermal power plants, to reach legal emission standards.
## Smouldering
Smouldering combustion is a flameless form of combustion, deriving its heat from heterogeneous reactions occurring on the surface of a solid fuel when heated in an oxidizing environment. The fundamental difference between smouldering and flaming combustion is that in smouldering, the oxidation of the reactant species occurs on the surface of the solid rather than in the gas phase. The characteristic temperature and heat released during smouldering are low compared to those in the flaming combustion of a solid. Typical values in smouldering are around 600 °C for the peak temperature and 5 kJ/g-O2 for the heat released; typical values during flaming are around 1500 °C and 13 kJ/g-O2 respectively. These characteristics cause smoulder to propagate at low velocities, typically around 0.1 mm/s, which is about two orders of magnitude lower than the velocity of flame spread over a solid. In spite of its weak combustion characteristics, smouldering is a significant fire hazard.
# Combustion with other oxidants
Oxygen can be assumed as the oxidant when talking about combustion, but other oxidants exist. Nitrous oxide is used in rockets and in motorsport; it produces oxygen at over 1300 C. Fluorine, another oxidizing element, can produce a combustion reaction, to produce fluorinated products (rather than oxides). For example, mixtures of gaseous fluorine and methane are explosive, just like mixtures of oxygen and methane. Chlorine trifluoride is a strong fluorinating agent that ignites fuels more readily than oxygen.
# Chemical equation
Generally, the chemical equation for stoichiometric burning of hydrocarbon in oxygen is as follows:
For example, the burning of propane is:
The simple word equation for the combustion of a hydrocarbon in oxygen is:
If the combustion takes place using air as the oxygen source, the nitrogen can be added to the equation, although it does not react, to show the composition of the flue gas:
For example, the burning of propane is:
The simple word equation for the combustion of a hydrocarbon in air is:
Nitrogen may also oxidize when there is an excess of oxygen. The reaction is thermodynamically favored only at high temperatures. Diesel engines are run with an excess of oxygen to combust small particles that tend to form with only a stoichiometric amount of oxygen, necessarily producing nitrogen oxide emissions. Both the United States and European Union are planning to impose limits to nitrogen oxide emissions, which necessitate the use of a special catalytic converter or treatment of the exhaust with urea.
# Fuels
## Liquid fuels
Combustion of a liquid fuel in an oxidizing atmosphere actually happens in the gas phase. It is the vapour that burns, not the liquid. Therefore, a liquid will normally catch fire only above a certain temperature, its flash point. The flash point of a liquid fuel is the lowest temperature at which it can form an ignitable mix with air. It is also the minimum temperature at which there is enough evaporated fuel in the air to start combustion.
## Solid fuels
The act of combustion consists of three relatively distinct but overlapping phases:
- Preheating phase, when the unburned fuel is heated up to its flash point and then fire point. Flammable gases start being evolved in a process similar to dry distillation.
- Distillation phase or gaseous phase, when the mix of evolved flammable gases with oxygen is ignited. Energy is produced in the form of heat and light. Flames are often visible. Heat transfer from the combustion to the solid maintains the evolution of flammable vapours.
- Charcoal phase or solid phase, when the output of flammable gases from the material is too low for persistent presence of flame and the charred fuel does not burn rapidly anymore but just glows and later only smoulders.
# Reaction mechanism
Combustion in oxygen is a radical chain reaction where many distinct radical intermediates participate.
The high energy required for initiation is explained by the unusual structure of the dioxygen molecule. The lowest-energy configuration of the dioxygen molecule is a stable, relatively unreactive diradical in a triplet spin state. Bonding can be described with three bonding electron pairs and two antibonding electrons, whose spins are aligned, such that the molecule has nonzero total angular momentum. Most fuels, on the other hand, are in a singlet state, with paired spins and zero total angular momentum. Interaction between the two is quantum mechanically a "forbidden transition", i.e. possible with a very low probability. To initiate combustion, energy is required to force dioxygen into a spin-paired state, or singlet oxygen. This intermediate is extremely reactive. The energy is supplied as heat. The reaction produces heat, which keeps it going.
Combustion of hydrocarbons is thought to be initiated by the abstraction of a hydride radical (H) from the fuel to oxygen, to give a hydroperoxide radical (HOO). This reacts further to give hydroperoxides, which break up to give hydroxyl radicals. There are a great variety of these processes that produce fuel radicals and oxidizing radicals. Oxidizing species include singlet oxygen, hydroperoxide, hydroxyl, monatomic oxygen, and hydroperoxyl (OH2). Such intermediates are short-lived and cannot be isolated. However, non-radical intermediates are stable and are produced in incomplete combustion. An example is acetaldehyde produced in the combustion of ethanol. An intermediate in the combustion of carbon and hydrocarbons, carbon monoxide, is of special importance because it is a poisonous gas.
Solid fuels also undergo a great number of pyrolysis reactions that give more easily oxidized, gaseous fuels. These reactions are endothermic and require constant energy input from the combustion reactions. A lack of oxygen or other poorly designed conditions result in these noxious and carcinogenic pyrolysis products being emitted as thick, black smoke.
# Temperature
Assuming perfect combustion conditions, such as complete combustion under adiabatic conditions (i.e., no heat loss or gain), the adiabatic combustion temperature can be determined. The formula that yields this temperature is based on the first law of thermodynamics and takes note of the fact that the heat of combustion is used entirely for heating the fuel, the combustion air or oxygen, and the combustion product gases (commonly referred to as the flue gas).
In the case of fossil fuels burnt in air, the combustion temperature depends on
- the heating value
- the stoichiometric air to fuel ratio <math>{\lambda}</math>
- the specific heat capacity of fuel and air
- the air and fuel inlet temperatures
The adiabatic combustion temperature (also known as the adiabatic flame temperature) increases for higher heating values and inlet air and fuel temperatures and for stoichiometric air ratios approaching one.
Most commonly, the adiabatic combustion temperatures for coals are around 2200 °C (for inlet air and fuel at ambient temperatures and for <math>\lambda = 1.0</math>), around 2150 °C for oil and 2000 °C for natural gas.
In industrial fired heaters, power plant steam generators, and large gas-fired turbines, the more common way of expressing the usage of more than the stoichiometric combustion air is percent excess combustion air. For example, excess combustion air of 15 percent means that 15 percent more than the required stoichiometric air is being used.
# Combustion analysis
This section provides a combustion analysis for a few typical fuels (carbon, hydrogen, sulfur, coal, oil and gas) when the fuel reacts with air at stoichiometric conditions. For this analysis, both fuel and air are taken to be at inlet combustion conditions of 298 K and 1 atm of absolute pressure, and combustion is taken to be complete and with no heat loss.
The analysis also requires knowing the physical properties for the reactants and combustion products, as well as knowing the composition of both the fuel and oxidant compositions.
For solid and liquid type fuels, the fuel compositions is given on weight fraction basis. In this analysis, CH4 is the only gas fuel considered. In order to keep the combustion analysis simple and straightforward, the CH4 composition is also provided on the weight fraction basis. Oxidant composition is usually given on the mole or volume basis.
Table 1 provides some fuel compositions on a weight fraction basis:
Table 2 provides the composition of air:
Again, in this combustion analysis, only the stoichiometric combustion is analyzed. Results of such analysis are provided, including the composition of the combustion gas products on a weight and mole/volume basis, the adiabatic flame temperature, the stoichiometric ratio and the fuel's higher heating value (HHV).
Table 3 provides the composition of the combustion gas products on a weight fraction basis:
Table 4 provides the composition of the combustion gas products on a mole fraction basis (which is the same as a volume basis):
When considering coal, oil and gas as the fuel, coal has the largest amount of CO2 in the combustion gas products on both a weight and mole basis.
Table 5 provides the combustion adiabatic flame temperature, stoichiometric ratio and the fuel's higher heating value:
# Instabilities
Combustion instabilities are typically violent pressure oscillations in a combustion chamber. These pressure oscillations can be as high as 180dB, and long term exposure to these cyclic pressure and thermal loads reduces the life of engine components. In rockets, such as the F1 used in the Saturn V program, instabilities led to massive damage of the combustion chamber and surrounding components. This problem was solved by re-designing the fuel injector. In liquid jet engines the droplet size and distribution can be used to attenuate the instabilities. Combustion instabilities are a major concern in ground-based gas turbine engines because of NOx emissions. The tendency is to run lean, an equivalence ratio less than 1, to reduce the combustion temperature and thus reduce the NOx emissions; however, running the combustor lean makes it very susceptible to combustion instabilities.
The Rayleigh Criterion is the basis for analysis of thermoacoustic combustion instabilities and is evaluated using the Rayleigh Index over one cycle of instability.[citation needed]
When the heat release oscillations are in phase with the pressure oscillations the Rayleigh Index is positive and the magnitude of the thermoacoustic instability increases. Consecutively if the Rayleigh Index is negative then thermoacoustic damping occurs. The Rayleigh Criterion implies that a thermoacoustic instability can be optimally controlled by having heat release oscillations 180 degrees out of phase with pressure oscillations at the same frequency. This minimizes the Rayleigh Index.[citation needed] | https://www.wikidoc.org/index.php/Combustion | |
70599044d2866e6ee85b27024d921aa4eefb42e6 | wikidoc | Commissure | Commissure
A commissure is the place where two things are joined. The term is used especially in the fields of anatomy and biology.
In anatomy, commissure can refer to a number of such bodily junctions. The most common usage of the term refers to the brain's commissures, of which there are two—the anterior and posterior—and which consist of fibre tracts that connect the two cerebral hemispheres and span the longitudinal fissure. The term may also refer to the junction of the upper and lower lips, or of the upper and lower eyelids.
In biology, the meeting of the two valves of a brachiopod or clam is a commissure; and in botany, when a fern's laterally expanded vein endings come together in a continuous marginal sorus.
de:Kommissur | Commissure
Template:Wikt
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A commissure is the place where two things are joined. The term is used especially in the fields of anatomy and biology.
In anatomy, commissure can refer to a number of such bodily junctions. The most common usage of the term refers to the brain's commissures, of which there are two—the anterior and posterior—and which consist of fibre tracts that connect the two cerebral hemispheres and span the longitudinal fissure. The term may also refer to the junction of the upper and lower lips, or of the upper and lower eyelids.
In biology, the meeting of the two valves of a brachiopod or clam is a commissure; and in botany, when a fern's laterally expanded vein endings come together in a continuous marginal sorus.
de:Kommissur
Template:WS | https://www.wikidoc.org/index.php/Commissure | |
1b53b9c4c572f7ef964aede2d379d8f0aab8f0b6 | wikidoc | Common Rue | Common Rue
The Common Rue (Ruta graveolens), also known as Herb-of-grace, is a species of rue grown as a herb. It is native to southern Europe. It is sometimes grown as an ornamental plant in gardens, especially because of its bluish leaves, and also sometimes for its tolerance of hot and dry soil conditions. It also is grown as both a medicinal herb and as a condiment.
In European folk medicine, rue is said to relieve gas pains and colic, improve appetite and digestion, and promote the onset of menstruation and uteral contractions. For this reason the refined oil of rue has been cited by the Roman historian Pliny the Elder and the gynecologist Soranus, as a potent abortifacient (inducing abortion). Rue contains pilocarpine which is used in horses to induce abortion, and is a traditional abortifacient among Hispanic people in New Mexico.
Rue can also be made into an ointment for external use against gout, arthritis, rheumatism and neuralgia.
Rue does have a culinary use if used sparingly but it is incredibly bitter and severe discomfort on ingestion may be experienced by some individuals. Although used more extensively in former times it is not a herb that typically suits modern tastes, and thus its use declined considerably over the course of the 20th century to the extent that it is today largely unknown to the general public and most chefs, and unavailable in grocery stores. Rue leaves and berries are an important part of the cuisine of Ethiopia and rue is also used as a traditional flavouring in Greece and other Mediterranean countries. In Istria, there is a grappa/rakija recipe that calls for a sprig of rue. The plant produces seeds that can be used for porridge. The bitter leaf can be added to eggs, cheese, fish, or mixed with damson plums and wine to produce a meat sauce.
Rue is also grown as an ornamental plant, both as a low hedge and so the leaves can be used in nosegays. Most cats dislike the smell of it and therefore it can be used as a deterrent to them (see also Plectranthus caninus). | Common Rue
The Common Rue (Ruta graveolens), also known as Herb-of-grace, is a species of rue grown as a herb. It is native to southern Europe. It is sometimes grown as an ornamental plant in gardens, especially because of its bluish leaves, and also sometimes for its tolerance of hot and dry soil conditions. It also is grown as both a medicinal herb and as a condiment.
In European folk medicine, rue is said to relieve gas pains and colic, improve appetite and digestion, and promote the onset of menstruation and uteral contractions. For this reason the refined oil of rue has been cited by the Roman historian Pliny the Elder and the gynecologist Soranus, as a potent abortifacient (inducing abortion). Rue contains pilocarpine which is used in horses to induce abortion, and is a traditional abortifacient among Hispanic people in New Mexico.[1]
Rue can also be made into an ointment for external use against gout, arthritis, rheumatism and neuralgia.
Rue does have a culinary use if used sparingly but it is incredibly bitter and severe discomfort on ingestion may be experienced by some individuals. Although used more extensively in former times it is not a herb that typically suits modern tastes, and thus its use declined considerably over the course of the 20th century to the extent that it is today largely unknown to the general public and most chefs, and unavailable in grocery stores.[2] Rue leaves and berries are an important part of the cuisine of Ethiopia and rue is also used as a traditional flavouring in Greece and other Mediterranean countries. In Istria, there is a grappa/rakija recipe that calls for a sprig of rue. The plant produces seeds that can be used for porridge. The bitter leaf can be added to eggs, cheese, fish, or mixed with damson plums and wine to produce a meat sauce.
Rue is also grown as an ornamental plant, both as a low hedge and so the leaves can be used in nosegays. Most cats dislike the smell of it and therefore it can be used as a deterrent to them (see also Plectranthus caninus). | https://www.wikidoc.org/index.php/Common_Rue | |
e52f545e195ae19877e908740f89b2d93619f1cb | wikidoc | Complement | Complement
# Biology
- complement system, a cascade of proteins in the blood that form part of innate immunity
- complementary DNA, DNA reverse transcribed from a mature mRNA template
- complementarity (molecular biology), a property whereby double stranded nucleic acids pair with each other
- complementation (genetics), a test to determine if independent recessive mutant phenotypes are caused by mutations in the same gene or in different genes | Complement
# Biology
- complement system, a cascade of proteins in the blood that form part of innate immunity
- complementary DNA, DNA reverse transcribed from a mature mRNA template
- complementarity (molecular biology), a property whereby double stranded nucleic acids pair with each other
- complementation (genetics), a test to determine if independent recessive mutant phenotypes are caused by mutations in the same gene or in different genes
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Complement | |
ae0d336f53fce8b14bb6a8338a4131054c2e9bae | wikidoc | Epithelium | Epithelium
# Overview
In biology and medicine, epithelium is a tissue composed of a layer of cells. Epithelium lines both the outside (skin) and the inside cavities and lumen of bodies. The outermost layer of our skin is composed of dead stratified squamous, keratinized epithelial cells.
Mucous membranes lining the inside of the mouth, the esophagus, and part of the rectum are lined by nonkeratinized stratified squamous epithelium. Other, open to outside body cavities are lined by simple squamous or columnar epithelial cells.
Other epithelial cells line the insides of the lungs, the gastrointestinal tract, the reproductive and urinary tracts, and make up the exocrine and endocrine glands. The outer surface of the cornea is covered with fast-growing, easily-regenerated epithelial cells.
Functions of epithelial cells include secretion, absorption, protection, transcellular transport, sensation detection, and selective permeability.
Endothelium (the inner lining of blood vessels, the heart, and lymphatic vessels) is a specialized form of epithelium. Another type, Mesothelium, forms the walls of the pericardium, pleurae, and peritoneum.
In humans, epithelium is classified as a primary body tissue, the other ones being connective tissue, muscle tissue and nervous tissue.
# Classification
Epithelial cells are classified by the following three factors:
- Shape
- Stratification
- Specializations
## Shape
- Squamous: All Squamous cells are flat cells with an irregular flattened shape. A one-cell layer of simple squamous epithelium forms the alveoli of the respiratory membrane, and the endothelium of capillaries, and is a minimal barrier to diffusion. Other places where squamous cells can be found include the filtration tubules of the kidneys, and the major cavities of the body. These cells are relatively inactive metabolically, and are associated with the diffusion of water, electrolytes, and other substances.
- Cuboidal: As the name suggests, these cells have a shape similar to a cube, meaning its width is the same size as its height. The nuclei of these cells are usually located in the center.
- Columnar: These cells are taller than they are wide. Simple columnar epithelium is made up of a single layer of cells that are longer than they are wide. The nucleus is also closer to the base of the cell. The small intestine is a tubular organ lined with this type of tissue. Unicellular glands called goblet cells are scattered throughout the simple columnar epithelial cells and secrete mucus. The free surface of the columnar cell has tiny hairlike projections called microvilli. They increase the surface area for absorption.
- Transitional: This is a specialized type of epithelium found lining organs that can stretch, such as the urothelium that lines the bladder and ureter of mammals. Since the cells can slide over each other, the appearance of this epithelium depends on whether the organ is distended or contracted: if distended, it appears as if there are only a few layers; when contracted, it appears as if there are several layers.
## Stratification
- Simple: There is a single layer of cells.
- Stratified: More than one layer of cells. The superficial layer is used to classify the layer. Only one layer touches the basal lamina. Stratified cells can usually withstand large amounts of stress.
- Pseudostratified with cilia: This is used mainly in one type of classification (pseudostratified columnar epithelium). There is only a single layer of cells, but the position of the nuclei gives the impression that it is stratified. If a specimen looks stratified, but you can identify cilia, the specimen is pseudostratified ciliated epithelium since stratified epithelium cannot have cilia but may be very rarely found in fetal oesophagus. A cell that contains hairs will be around ten times stronger than a regular cell
## Specializations
- Keratinized cells contain keratin (a cytoskeletal protein). While keratinized epithelium occurs mainly in the skin, it is also found in the mouth and nose, providing a tough, impermeable barrier.
- Ciliated cells have apical plasma membrane extensions composed of microtubules capable of beating rhythmically to move mucus or other substances through a duct. Cilia are common in the respiratory system and the lining of the oviduct.
# Headline text
# Examples
# Cell junctions
A cell junction is a structure within a tissue of a multicellular organism. Cell junctions are especially abundant in epithelial tissues. They consist of protein complexes and provide contact between neighbouring cells, between a cell and the extracellular matrix, or they built up the paracellular barrier of epithelia and control the paracellular transport.
# Secretory epithelia
As stated above, secretion is one major function of epithelial cells. Glands are formed from the invagination / infolding of epithelial cells and subsequent growth in the underlying connective tissue. There are two major classification of glands: endocrine glands and exocrine glands. Endocrine glands are glands that secrete their product directly onto a surface rather than through a duct. This group contains the glands of the Endocrine system
# Embryology
Generally, there are epithelial tissues deriving from all of the embryological germ layers:
- from ectoderm (e.g., the epidermis);
- from endoderm (e.g., the lining of the gastrointestinal tract);
- from mesoderm (e.g., the inner linings of body cavities).
However, it is important to note that pathologists do not consider endothelium and mesothelium (both derived from mesoderm) to be true epithelium. This is because such tissues present very different pathology. For that reason, pathologists label cancers in endothelium and mesothelium sarcomas, while true epithelial cancers are called carcinomas. Also, the filaments that support these mesodermally derived tissues are very distinct. Outside of the field of pathology, the idea that epithelium arise from all three germ layers is generally accepted
# Additional images
# Links
- Parietal cell antibody
- Antibody to GPC
- An Example (cholesteatoma) | Epithelium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In biology and medicine, epithelium is a tissue composed of a layer of cells. Epithelium lines both the outside (skin) and the inside cavities and lumen of bodies. The outermost layer of our skin is composed of dead stratified squamous, keratinized epithelial cells.
Mucous membranes lining the inside of the mouth, the esophagus, and part of the rectum are lined by nonkeratinized stratified squamous epithelium. Other, open to outside body cavities are lined by simple squamous or columnar epithelial cells.
Other epithelial cells line the insides of the lungs, the gastrointestinal tract, the reproductive and urinary tracts, and make up the exocrine and endocrine glands. The outer surface of the cornea is covered with fast-growing, easily-regenerated epithelial cells.
Functions of epithelial cells include secretion, absorption, protection, transcellular transport, sensation detection, and selective permeability.
Endothelium (the inner lining of blood vessels, the heart, and lymphatic vessels) is a specialized form of epithelium. Another type, Mesothelium, forms the walls of the pericardium, pleurae, and peritoneum.
In humans, epithelium is classified as a primary body tissue, the other ones being connective tissue, muscle tissue and nervous tissue.
# Classification
Epithelial cells are classified by the following three factors:
- Shape
- Stratification
- Specializations
## Shape
- Squamous: All Squamous cells are flat cells with an irregular flattened shape. A one-cell layer of simple squamous epithelium forms the alveoli of the respiratory membrane, and the endothelium of capillaries, and is a minimal barrier to diffusion. Other places where squamous cells can be found include the filtration tubules of the kidneys, and the major cavities of the body. These cells are relatively inactive metabolically, and are associated with the diffusion of water, electrolytes, and other substances.
- Cuboidal: As the name suggests, these cells have a shape similar to a cube, meaning its width is the same size as its height. The nuclei of these cells are usually located in the center.
- Columnar: These cells are taller than they are wide. Simple columnar epithelium is made up of a single layer of cells that are longer than they are wide. The nucleus is also closer to the base of the cell. The small intestine is a tubular organ lined with this type of tissue. Unicellular glands called goblet cells are scattered throughout the simple columnar epithelial cells and secrete mucus. The free surface of the columnar cell has tiny hairlike projections called microvilli. They increase the surface area for absorption.
- Transitional: This is a specialized type of epithelium found lining organs that can stretch, such as the urothelium that lines the bladder and ureter of mammals. Since the cells can slide over each other, the appearance of this epithelium depends on whether the organ is distended or contracted: if distended, it appears as if there are only a few layers; when contracted, it appears as if there are several layers.
## Stratification
- Simple: There is a single layer of cells.
- Stratified: More than one layer of cells. The superficial layer is used to classify the layer. Only one layer touches the basal lamina. Stratified cells can usually withstand large amounts of stress.
- Pseudostratified with cilia: This is used mainly in one type of classification (pseudostratified columnar epithelium). There is only a single layer of cells, but the position of the nuclei gives the impression that it is stratified. If a specimen looks stratified, but you can identify cilia, the specimen is pseudostratified ciliated epithelium since stratified epithelium cannot have cilia but may be very rarely found in fetal oesophagus. A cell that contains hairs will be around ten times stronger than a regular cell
## Specializations
- Keratinized cells contain keratin (a cytoskeletal protein). While keratinized epithelium occurs mainly in the skin, it is also found in the mouth and nose, providing a tough, impermeable barrier.
- Ciliated cells have apical plasma membrane extensions composed of microtubules capable of beating rhythmically to move mucus or other substances through a duct. Cilia are common in the respiratory system and the lining of the oviduct.
# Headline text
# Examples
# Cell junctions
A cell junction is a structure within a tissue of a multicellular organism. Cell junctions are especially abundant in epithelial tissues. They consist of protein complexes and provide contact between neighbouring cells, between a cell and the extracellular matrix, or they built up the paracellular barrier of epithelia and control the paracellular transport.
# Secretory epithelia
As stated above, secretion is one major function of epithelial cells. Glands are formed from the invagination / infolding of epithelial cells and subsequent growth in the underlying connective tissue. There are two major classification of glands: endocrine glands and exocrine glands. Endocrine glands are glands that secrete their product directly onto a surface rather than through a duct. This group contains the glands of the Endocrine system
# Embryology
Generally, there are epithelial tissues deriving from all of the embryological germ layers:
- from ectoderm (e.g., the epidermis);
- from endoderm (e.g., the lining of the gastrointestinal tract);
- from mesoderm (e.g., the inner linings of body cavities).
However, it is important to note that pathologists do not consider endothelium and mesothelium (both derived from mesoderm) to be true epithelium. This is because such tissues present very different pathology. For that reason, pathologists label cancers in endothelium and mesothelium sarcomas, while true epithelial cancers are called carcinomas. Also, the filaments that support these mesodermally derived tissues are very distinct. Outside of the field of pathology, the idea that epithelium arise from all three germ layers is generally accepted
# Additional images
-
# Links
- Parietal cell antibody
- Antibody to GPC
- An Example (cholesteatoma) | https://www.wikidoc.org/index.php/Complex_epithelial | |
3e1e22ee8e1d0b09269a780790ee3fe676b4ad7f | wikidoc | Composting | Composting
Composting is the aerobic decomposition of biodegradable organic matter, producing compost. (Or in a simpler form: Composting is the decaying of food, mostly vegetables or manure.) The decomposition is performed primarily by facultative and obligate aerobic bacteria, yeasts and fungi, helped in the cooler initial and ending phases by a number of larger organisms, such as ils, and other families representing ants, nematodes and oligochaete worms.
Composting can be divided into home composting and industrial composting. Essentially the same biological processes are involved in both scales of composting, however techniques and different factors must be taken into account.
# Importance
Composting recycles or "downcycles" organic household and yard waste and manures into an extremely useful humus-like, soil end-product called compost. Examples are fruits, vegetables and yard clippings. Ultimately this permits the return of needed organic matter and nutrients into the foodchain and reduces the amount of "green" waste going into landfills. Composting is widely believed to speed up the natural process of decomposition appreciably as a result of the raised temperatures that often accompany it. The elevated heat results from exothermic processes, and the heat in turn reduces the generational time of microorganisms and thereby speeds the energy and nutrient exchanges taking place. It is a popular misconception that composting is a "controlled" process; if the right environmental circumstances are present the process virtually runs itself. Hence a popular expression, "compost happens". It is nonetheless very necessary to provide as optimal circumstances as possible for large amounts of organic waste to break down properly. This is especially so when it is accompanied by heating, since at elevated temperatures oxygen within the piles is consumed more rapidly, and if not controlled, will lead to malodor.
Decomposition similar to composting occurs throughout nature as garbage dissolves in the absence of all the conditions that modern composters talk about; however, the process can be slow. For example, in the forest bark, wood and leaves break down into humus over 3-7 years. In restricted environments, for example, vegetables in a plastic trash container, decomposition with a lack of air encourages growth of anaerobic microbes, which produce disagreeable odors. Another form of degradation practiced deliberately in absence of oxygen is called anaerobic digestion- an increasingly popular companion to composting as it enables capture of residual energy in the form of biogas, whereas composting releases the majority of bound carbon-energy as excess heat (which helps sanitize the material) as well as copious amounts of biogenic CO2 to the atmosphere.
It is important to distinguish between terms such as "biodegradable", "compostable", and "compost-compatible".
- A biodegradable material is capable of being broken down completely under the action of microorganisms into carbon dioxide, water and biomass. It may take a very long time for a material to biodegrade depending on its environment (e.g. hardwood in an arid area), but it ultimately breaks down completely.
- A compostable material biodegrades substantially under composting conditions, into carbon dioxide, methane, water and compost biomass. Compost biomass refers to the portion of the material that is metabolized by the microorganisms and which is incorporated into the cellular structure of the organisms or converted into humic acids etc. Compost biomass residues from a compostable material are fully biodegradable. "Compostable" is thus a subset of "biodegradable". The size of the material is a factor in determining compostability because it affects the rate of degradation. Large pieces of hardwood may not be compostable under a specific set of composting conditions, whereas sawdust of the same type of wood may be.
- A compost-compatible material does not have to be compostable or even biodegradable. It may biodegrade too slowly to be compostable itself, or it may not biodegrade at all. However, it is not readily distinguishable from the compost on a macroscopic scale and does not have a deleterious effect on the compost (e.g. it is not a biocide). Compost-compatible materials are generally inert and are present in compost at relatively low levels. Examples of compost-compatible materials include sand particles and inert particles of plastic.
## Reducing Waste
Although composting has historically focussed on creating garden-ready soil, it is becoming more important as a tool is reducing solid waste. More than 60 percent of household waste in the United States is recyclable or compostable. But Americans only compost 8 percent of their waste. Surveys have shown that the #1 reason Americans don't compost their waste is because they feel the process is complicated, time-consuming or requires special equipment. However, especially in rural areas, much of the solid waste could be removed from the waste stream by promoting "extremely passive composting" where consumers simply discard their yard waste and kitchen scraps on their own land, regardless of whether the material is ever re-used as "compost". ()
# Materials
Many different materials are suitable for composting organisms. Composters often refer to "C:N" requirements; some materials contain high amounts of carbon in the form of cellulose which the bacteria need for their energy. Other materials contain nitrogen in the form of protein, which provide nutrients for the energy exchanges. It would however be an over-simplification to describe composting as about carbon and nitrogen, as is often portrayed in popular literature. Elemental carbon - such as charcoal - is not compostable nor is a pure form of nitrogen, even in combination with carbon. Not only this, but a great variety of man-made, carbon-containing products, including many textiles and polyethylene, are not compostable - hence the push for biodegradable plastics.
Suitable ingredients with relatively high carbon content include:
- Dry, straw-type material, such as cereal straws
- Autumn leaves
- Sawdust and wood chips
- paper and cardboard (such as corrugated cardboard or newsprint with soy-based inks)
Ingredients with relatively high nitrogen content include:
- Green plant material (fresh or wilted) such as crop residues, hay, grass clippings, weeds
- Manure of poultry and herbivorous animals such as horses, cows and llamas
- Fruit and vegetable trimmings
The most efficient composting occurs by seeking to obtain an initial C:N mix of 25/30 by dry chemical weight. Grass clippings have an average ratio of 10-19 to 1 and dry autumn leaves from 55-100 to 1. Mixing equal parts by volume approximates the ideal range.
Poultry manure provides much nitrogen but with a ratio to carbon that is imbalanced. If composted alone, this results in excessive N-loss in the form of ammonia - and some odor. Horse manure provides a good mix of both, although in modern stables, so much bedding may be used as to make the mix too carbonaceous.
For home-scale composting, mixing the materials as they are added increases the rate of decomposition, but it can be easier to place the materials in alternating layers, approximately 15 cm (6 in) thick, to help estimate the quantities. Keeping carbon and nitrogen sources separated in the pile can slow down the process, but decomposition will still occur.
Some people put special materials and activators into their compost. A light dusting of agricultural lime (not on animal manure layers) can curb excessive acidity, especially with food waste. Seaweed meal provides a ready source of trace elements. Finely pulverized rock (rock flour or rock dust) can also provide minerals, while clay and leached rock dust are poor in trace minerals.
Composting in the form of bioremediation can break down petroleum hydrocarbons, TNT and a variety of toxic compounds. This is the bacterial and in some cases fungal content of the compost, that possess the enzymatic properties to de-polymerize the complex man-made molecules. In other words, there is nothing about the composting process per se that adds or detracts from this, unless as noted above, by warming, to increase the metabolic rate of the constituent organisms.
Some materials are best left to high-rate, a thermophilic composting system, as they decompose slower, attract vermin and require higher temperatures to kill pathogens than backyard composting provides. These materials include meat, dairy products, eggs, restaurant grease, cooking oil, manure and bedding of non-herbivores, and residuals from the treatment of wastewater and drinking water. Meat and dairy products can be recycled using bokashi, a fermentation method.
Human waste can be composted by industrial, high-heat methods and also composting toilets, even though most composting toilets do not allow for the thermophilic decomposition believed to be necessary rapid kill of pathogens, such as Salmonella This is not a problem, however, since composting toilets also incorporate the essential element of time required to reduce available substrate on which pathogens can feed, while increasing the growth of competing microbes. If these high temperatures are reached, the resulting compost can be safely used as a fertilizer for food crops and even directly edible crops provided it is not illegal in the regions where the sludge is applied. Careful filtration of the compost also prevents contamination.
# Approaches
There are two major approaches to composting: active and passive. These terms are somewhat of a misnomer since both active and passive composts can attain high heating, which increases the rate of biochemical processes. But the terms active and passive are appropriate descriptions for the nature of human intervention used.
## Active
Active (hot) composting is composting at close to ideal conditions, allowing aerobic bacteria to thrive. Aerobic bacteria break down material faster and produce less odor and fewer pathogens and destructive greenhouse gases than anaerobic bacteria. Commercial-grade composting operations actively control the composting conditions such as the carbon-to-nitrogen ratio. For backyard composters, the charts of carbon and nitrogen ratios in various ingredients and the calculations required to get the ideal mixture can be intimidating, so many rules of thumb exist for approximating it.
Pasteurisation is a misnomer in composting, as no compost will become truly sterilized by high temperatures alone. Rather, in a very hot compost where the temperature exceeds 55 °C (130 °F) for several days, the ability of organisms to survive is greatly compromised. Nevertheless, there are many organisms in nature that can survive extreme temperatures, including the group of pathogenic Clostridium, and so no compost is completely safe. To achieve the elevated temperatures, the compost bin must be kept warm, insulated and damp.
Aerated Composting is an efficient form of composting from the chemical point of view as it produces ultimately only energy in the form of waste heat and CO2 and H2O . With aerated composting, fresh air (i.e. oxygen) is introduced throughout the mix of materials using any appropriate mechanism. The air stimulates the microorganisms that are already in the mix, and their by-product is heat. In a properly operated compost system, pile temperatures are sufficient to stabilize the raw material, and the oxygen-rich conditions within the core of the pile eliminate offensive odors. High temperatures also destroy fly larvae and weed seeds, yielding a safe, high-quality finished product.
Finally, aeration expedites the composting process through the mechanism of heating insofar as the elevated heat will drive biochemical processes faster, so that a finished product can be rendered in 60 to 120 days. Aerated compost is an excellent source of macro- and micro-nutrients as well as stable organic matter, all of which support healthy plant growth. In addition, the micro-organisms in compost aid in the suppression of plant pathogens. Finally, compost retains water extremely well resulting in improved drought resistance, a longer growing season, and reduced soil erosion.
In Thailand, May 2008, this system has been used by farmer groups for more than 445 sites. The process needs only 30 days to be finished and 10 metric tons of compost is obtained each time. A blower (15 inch squirrel-caged blower with 3 hp motor) is needed to force the air through 10 piles of compost twice a day and 15 minutes each. The raw materials consist of agricultural wastes and animal manure in the ratio of 3 : 1 by volume. For more information please visit www.compost.mju.ac.th/eng
# Passive
Passive composting is composting in which the level of physical intervention is kept to a minimum, and often as a result the temperatures never reach much above 30°C (86 °F). It is slower but is the more common type of composting in most domestic garden compost bins. Such composting systems may be either enclosed (home container composting, industrial in-vessel composting) or in exposed piles (industrial windrow composting). Kitchen scraps are put in the garden compost bin and left untended. This scrap bin can have a very high water content which reduces aeration, and so becomes odorous. To improve drainage and airflow, a gardener can mix in wood chips, small pieces of bark, leaves or twigs, or make physical holes through the pile.
## Natural
An unusual form of natural composting in nature is seen in the case of the mound-builders (megapodes) of eastern Indonesia, New Guinea, and Australia as well as in the case of bowerbirds of New Guinea and Australia. These Megapodes are fowl-sized birds famous for building nests in the form of huge compost heaps containing leaf litter, in which they incubate their eggs. The birds work constantly to maintain the correct, almost exact, incubation temperatures, by adding and removing leaves from the compost pile. In effect, this teaches us that thermophilic high-temperature composting is not man-made.
# Home composting
Home composters use a range of techniques, varying from extremely passive (throw everything in a pile and leave it for a year or two) to extremely active (monitor the temperature, turn the pile regularly, and adjust the ingredients over time). Some composters use mineral powders to absorb smells, although a well-maintained pile seldom has bad odors. It is usually located in the back garden.
## Moisture and heat
An effective compost pile is about as damp as a well wrung-out sponge. This provides the moisture that all life requires. Microorganisms vary by their ideal temperature and the heat they generate as they digest. Mesophilic bacteria survive best at temperatures of 20 to 44 °C (70 to 120 °F). thermophilic (heat-surviving) bacteria grow optimally at around 55°C (130 °F), and can attain the fastest decomposition, since metabolic processes proceed more rapidly under higher temperatures. Elevated temperature is also preferred since it causes the most rapid pathogen reduction, and is more destructive of weed seeds. To minimally achieve it, the heap should be about 1 m (3 ft) wide, 1 m (3 ft) tall, and as long as is practicable. This provides enough insulating mass to build up heat but also allows aeration. The center of the pile heats up the most.
If the pile does not heat up, common reasons include that:
- The heap is too wet, limiting the oxygen which bacteria require
- The heap is too dry for the bacteria to survive and reproduce
- There is insufficient protein (nitrogen-rich material)
The necessary material should be added, or the pile should be turned to aerate it and bring the outer layers inside and vice versa. You should add water at this time to help keep the pile damp. One guideline is to turn the pile when the high temperature has begun to drop, indicating that the food source for the fastest-acting bacteria (in the center of the pile) has been largely consumed. When turning the pile does not cause a temperature rise, it brings no further advantage. When all the material has turned into dark brown crumbly matter, it is ready to use.
## Worm composting
Worm composting or vermicomposting is a method of composting using Red Wiggler worms in a container. Food waste and moistened bedding are added, and the worms and micro-organisms eventually convert them to rich compost. The worms excrete a soil-nutrient material called worm castings. Worm composting can be done indoors, allowing year-round composting, and providing apartment dwellers with a means of composting.
Worms are low in the food chain, and so are critical to healthy soil. This is why farmers have historically wanted healthy worm populations to live in their fields.
The nutrients and micro-organisms can be concentrated in liquid form called worm tea, made by running distilled water through worm castings. When it is poured into the soil, the microorganisms multiply, creating a healthy growing environment for plants.
# Industrial composting
Industrial composting systems are increasingly being installed as a waste management alternative to landfills, along with other advanced waste processing systems. Industrial composting or anaerobic digestion combined with mechanical sorting of mixed waste streams is called mechanical biological treatment increasingly used in Europe due to stringent new regulations controlling the amount of organic matter allowed in landfills. Treating biodegradable waste before it enters a landfill reduces global warming from fugitive methane; untreated waste breaks down anaerobically in a landfill, producing landfill gas that contains methane, a greenhouse gas even more potent than carbon dioxide.
Most commercial and industrial composting operations use active composting techniques. These ensure that the process does not get out of control especially with the high through-put demand imposed by contracted, incoming waste. This means that as short as possible a processing time must be maintained to keep the facility properly functioning (see compost windrow turner). Partly for this reason composters have declined to support compost maturity standards if it would increase the required holding time. The greatest amount of technological control of composting is seen in systems using an enclosed vessel and controlling its temperature, air flow, moisture and other parameters. See In-vessel composting (indoor composting).
Large-scale composting systems are used by many urban centers around the world. Co-composting is a technique which combines solid waste with de-watered biosolids, which originated in the 1960s and has fallen somewhat out of favor due to difficulties controlling inert and plastic contamination from MSW. In Europe, mixed waste composting is virtually illegal. The world's largest MSW co-composter is the Edmonton Composting Facility in Edmonton in Alberta, Canada, which turns 220,000 tonnes of residential solid waste and 22,500 dry tonnes of biosolids per year into 80,000 tonnes of compost. The facility is 38,690 square metres (416,500 ft²) large (equivalent to 4½ Canadian football fields), and the aeration building alone is the largest stainless steel building in North America, the size of 14 NHL rinks. | Composting
Template:Portalpar
Template:Repetition
Composting is the aerobic decomposition of biodegradable organic matter, producing compost. (Or in a simpler form: Composting is the decaying of food, mostly vegetables or manure.) The decomposition is performed primarily by facultative and obligate aerobic bacteria, yeasts and fungi, helped in the cooler initial and ending phases by a number of larger organisms, such as ils, and other families representing ants, nematodes and oligochaete worms.
Composting can be divided into home composting and industrial composting. Essentially the same biological processes are involved in both scales of composting, however techniques and different factors must be taken into account.
# Importance
Composting recycles or "downcycles" organic household and yard waste and manures into an extremely useful humus-like, soil end-product called compost. Examples are fruits, vegetables and yard clippings. Ultimately this permits the return of needed organic matter and nutrients into the foodchain and reduces the amount of "green" waste going into landfills. Composting is widely believed to speed up the natural process of decomposition appreciably as a result of the raised temperatures that often accompany it. The elevated heat results from exothermic processes, and the heat in turn reduces the generational time of microorganisms and thereby speeds the energy and nutrient exchanges taking place. It is a popular misconception that composting is a "controlled" process; if the right environmental circumstances are present the process virtually runs itself. Hence a popular expression, "compost happens". It is nonetheless very necessary to provide as optimal circumstances as possible for large amounts of organic waste to break down properly. This is especially so when it is accompanied by heating, since at elevated temperatures oxygen within the piles is consumed more rapidly, and if not controlled, will lead to malodor.
Decomposition similar to composting occurs throughout nature as garbage dissolves in the absence of all the conditions that modern composters talk about; however, the process can be slow. For example, in the forest bark, wood and leaves break down into humus over 3-7 years. In restricted environments, for example, vegetables in a plastic trash container, decomposition with a lack of air encourages growth of anaerobic microbes, which produce disagreeable odors. Another form of degradation practiced deliberately in absence of oxygen is called anaerobic digestion- an increasingly popular companion to composting as it enables capture of residual energy in the form of biogas, whereas composting releases the majority of bound carbon-energy as excess heat (which helps sanitize the material) as well as copious amounts of biogenic CO2 to the atmosphere.
It is important to distinguish between terms such as "biodegradable", "compostable", and "compost-compatible".
- A biodegradable material is capable of being broken down completely under the action of microorganisms into carbon dioxide, water and biomass. It may take a very long time for a material to biodegrade depending on its environment (e.g. hardwood in an arid area), but it ultimately breaks down completely.
- A compostable material biodegrades substantially under composting conditions, into carbon dioxide, methane, water and compost biomass. Compost biomass refers to the portion of the material that is metabolized by the microorganisms and which is incorporated into the cellular structure of the organisms or converted into humic acids etc. Compost biomass residues from a compostable material are fully biodegradable. "Compostable" is thus a subset of "biodegradable". The size of the material is a factor in determining compostability because it affects the rate of degradation. Large pieces of hardwood may not be compostable under a specific set of composting conditions, whereas sawdust of the same type of wood may be.
- A compost-compatible material does not have to be compostable or even biodegradable. It may biodegrade too slowly to be compostable itself, or it may not biodegrade at all. However, it is not readily distinguishable from the compost on a macroscopic scale and does not have a deleterious effect on the compost (e.g. it is not a biocide). Compost-compatible materials are generally inert and are present in compost at relatively low levels. Examples of compost-compatible materials include sand particles and inert particles of plastic.
## Reducing Waste
Although composting has historically focussed on creating garden-ready soil, it is becoming more important as a tool is reducing solid waste. More than 60 percent of household waste in the United States is recyclable or compostable. But Americans only compost 8 percent of their waste. Surveys have shown that the #1 reason Americans don't compost their waste is because they feel the process is complicated, time-consuming or requires special equipment. However, especially in rural areas, much of the solid waste could be removed from the waste stream by promoting "extremely passive composting" where consumers simply discard their yard waste and kitchen scraps on their own land, regardless of whether the material is ever re-used as "compost". (http://www.nrdc.org/cities/recycling/fover.asp)
# Materials
Many different materials are suitable for composting organisms. Composters often refer to "C:N" requirements; some materials contain high amounts of carbon in the form of cellulose which the bacteria need for their energy. Other materials contain nitrogen in the form of protein, which provide nutrients for the energy exchanges. It would however be an over-simplification to describe composting as about carbon and nitrogen, as is often portrayed in popular literature. Elemental carbon - such as charcoal - is not compostable nor is a pure form of nitrogen, even in combination with carbon. Not only this, but a great variety of man-made, carbon-containing products, including many textiles and polyethylene, are not compostable - hence the push for biodegradable plastics.
Suitable ingredients with relatively high carbon content include:
- Dry, straw-type material, such as cereal straws
- Autumn leaves
- Sawdust and wood chips
- paper and cardboard (such as corrugated cardboard or newsprint with soy-based inks)
Ingredients with relatively high nitrogen content include:
- Green plant material (fresh or wilted) such as crop residues, hay, grass clippings, weeds
- Manure of poultry and herbivorous animals such as horses, cows and llamas
- Fruit and vegetable trimmings
The most efficient composting occurs by seeking to obtain an initial C:N mix of 25/30 by dry chemical weight. Grass clippings have an average ratio of 10-19 to 1 and dry autumn leaves from 55-100 to 1. Mixing equal parts by volume approximates the ideal range.
Poultry manure provides much nitrogen but with a ratio to carbon that is imbalanced. If composted alone, this results in excessive N-loss in the form of ammonia - and some odor. Horse manure provides a good mix of both, although in modern stables, so much bedding may be used as to make the mix too carbonaceous.
For home-scale composting, mixing the materials as they are added increases the rate of decomposition, but it can be easier to place the materials in alternating layers, approximately 15 cm (6 in) thick, to help estimate the quantities. Keeping carbon and nitrogen sources separated in the pile can slow down the process, but decomposition will still occur.
Some people put special materials and activators into their compost. A light dusting of agricultural lime (not on animal manure layers) can curb excessive acidity, especially with food waste. Seaweed meal provides a ready source of trace elements. Finely pulverized rock (rock flour or rock dust) can also provide minerals, while clay and leached rock dust are poor in trace minerals.
Composting in the form of bioremediation can break down petroleum hydrocarbons, TNT and a variety of toxic compounds. This is the bacterial and in some cases fungal content of the compost, that possess the enzymatic properties to de-polymerize the complex man-made molecules. In other words, there is nothing about the composting process per se that adds or detracts from this, unless as noted above, by warming, to increase the metabolic rate of the constituent organisms.
Some materials are best left to high-rate, a thermophilic composting system, as they decompose slower, attract vermin and require higher temperatures to kill pathogens than backyard composting provides. These materials include meat, dairy products, eggs, restaurant grease, cooking oil, manure and bedding of non-herbivores, and residuals from the treatment of wastewater and drinking water. Meat and dairy products can be recycled using bokashi, a fermentation method.
Human waste can be composted by industrial, high-heat methods and also composting toilets, even though most composting toilets do not allow for the thermophilic decomposition believed to be necessary rapid kill of pathogens, such as Salmonella This is not a problem, however, since composting toilets also incorporate the essential element of time required to reduce available substrate on which pathogens can feed, while increasing the growth of competing microbes. If these high temperatures are reached, the resulting compost can be safely used as a fertilizer for food crops and even directly edible crops provided it is not illegal in the regions where the sludge is applied. Careful filtration of the compost also prevents contamination.
# Approaches
There are two major approaches to composting: active and passive. These terms are somewhat of a misnomer since both active and passive composts can attain high heating, which increases the rate of biochemical processes. But the terms active and passive are appropriate descriptions for the nature of human intervention used.
## Active
Active (hot) composting is composting at close to ideal conditions, allowing aerobic bacteria to thrive. Aerobic bacteria break down material faster and produce less odor and fewer pathogens and destructive greenhouse gases than anaerobic bacteria. Commercial-grade composting operations actively control the composting conditions such as the carbon-to-nitrogen ratio. For backyard composters, the charts of carbon and nitrogen ratios in various ingredients and the calculations required to get the ideal mixture can be intimidating, so many rules of thumb exist for approximating it.
Pasteurisation is a misnomer in composting, as no compost will become truly sterilized by high temperatures alone. Rather, in a very hot compost where the temperature exceeds 55 °C (130 °F) for several days, the ability of organisms to survive is greatly compromised. Nevertheless, there are many organisms in nature that can survive extreme temperatures, including the group of pathogenic Clostridium, and so no compost is completely safe. To achieve the elevated temperatures, the compost bin must be kept warm, insulated and damp.
Aerated Composting is an efficient form of composting from the chemical point of view as it produces ultimately only energy in the form of waste heat and CO2 and H2O . With aerated composting, fresh air (i.e. oxygen) is introduced throughout the mix of materials using any appropriate mechanism. The air stimulates the microorganisms that are already in the mix, and their by-product is heat. In a properly operated compost system, pile temperatures are sufficient to stabilize the raw material, and the oxygen-rich conditions within the core of the pile eliminate offensive odors. High temperatures also destroy fly larvae and weed seeds, yielding a safe, high-quality finished product.
Finally, aeration expedites the composting process through the mechanism of heating insofar as the elevated heat will drive biochemical processes faster, so that a finished product can be rendered in 60 to 120 days. Aerated compost is an excellent source of macro- and micro-nutrients as well as stable organic matter, all of which support healthy plant growth. In addition, the micro-organisms in compost aid in the suppression of plant pathogens. Finally, compost retains water extremely well resulting in improved drought resistance, a longer growing season, and reduced soil erosion.
In Thailand, May 2008, this system has been used by farmer groups for more than 445 sites. The process needs only 30 days to be finished and 10 metric tons of compost is obtained each time. A blower (15 inch squirrel-caged blower with 3 hp motor) is needed to force the air through 10 piles of compost twice a day and 15 minutes each. The raw materials consist of agricultural wastes and animal manure in the ratio of 3 : 1 by volume. For more information please visit www.compost.mju.ac.th/eng
# Passive
Passive composting is composting in which the level of physical intervention is kept to a minimum, and often as a result the temperatures never reach much above 30°C (86 °F). It is slower but is the more common type of composting in most domestic garden compost bins. Such composting systems may be either enclosed (home container composting, industrial in-vessel composting) or in exposed piles (industrial windrow composting). Kitchen scraps are put in the garden compost bin and left untended. This scrap bin can have a very high water content which reduces aeration, and so becomes odorous. To improve drainage and airflow, a gardener can mix in wood chips, small pieces of bark, leaves or twigs, or make physical holes through the pile.
## Natural
An unusual form of natural composting in nature is seen in the case of the mound-builders (megapodes) of eastern Indonesia, New Guinea, and Australia as well as in the case of bowerbirds of New Guinea and Australia. These Megapodes are fowl-sized birds famous for building nests in the form of huge compost heaps containing leaf litter, in which they incubate their eggs. The birds work constantly to maintain the correct, almost exact, incubation temperatures, by adding and removing leaves from the compost pile. In effect, this teaches us that thermophilic high-temperature composting is not man-made.
# Home composting
Home composters use a range of techniques, varying from extremely passive (throw everything in a pile and leave it for a year or two) to extremely active (monitor the temperature, turn the pile regularly, and adjust the ingredients over time). Some composters use mineral powders to absorb smells, although a well-maintained pile seldom has bad odors. It is usually located in the back garden.
## Moisture and heat
An effective compost pile is about as damp as a well wrung-out sponge. This provides the moisture that all life requires. Microorganisms vary by their ideal temperature and the heat they generate as they digest. Mesophilic bacteria survive best at temperatures of 20 to 44 °C (70 to 120 °F). thermophilic (heat-surviving) bacteria grow optimally at around 55°C (130 °F), and can attain the fastest decomposition, since metabolic processes proceed more rapidly under higher temperatures. Elevated temperature is also preferred since it causes the most rapid pathogen reduction, and is more destructive of weed seeds. To minimally achieve it, the heap should be about 1 m (3 ft) wide, 1 m (3 ft) tall, and as long as is practicable. This provides enough insulating mass to build up heat but also allows aeration. The center of the pile heats up the most.
If the pile does not heat up, common reasons include that:
- The heap is too wet, limiting the oxygen which bacteria require
- The heap is too dry for the bacteria to survive and reproduce
- There is insufficient protein (nitrogen-rich material)
The necessary material should be added, or the pile should be turned to aerate it and bring the outer layers inside and vice versa. You should add water at this time to help keep the pile damp. One guideline is to turn the pile when the high temperature has begun to drop, indicating that the food source for the fastest-acting bacteria (in the center of the pile) has been largely consumed. When turning the pile does not cause a temperature rise, it brings no further advantage. When all the material has turned into dark brown crumbly matter, it is ready to use.
## Worm composting
Worm composting or vermicomposting is a method of composting using Red Wiggler worms in a container. Food waste and moistened bedding are added, and the worms and micro-organisms eventually convert them to rich compost. The worms excrete a soil-nutrient material called worm castings. Worm composting can be done indoors, allowing year-round composting, and providing apartment dwellers with a means of composting.
Worms are low in the food chain, and so are critical to healthy soil. This is why farmers have historically wanted healthy worm populations to live in their fields.
The nutrients and micro-organisms can be concentrated in liquid form called worm tea, made by running distilled water through worm castings. When it is poured into the soil, the microorganisms multiply, creating a healthy growing environment for plants.
# Industrial composting
Industrial composting systems are increasingly being installed as a waste management alternative to landfills, along with other advanced waste processing systems. Industrial composting or anaerobic digestion combined with mechanical sorting of mixed waste streams is called mechanical biological treatment increasingly used in Europe due to stringent new regulations controlling the amount of organic matter allowed in landfills. Treating biodegradable waste before it enters a landfill reduces global warming from fugitive methane; untreated waste breaks down anaerobically in a landfill, producing landfill gas that contains methane, a greenhouse gas even more potent than carbon dioxide.
Most commercial and industrial composting operations use active composting techniques. These ensure that the process does not get out of control especially with the high through-put demand imposed by contracted, incoming waste. This means that as short as possible a processing time must be maintained to keep the facility properly functioning (see compost windrow turner). Partly for this reason composters have declined to support compost maturity standards if it would increase the required holding time. The greatest amount of technological control of composting is seen in systems using an enclosed vessel and controlling its temperature, air flow, moisture and other parameters. See In-vessel composting (indoor composting).
Large-scale composting systems are used by many urban centers around the world. Co-composting is a technique which combines solid waste with de-watered biosolids, which originated in the 1960s and has fallen somewhat out of favor due to difficulties controlling inert and plastic contamination from MSW. In Europe, mixed waste composting is virtually illegal. The world's largest MSW co-composter is the Edmonton Composting Facility in Edmonton in Alberta, Canada, which turns 220,000 tonnes of residential solid waste and 22,500 dry tonnes of biosolids per year into 80,000 tonnes of compost. The facility is 38,690 square metres (416,500 ft²) large (equivalent to 4½ Canadian football fields), and the aeration building alone is the largest stainless steel building in North America, the size of 14 NHL rinks. | https://www.wikidoc.org/index.php/Compostable | |
b2f591cfb3c29db6852e98d068dd0adc146e4ae3 | wikidoc | Concoction | Concoction
# Overview
A concoction (sometimes spelled concotion) is -strictly speaking- a combination of various ingredients, usually herbs, spices, condiments, powdery substances or minerals, mixed up together, minced, dissolved or macerated into a liquid so as they can be ingested or drunk. Concoctions are sometimes associated with poisons, alternative or magic cures or, in the past, even with witchcraft.
The term "concoction" is sometimes loosely used metaphorically in order to describe a cocktail or a motley assembly of things, persons or ideas.
Quite often various very pungent and spicy ketchups or hot sauces, usually based on Cayenne peppers are inadverdently -or for commercial reasons- called "concoctions".
# Advantages
vitamin-enriched concoction is used in curing and preventing malnutrition. | Concoction
# Overview
A concoction (sometimes spelled concotion) is -strictly speaking- a combination of various ingredients, usually herbs, spices, condiments, powdery substances or minerals, mixed up together, minced, dissolved or macerated into a liquid so as they can be ingested or drunk. Concoctions are sometimes associated with poisons, alternative or magic cures or, in the past, even with witchcraft.
The term "concoction" is sometimes loosely used metaphorically in order to describe a cocktail or a motley assembly of things, persons or ideas.
Quite often various very pungent and spicy ketchups or hot sauces, usually based on Cayenne peppers are inadverdently -or for commercial reasons- called "concoctions".
# Advantages
vitamin-enriched concoction is used in curing and preventing malnutrition. | https://www.wikidoc.org/index.php/Concoction | |
ed218fe92c3ae3d590e2b434fa0b190bc8bec8a7 | wikidoc | Configuron | Configuron
# Overview
Some of the internal kinetic energy of amorphous substances can be in the form of interparticle bonds. A broken interparticle chemical bond and associated strain-releasing local adjustment in centers of vibration form a configuron, an elementary configurational excitation in an amorphous material. Configurons help to understand the transition from a solid to a fluid with viscous flow.
# Introduction
An amorphous substance is any in which there is no long-range order over the positions of its constituent particles; i.e., no translational periodicity. Some of the internal kinetic energy of these substances can be in the form of interparticle bonds. The particles making up an amorphous substance can range in size from an electron to stars in a galaxy or galaxies in a galactic cluster. Water is an amorphous substance that also can be crystalline. Amorphous substances undergo transitions from solid to liquid, solid to gas, or liquid to gas, or gas to plasma, for example.
The chemical bonding within many amorphous substances can produce short-range order while there is long-range disorder. The short-range order is often a symmetrical arrangement of polyhedra. The long-range disorder can be approached with the disordered arrangement of space-filling polyhedra. These polyhedra are bonded together in a solid and undergo bond breaking through the transitions from solid to fluid. A model based on the configuron or configurational microstate is an approach to understanding the viscosity changes that occur with changes in temperature.
# Amorphous substances
The particles in an amorphous substance can be subatoms, atoms, ions, molecules, dust, crystallites, or grains, stones, boulders, or larger debris. From the point of view of bonding by gravity the universe is an amorphous substance.
Amorphous substances can fall into the usual categories of solid, liquid, gas, or plasma. But some substances which are amorphous, such as sand, are fluids.
Water as a liquid has much of the available kinetic energy expressed through additional degrees of freedom than water vapor. Some of this energy is in the form of intermolecular bonds. These bonds are a resistance to flow. Water has a resistance to flow that is considered relatively "thin", having a lower viscosity (µL) than other liquids such as vegetable oil. At 25°C, water has a nominal viscosity of 1.0 × 10-3 Pa∙s and motor oil has a nominal apparent viscosity of 250 × 10-3 Pa∙s.
Viscous flow, which results from viscosity, in amorphous materials such as water is a thermally activated process as is viscosity:
where QL is the activation energy in the liquid state, T is temperature (K), R is the molar gas constant and AL is approximately a constant.
With
where Hm is the enthalpy of motion of the broken hydrogen bonds.
# Solid-liquid transition in amorphous substances
In principle, given a sufficiently high cooling rate, any liquid can be made into an amorphous solid. Cooling reduces molecular mobility. If the cooling rate is faster than the rate at which molecules can organize into a more thermodynamically favorable crystalline state, then an amorphous solid will be formed. Because of entropy considerations, many polymers can be made into amorphous solids by cooling even at slow rates. In contrast, if molecules have sufficient time to organize into a structure with two- or three-dimensional order, then a crystalline (or semi-crystalline) solid is formed. Water is one example. Because of its small molecular size and ability to quickly rearrange, it cannot be made amorphous without resorting to specialized hyperquenching techniques. These produce amorphous ice, which has a quenching rate in the range of metallic glasses.
The higher the temperature of an amorphous material the higher the configuron concentration. The higher the configuron concentration the lower the viscosity. As configurons form percolating clusters, an amorphous solid can transition to a liquid. This clustering facilitates viscous flow. Thermodynamic parameters of configurons can be found from viscosity-temperature relationships.
# Short-range order
Like a liquid an amorphous solid has a topologically disordered distribution of particles but elastic properties of an isotropic solid. The symmetry similarity of both liquid and solid phases cannot explain the qualitative differences in their behavior.
Due to chemical bonding characteristics amorphous solids such as glasses do possess a high degree of short-range order with respect to local atomic polyhedra. The amorphous structure of glassy silica has no long range order but shows local ordering with respect to the tetrahedral arrangement of oxygen atoms around silicon atoms.
# Bond structure
One useful approach is to consider the bond system instead of considering the set of particles that form the substance. For each state of matter we can define the set of bonds by a bond lattice model. The congruent bond lattice for amorphous materials is a disordered structure. Moreover the bond lattices of amorphous solids and liquids may have different symmetries in contrast to the symmetry similarity of particles in a liquid or fluid and solid phases.
For an amorphous material a given unit can be delimited by its nearest neighbors so that its structure may be characterized by a distribution of Voronoi polyhedra filling the space of the disordered material. Molecular dynamics simulations have revealed that the difference between a liquid and glass of an amorphous material results from the formation of percolation clusters of broken bonds in the Voronoi network.
# Hausdorff dimension
The Hausdorff dimension (d) generalizes the notion of the dimension of a real vector space. In particular, the Hausdorff dimension of a single point is zero, a line is one, a plane is two, a solid is three, etc. The Hausdorff dimension can be thought of as the power of radii for a set of space filling balls formally expressed by
where C is the space (S)-filling Content of a countable number (the index number - i) of balls whose radii (ri) are dimensioned (volumed) to produce the space-filling balls.
In three dimensions, the balls can be spheres of many different radii and the volume of each ball is proportional to its r3. Hence the Hausdorff dimension, d = 3. In four dimensions, the balls can be hyperspheres of many different radii and the volume of each ball is proportional to its r4. Consider a sphere that changes its radius with time. At each time the sphere has a finite radius rti that differs from each t-1(i-1) before and after t+1(i+1). The volume calculated is proportional to rspace-filling4 that equals the space occupied for all time.
Fractals often are spaces whose Hausdorff dimension strictly exceeds the topological dimension. A 2-dimensional fractal has a Hausdorff dimension, d as 2<d<3.
There is a symmetry change expressed by step-wise variation in the Hausdorff dimension (d) for bonds at the solid-liquid transition. In the solid state d=3 but for the liquid state d=df (the fractal d) = 2.55 ± 0.05. df occurs at each broken bond.
# Glass transition temperature of water
The glass transition temperature for water is about 136 K or -137°C. Factors in the formation of amorphous ice include ingredients that form a heterogenous mixture with water (such as is used in the production of ice cream), pressure (which may convert one form into another), and cryoprotectants that lower its freezing point and increase viscosity. Melting low-density amorphous ice (LDA) between 140 and 210 K through its transition temperature shows that it is more viscous than normal water. LDA has a density of 0.94 g/cm³, less dense than the densest water (1.00 g/cm³ at 277 K), but denser than ordinary ice.
Amorphous ice is used in some scientific experiments, especially in electron cryomicroscopy of biomolecules. The individual molecules can be preserved for imaging in a state close to what they are in liquid water.
Hydrated proteins may also be classed among glass-forming systems, but they show great departures from thermorheological simplicity.
# Enthalpy of motion for water configurons
A simple estimate of QL can be obtained by using the two temperatures 0°C and 100°C, where µ=1.79 x 10-3 Pa·s at 0°C and 0.28 x 10-3 Pa·s at 100°C, and solving for AL and QL. AL = 7.7 x 10-7 Pa·s and QL = 18 kJmol-1. R=8.314472 JK-1mol-1. Temperature is in K (273.15 + °C). QL includes the energy to break the hydrogen bond and move the configuron, as such HM ≤ QL. Using
AL and QL to calculate the viscosity of water and comparing the calculated values to the experimentally determined ones for a range of temperature values shows that there is a systematic deviation at the higher temperatures. As the data for the viscosity of water vapor is available, AV and QV can be estimated: AV ~ 1.2 x 10-4 Pa·s and QV ~ - 6.0 kJmol-1. This added to the calculated configuron contribution
improves the fit to the liquid water viscosity data remarkably well, suggesting that like other gas molecules mixed into water, water vapor can also be.
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikipedia. | Configuron
Editor-In-Chief: Henry A. Hoff
# Overview
Some of the internal kinetic energy of amorphous substances can be in the form of interparticle bonds. A broken interparticle chemical bond and associated strain-releasing local adjustment in centers of vibration form a configuron, an elementary configurational excitation in an amorphous material.[1] Configurons help to understand the transition from a solid to a fluid with viscous flow.
# Introduction
An amorphous substance is any in which there is no long-range order over the positions of its constituent particles; i.e., no translational periodicity. Some of the internal kinetic energy of these substances can be in the form of interparticle bonds. The particles making up an amorphous substance can range in size from an electron to stars in a galaxy or galaxies in a galactic cluster. Water is an amorphous substance that also can be crystalline. Amorphous substances undergo transitions from solid to liquid, solid to gas, or liquid to gas, or gas to plasma, for example.
The chemical bonding within many amorphous substances can produce short-range order while there is long-range disorder. The short-range order is often a symmetrical arrangement of polyhedra. The long-range disorder can be approached with the disordered arrangement of space-filling polyhedra. These polyhedra are bonded together in a solid and undergo bond breaking through the transitions from solid to fluid. A model based on the configuron or configurational microstate[2] is an approach to understanding the viscosity changes that occur with changes in temperature.
# Amorphous substances
The particles in an amorphous substance can be subatoms, atoms, ions, molecules, dust, crystallites, or grains, stones, boulders, or larger debris. From the point of view of bonding by gravity the universe is an amorphous substance.
Template:Wiktionarypar
Amorphous substances can fall into the usual categories of solid, liquid, gas, or plasma. But some substances which are amorphous, such as sand, are fluids.
Water as a liquid has much of the available kinetic energy expressed through additional degrees of freedom than water vapor. Some of this energy is in the form of intermolecular bonds. These bonds are a resistance to flow. Water has a resistance to flow that is considered relatively "thin", having a lower viscosity (µL) than other liquids such as vegetable oil. At 25°C, water has a nominal viscosity of 1.0 × 10-3 Pa∙s and motor oil has a nominal apparent viscosity of 250 × 10-3 Pa∙s.[3]
Viscous flow, which results from viscosity, in amorphous materials such as water is a thermally activated process as is viscosity:[4]
where QL is the activation energy in the liquid state, T is temperature (K), R is the molar gas constant and AL is approximately a constant.
With
where Hm is the enthalpy of motion of the broken hydrogen bonds.
# Solid-liquid transition in amorphous substances
In principle, given a sufficiently high cooling rate, any liquid can be made into an amorphous solid. Cooling reduces molecular mobility. If the cooling rate is faster than the rate at which molecules can organize into a more thermodynamically favorable crystalline state, then an amorphous solid will be formed. Because of entropy considerations, many polymers can be made into amorphous solids by cooling even at slow rates. In contrast, if molecules have sufficient time to organize into a structure with two- or three-dimensional order, then a crystalline (or semi-crystalline) solid is formed. Water is one example. Because of its small molecular size and ability to quickly rearrange, it cannot be made amorphous without resorting to specialized hyperquenching techniques. These produce amorphous ice, which has a quenching rate in the range of metallic glasses.[5]
The higher the temperature of an amorphous material the higher the configuron concentration. The higher the configuron concentration the lower the viscosity. As configurons form percolating clusters, an amorphous solid can transition to a liquid. This clustering facilitates viscous flow. Thermodynamic parameters of configurons can be found from viscosity-temperature relationships.[5]
# Short-range order
Like a liquid an amorphous solid has a topologically disordered distribution of particles but elastic properties of an isotropic solid. The symmetry similarity of both liquid and solid phases cannot explain the qualitative differences in their behavior.
Due to chemical bonding characteristics amorphous solids such as glasses do possess a high degree of short-range order with respect to local atomic polyhedra.[6] The amorphous structure of glassy silica has no long range order but shows local ordering with respect to the tetrahedral arrangement of oxygen atoms around silicon atoms.
# Bond structure
One useful approach is to consider the bond system instead of considering the set of particles that form the substance.[5] For each state of matter we can define the set of bonds by a bond lattice model.[5] The congruent bond lattice for amorphous materials is a disordered structure. Moreover the bond lattices of amorphous solids and liquids may have different symmetries in contrast to the symmetry similarity of particles in a liquid or fluid and solid phases.
For an amorphous material a given unit can be delimited by its nearest neighbors so that its structure may be characterized by a distribution of Voronoi polyhedra filling the space of the disordered material. Molecular dynamics simulations have revealed that the difference between a liquid and glass of an amorphous material results from the formation of percolation clusters of broken bonds in the Voronoi network.[7]
# Hausdorff dimension
The Hausdorff dimension (d) generalizes the notion of the dimension of a real vector space. In particular, the Hausdorff dimension of a single point is zero, a line is one, a plane is two, a solid is three, etc. The Hausdorff dimension can be thought of as the power of radii for a set of space filling balls formally expressed by
where C is the space (S)-filling Content of a countable number (the index number - i) of balls whose radii (ri) are dimensioned (volumed) to produce the space-filling balls.
In three dimensions, the balls can be spheres of many different radii and the volume of each ball is proportional to its r3. Hence the Hausdorff dimension, d = 3. In four dimensions, the balls can be hyperspheres of many different radii and the volume of each ball is proportional to its r4. Consider a sphere that changes its radius with time. At each time the sphere has a finite radius rti that differs from each t-1(i-1) before and after t+1(i+1). The volume calculated is proportional to rspace-filling4 that equals the space occupied for all time.
Fractals often are spaces whose Hausdorff dimension strictly exceeds the topological dimension. A 2-dimensional fractal has a Hausdorff dimension, d as 2<d<3.
There is a symmetry change expressed by step-wise variation in the Hausdorff dimension (d) for bonds at the solid-liquid transition.[5] In the solid state d=3 but for the liquid state d=df (the fractal d) = 2.55 ± 0.05.[8] df occurs at each broken bond.
# Glass transition temperature of water
The glass transition temperature for water is about 136 K or -137°C. Factors in the formation of amorphous ice include ingredients that form a heterogenous mixture with water (such as is used in the production of ice cream), pressure (which may convert one form into another), and cryoprotectants that lower its freezing point and increase viscosity. Melting low-density amorphous ice (LDA) between 140 and 210 K through its transition temperature shows that it is more viscous than normal water.[9] LDA has a density of 0.94 g/cm³, less dense than the densest water (1.00 g/cm³ at 277 K), but denser than ordinary ice.
Amorphous ice is used in some scientific experiments, especially in electron cryomicroscopy of biomolecules.[10] The individual molecules can be preserved for imaging in a state close to what they are in liquid water.
Hydrated proteins may also be classed among glass-forming systems, but they show great departures from thermorheological simplicity.[11]
# Enthalpy of motion for water configurons
A simple estimate of QL can be obtained by using the two temperatures 0°C and 100°C, where µ=1.79 x 10-3 Pa·s at 0°C and 0.28 x 10-3 Pa·s at 100°C, and solving for AL and QL. AL = 7.7 x 10-7 Pa·s and QL = 18 kJmol-1. R=8.314472 JK-1mol-1. Temperature is in K (273.15 + °C). QL includes the energy to break the hydrogen bond and move the configuron, as such HM ≤ QL. Using
AL and QL to calculate the viscosity of water and comparing the calculated values to the experimentally determined ones for a range of temperature values shows that there is a systematic deviation at the higher temperatures. As the data for the viscosity of water vapor is available, AV and QV can be estimated: AV ~ 1.2 x 10-4 Pa·s and QV ~ - 6.0 kJmol-1. This added to the calculated configuron contribution
improves the fit to the liquid water viscosity data remarkably well, suggesting that like other gas molecules mixed into water, water vapor can also be.[12]
# Acknowledgements
The content on this page was first contributed by: Henry A. Hoff.
Initial content for this page in some instances came from Wikipedia. | https://www.wikidoc.org/index.php/Configuron | |
3d0376b2fcc4d6a6ad10cef622a220bea7536e3e | wikidoc | Confounder | Confounder
# Overview
A confounding variable (also confounding factor, lurking variable, a confound, or confounder) is an extraneous variable in a statistical model that correlates (positively or negatively) with both the dependent variable and the independent variable. The methodologies of scientific studies therefore need to control for these factors to avoid what is known as a type 1 error: A 'false positive' conclusion that the dependent variables are in a causal relationship with the independent variable. Such a relation between two observed variables is termed a spurious relationship. Thus, confounding is a major threat to the validity of inferences made about cause and effect, i.e. internal validity, as the observed effects should be attributed to the confounder rather than the independent variable.
For example, assume that a child's weight and a country's gross domestic product (GDP) rise with time. A person carrying out an experiment could measure weight and GDP, and conclude that a higher GDP causes children to gain weight, or that children's weight gain boosts the GDP. However, the confounding variable, time, was not accounted for, and is the real cause of both rises.
By definition, a confounding variable is associated with both the probable cause and the outcome. The confounder is not allowed to lie in the causal pathway between the cause and the outcome: If A is thought to be the cause of disease C, the confounding variable B may not be solely caused by behaviour A; and behaviour B shall not always lead to behaviour C. An example: Being female does not always lead to smoking tobacco, and smoking tobacco does not always lead to cancer. Therefore, in any study that tries to elucidate the relation between being female and cancer should take smoking into account as a possible confounder. In addition, a confounder is always a risk factor that has a different prevalence in two risk groups (e.g. females/males). (Hennekens, Buring & Mayrent, 1987).
Though criteria for causality in statistical studies have been researched intensely, Pearl has shown that confounding variables cannot be defined in terms of statistical notions alone; some causal assumptions are necessary. In a 1965 paper, Austin Bradford Hill proposed a set of causal criteria..
Many working epidemiologists take these as a good place to start when considering confounding and causation. However, these are of heuristic value at best. When causal assumptions are articulated in the form of causal graph, a simple criterion is available, called backdoor, to identify sets of confounding variables.
# How to remove confounding in a study
There are various ways to modify a study design to actively exclude or control confounding variables:
- Case-control studies assign confounders to both groups, cases and controls, equally. For example if somebody wanted to study the cause of myocardial infarct and thinks that the age is a probable confounding variable, each 67 years old infarct patient will be matched with a healthy 67 year old "control" person. In case-control studies, matched variables most often are the age and sex.
- Cohort studies: A degree of matching is also possible and it is often done by only admitting certain age groups or a certain sex into the study population, and thus all cohorts are comparable in regard to the possible confounding variable. For example, if age and sex are thought to be a confounders, only 40 to 50 years old males would be involved in a cohort study that would assess the myocardial infarct risk in cohorts that either are physically active or inactive.
- Stratification: As in the example above, physical activity is thought to be a behaviour that protects from myocardial infarct; and age is assumed to be a possible confounder. The data sampled is then stratified by age group – this means, the association between activity and infarct would be analyzed per each age group. If the different age groups (or age strata) yield much different risk ratios, age must be viewed as a confounding variable. There are statistical tools like Mantel-Haenszel methods that deal with stratified data.
All these methods have their drawbacks. This can be clearly seen in this example: A 45 years old Afro-American from Alaska, avid football player and vegetarian, working in education, suffers from a disease and is enrolled into a case-control study. Proper matching would call for a person with the same characteristics, with the sole difference of being healthy – but finding such one would be an enormous task. Additionally, there is always the risk of over- and undermatching of the study population. In cohort studies, too many people can be excluded; and in stratification, single strata can get too thin and thus contain only a small, non-significant number of samples.
- Controlling for confounding by measuring the known confounders and including them as covariates in multivariate analyses. A drawback of these is that they give little information about the strength of the confounding variable compared to stratification methods.
One major problem is that confounding variables are not always known or measurable. This leads to 'residual confounding' - epidemiological jargon for incompletely controlled confounding. Hence, randomization is often the best solution as, if performed successfully on sufficiently large numbers, all confounding variables (known and unknown) will be equally distributed across all study groups. | Confounder
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A confounding variable (also confounding factor, lurking variable, a confound, or confounder) is an extraneous variable in a statistical model that correlates (positively or negatively) with both the dependent variable and the independent variable. The methodologies of scientific studies therefore need to control for these factors to avoid what is known as a type 1 error: A 'false positive' conclusion that the dependent variables are in a causal relationship with the independent variable. Such a relation between two observed variables is termed a spurious relationship. Thus, confounding is a major threat to the validity of inferences made about cause and effect, i.e. internal validity, as the observed effects should be attributed to the confounder rather than the independent variable.
For example, assume that a child's weight and a country's gross domestic product (GDP) rise with time. A person carrying out an experiment could measure weight and GDP, and conclude that a higher GDP causes children to gain weight, or that children's weight gain boosts the GDP. However, the confounding variable, time, was not accounted for, and is the real cause of both rises.
By definition, a confounding variable is associated with both the probable cause and the outcome. The confounder is not allowed to lie in the causal pathway between the cause and the outcome: If A is thought to be the cause of disease C, the confounding variable B may not be solely caused by behaviour A; and behaviour B shall not always lead to behaviour C. An example: Being female does not always lead to smoking tobacco, and smoking tobacco does not always lead to cancer. Therefore, in any study that tries to elucidate the relation between being female and cancer should take smoking into account as a possible confounder. In addition, a confounder is always a risk factor that has a different prevalence in two risk groups (e.g. females/males). (Hennekens, Buring & Mayrent, 1987).
Though criteria for causality in statistical studies have been researched intensely, Pearl has shown that confounding variables cannot be defined in terms of statistical notions alone; some causal assumptions are necessary.[1] In a 1965 paper, Austin Bradford Hill proposed a set of causal criteria.[2].
Many working epidemiologists take these as a good place to start when considering confounding and causation. However, these are of heuristic value at best. When causal assumptions are articulated in the form of causal graph, a simple criterion is available, called backdoor, to identify sets of confounding variables.
# How to remove confounding in a study
There are various ways to modify a study design to actively exclude or control confounding variables:[3]
- Case-control studies assign confounders to both groups, cases and controls, equally. For example if somebody wanted to study the cause of myocardial infarct and thinks that the age is a probable confounding variable, each 67 years old infarct patient will be matched with a healthy 67 year old "control" person. In case-control studies, matched variables most often are the age and sex.
- Cohort studies: A degree of matching is also possible and it is often done by only admitting certain age groups or a certain sex into the study population, and thus all cohorts are comparable in regard to the possible confounding variable. For example, if age and sex are thought to be a confounders, only 40 to 50 years old males would be involved in a cohort study that would assess the myocardial infarct risk in cohorts that either are physically active or inactive.
- Stratification: As in the example above, physical activity is thought to be a behaviour that protects from myocardial infarct; and age is assumed to be a possible confounder. The data sampled is then stratified by age group – this means, the association between activity and infarct would be analyzed per each age group. If the different age groups (or age strata) yield much different risk ratios, age must be viewed as a confounding variable. There are statistical tools like Mantel-Haenszel methods that deal with stratified data.
All these methods have their drawbacks. This can be clearly seen in this example: A 45 years old Afro-American from Alaska, avid football player and vegetarian, working in education, suffers from a disease and is enrolled into a case-control study. Proper matching would call for a person with the same characteristics, with the sole difference of being healthy – but finding such one would be an enormous task. Additionally, there is always the risk of over- and undermatching of the study population. In cohort studies, too many people can be excluded; and in stratification, single strata can get too thin and thus contain only a small, non-significant number of samples.
- Controlling for confounding by measuring the known confounders and including them as covariates in multivariate analyses. A drawback of these is that they give little information about the strength of the confounding variable compared to stratification methods.
One major problem is that confounding variables are not always known or measurable. This leads to 'residual confounding' - epidemiological jargon for incompletely controlled confounding. Hence, randomization is often the best solution as, if performed successfully on sufficiently large numbers, all confounding variables (known and unknown) will be equally distributed across all study groups.
# External links
These sites contain descriptions or examples of lurking variables:
- Linear Regression (Yale University)
- Scatterplots (Simon Fraser University)
- Pearl, J. "Why there is no statistical test for counfounding, why many think there is, and why they are almost right," UCLA Computer Science Department, Technical Report R-256, January 1998 | https://www.wikidoc.org/index.php/Confounder | |
68d1cf0257936f79df3afaa3643f185778944ef8 | wikidoc | Hemiplegia | Hemiplegia
# Overview
Hemiplegia is a condition where there is paralysis in one vertical half of a patient's body. This is not hemiparesis wherein one half of the body is weakened, i.e. one arm and its corresponding leg are weak. Hemiplegia is similar to hemiparesis, but hemiparesis is considered less severe.
# Causes
It can be congenital (occurring before, during, or soon after birth) or acquired (as from illness or stroke).
It is usually the result of a stroke, although disease processes affecting the spinal cord and other diseases affecting the hemispheres are equally capable of producing this clinical state. Hemiplegia can be a more serious consequence of stroke than spasticity.
Cerebral palsy can also affect one hemisphere, resulting in limited function. This does not cause paralysis but instead causes spasms. Cerebral palsy where this is the only symptom is often referred just as hemiplegia.
Type 2 diabetes mellitus can lead to transient hemiplegia.
A rare cause of hemiplegia is due to local anaesthetic injections given intra-arterially rapidly, instead of given in a nerve branch.
## Common Causes
- Stroke
- Intracranial hemorrhage
- Encephalitis
- Cerebral abscess
- Cerebral palsy
- Traumatic cerebral hemorrhage
- Neoplasm
- Cerebral agenesis
## Causes by Organ System
## Causes in Alphabetical Order
# Hemiplegic migraine
Hemiplegic migraine is a form of migraine during which the person will experience the feeling of numbness on one side of their body. This feeling will usually pass within 2-12 hour. | Hemiplegia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Naresh Mullaguri, M.B.B.S. [2]
# Overview
Hemiplegia is a condition where there is paralysis in one vertical half of a patient's body. This is not hemiparesis wherein one half of the body is weakened, i.e. one arm and its corresponding leg are weak. Hemiplegia is similar to hemiparesis, but hemiparesis is considered less severe.[1]
# Causes
It can be congenital (occurring before, during, or soon after birth) or acquired (as from illness or stroke).
It is usually the result of a stroke, although disease processes affecting the spinal cord and other diseases affecting the hemispheres are equally capable of producing this clinical state. Hemiplegia can be a more serious consequence of stroke than spasticity.[2]
Cerebral palsy can also affect one hemisphere, resulting in limited function. This does not cause paralysis but instead causes spasms. Cerebral palsy where this is the only symptom is often referred just as hemiplegia.
Type 2 diabetes mellitus can lead to transient hemiplegia.
A rare cause of hemiplegia is due to local anaesthetic injections given intra-arterially rapidly, instead of given in a nerve branch.
## Common Causes
- Stroke
- Intracranial hemorrhage
- Encephalitis
- Cerebral abscess
- Cerebral palsy
- Traumatic cerebral hemorrhage
- Neoplasm
- Cerebral agenesis
## Causes by Organ System
## Causes in Alphabetical Order
# Hemiplegic migraine
Hemiplegic migraine is a form of migraine during which the person will experience the feeling of numbness on one side of their body. This feeling will usually pass within 2-12 hour. | https://www.wikidoc.org/index.php/Congenital_Hemiplegia | |
c00cdd7cc37e572ac7029b27c90b1982b6e99ba3 | wikidoc | Ichthyosis | Ichthyosis
For patient information on this page, click here
Synonyms and keywords: Scaling skin, Fish scale disease
# Overview
Ichthyosis is a family of genetic dermatological conditions seen in humans and domestic animals. People or animals with ichthyosis have scaly skin which can vaguely resemble the scales of a fish.
# Historical Perspective
The word comes from Greek ιχθύωσις lit. "forming fish", as people or animals with ichthyosis have scaly skin which can vaguely resemble the scales of a fish.
The term ichthyosis is sometimes used to refer to the specific condition ichthyosis vulgaris. Ichthyosis was formerly referred to as "pseudo-leprosy," as it can produce an appearance superficially similar to that of leprosy.
# Classification
While ichthyosis acquisita is acquired (as its name indicates), most forms of ichthyosis are considered congenital. These types include:
Some types of ichthyosis include:
- Ichthyosis vulgaris
- X-linked ichthyosis
- Ichthyosis lamellaris
- Epidermolytic hyperkeratosis
- Harlequin type ichthyosis
- Netherton's syndrome
- Sjögren-Larsson syndrome
# Epidemiology and Demographics
Ethnicity is not associated with ichthyosis.
# Ichthyosis in domestic dogs
Ichthyosis of varying severity is well-documented in some popular breeds of domestic dogs. The most common breeds in which this condition manifests itself are Golden retrievers, American bulldogs, Jack Russell terriers, and Cairn terriers.
# Diagnosis
## Symptoms
- Dry skin
- Scaly skin
- Thick skin
## Physical Examination
- Dry, scaly skin
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
- Icthyosis vulgaris. Adapted from Dermatology Atlas.
## Lab tests
- Skin biopsy
# Treatments
Treatments for ichthyosis often take the form of topical application of creams and emollient oils, in an attempt to hydrate the skin. Retinoids are also used for some conditions. Exposure to sunlight may improve or worsen the condition.
There can be ocular manifestations of ichthyosis, such as corneal and ocular surface diseases. Vascularizing keratitis, which is more commonly found in congenital keratitis-ichythosis-deafness (KID), may worsen with isotretinoin therapy. Ectropion, if it occurs, can be treated surgically after skin hydration.
As of now, there is no way to prevent ichthyosis. | Ichthyosis
For patient information on this page, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Kiran Singh, M.D. [3]
Synonyms and keywords: Scaling skin, Fish scale disease
# Overview
Ichthyosis is a family of genetic dermatological conditions seen in humans and domestic animals. People or animals with ichthyosis have scaly skin which can vaguely resemble the scales of a fish.
# Historical Perspective
The word comes from Greek ιχθύωσις lit. "forming fish", as people or animals with ichthyosis have scaly skin which can vaguely resemble the scales of a fish.
The term ichthyosis is sometimes used to refer to the specific condition ichthyosis vulgaris. Ichthyosis was formerly referred to as "pseudo-leprosy," as it can produce an appearance superficially similar to that of leprosy.
# Classification
While ichthyosis acquisita is acquired (as its name indicates), most forms of ichthyosis are considered congenital. These types include:
Some types of ichthyosis include:
- Ichthyosis vulgaris
- X-linked ichthyosis
- Ichthyosis lamellaris
- Epidermolytic hyperkeratosis
- Harlequin type ichthyosis
- Netherton's syndrome
- Sjögren-Larsson syndrome
# Epidemiology and Demographics
Ethnicity is not associated with ichthyosis.
# Ichthyosis in domestic dogs
Ichthyosis of varying severity is well-documented in some popular breeds of domestic dogs. The most common breeds in which this condition manifests itself are Golden retrievers, American bulldogs, Jack Russell terriers, and Cairn terriers.
# Diagnosis
## Symptoms
- Dry skin
- Scaly skin
- Thick skin
## Physical Examination
- Dry, scaly skin
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
- Icthyosis vulgaris. Adapted from Dermatology Atlas.[1]
## Lab tests
- Skin biopsy
# Treatments
Treatments for ichthyosis often take the form of topical application of creams and emollient oils, in an attempt to hydrate the skin. Retinoids are also used for some conditions. Exposure to sunlight may improve or worsen the condition.
There can be ocular manifestations of ichthyosis, such as corneal and ocular surface diseases. Vascularizing keratitis, which is more commonly found in congenital keratitis-ichythosis-deafness (KID), may worsen with isotretinoin therapy. Ectropion, if it occurs, can be treated surgically after skin hydration.
As of now, there is no way to prevent ichthyosis. | https://www.wikidoc.org/index.php/Congenital_ichthyosis | |
95b39268f701094a253ab77c15ffe299d1fb7753 | wikidoc | Conivaptan | Conivaptan
# 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
Conivaptan is a Vasopressin antagonist that is FDA approved for the treatment of raising serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia.. Common adverse reactions include hypertension, orthostatic hypotension, peripheral edema, phlebitis, injection site reaction, hypokalemia, increased thirst, constipation, diarrhea, vomiting, headache, increased frequency of urination, polyuria, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Euvolemic and Hypervolemic Hyponatremia
- Dosing Information
- Treatment for the 1st day:
- Initial loading dosage:20 mg IV over 30 min
- Followed treatment: 20 mg IV continuously over 24 hours
- Treatment for 2nd-4th day:20 mg/day IV continuously
- If serum sodium is not rising at the desired rate, vaprisol may be titrated upward to a dose of 40 mg daily, administered in a continuous intravenous infusion.
- The total duration of infusion of vaprisol (after the loading dose) should not exceed 4 days. The maximum daily dose of vaprisol (after the loading dose) is 40 mg/day.
- vaprisol is for intravenous use only.
- vaprisol is for use in hospitalized patients only.
- Administer vaprisol through large veins and change of the infusion site every 24 hours to minimize the risk of vascular irritation.
- Patients receiving vaprisol must have frequent monitoring of serum sodium and volume status. An overly rapid rise in serum sodium (> 12 mEq/L/24 hours) may result in serious neurologic sequelae. For patients who develop an undesirably rapid rate of rise of serum sodium, vaprisol should be discontinued, and serum sodium and neurologic status should be carefully monitored. If the serum sodium continues to rise, vaprisol should not be resumed. If hyponatremia persists or recurs, and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, vaprisol may be resumed at a reduced dose. For patients who develop hypovolemia or hypotension while receiving vaprisol, vaprisol should be discontinued, and volume status and vital signs should be frequently monitored. Once the patient is again euvolemic and is no longer hypotensive, vaprisol may be resumed at a reduced dose if the patient remains hyponatremic.
### Hepatic Impairment
- In patients with moderate hepatic impairment, initiate vaprisol with a loading dose of 10 mg over 30 minutes followed by 10 mg per day as a continuous infusion for 2 to 4 days. If serum sodium is not rising at the desired rate, vaprisol may be titrated upward to 20 mg per dayand .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Conivaptan in adult patients.
### Non–Guideline-Supported Use
### Heart Failure
- Dosing information
- 10, 20 , 40 mg IV
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- FDA Package Insert for Conivaptan contains no information regarding Pediatric Indications and Dosage.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information about Off-Label Guideline-Supported Use of Conivaptan in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information about the non–guideline-supported off-label use.
# Contraindications
- Hypovolemic Hyponatremia
- vaprisol is contraindicated in patients with hypovolemic hyponatremia.
- Coadministration with Potent CYP3A Inhibitors
- The coadministration of vaprisol with potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated.
- Anuric Patients
- In patients unable to make urine, no benefit can be expected.
- Known Allergy to Corn or Corn Products
- Solutions containing dextrose are contraindicated in patients with known allergy to corn or corn products.
# Warnings
- Hypovolemic hyponatremia
- vaprisol is contraindicated in patients with hypovolemic hyponatremia.
- Coadministration with Potent CYP3A Inhibitors
- The coadministration of vaprisol with potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated.
- Anuric Patients
- In patients unable to make urine, no benefit can be expected.
- Known Allergy to Corn or Corn Products
- Solutions containing dextrose are contraindicated in patients with known allergy to corn or corn products.
- Hyponatremia Associated with Heart Failure
- The amount of safety data on the use of vaprisol in patients with hypervolemic hyponatremia associated with heart failure is limited. vaprisol should be used to raise serum sodium in such patients only after consideration of other treatment options.
- Overly Rapid Correction of Serum Sodium
- Osmotic demyelination syndrome is a risk associated with overly rapid correction of hyponatremia (i.e., > 12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, use slower rates of correction. In controlled clinical trials of vaprisol, about 9% of patients who received vaprisol in doses of 20-40 mg/day IV had rises of serum sodium >12 mEq/L/24 hours, but none of these patients had evidence of osmotic demyelination or permanent neurologic sequelae. Serum sodium concentration and neurologic status should be monitored appropriately during vaprisol administration, and vaprisol administration should be discontinued if the patient develops an undesirably rapid rate of rise of serum sodium. If the serum sodium concentration continues to rise, vaprisol should not be resumed. If hyponatremia persists or recurs (after initial discontinuation of vaprisol for an undesirably rapid rate of rise of serum sodium concentration), and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, vaprisol may be resumed at a reduced dose.
- Coadministration of vaprisol and Drugs Eliminated Primarily by CYP3A Mediated Metabolism
- In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving a CYP3A-metabolized HMG-CoA reductase inhibitor. Avoid concomitant use of vaprisol with drugs eliminated primarily by CYP3A-mediated metabolism. Subsequent treatment with CYP3A substrate drugs may be initiated no sooner than 1 week after the infusion of vaprisol is completed.
- Coadministration of vaprisol and digoxin
- Coadministration of digoxin with oral conivaptan resulted in a 1.8- and 1.4-fold increase in digoxin Cmax and AUC, respectively. Monitor digoxin levels .
- Infusion Site Reactions
- Infusion site reactions are common and can include serious reactions, even with proper infusion rates . Administer vaprisol via large veins, and rotate the infusion site every 24 hours.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reactions 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 adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
- The most common adverse reactions reported with vaprisol administration were infusion site reactions. In studies in patients and healthy volunteers, infusion site reactions occurred in 73% and 63% of subjects treated with vaprisol 20 mg/day and 40 mg/day, respectively, compared to 4% in the placebo group. Infusion site reactions were the most common type of adverse event leading to discontinuation of vaprisol. Discontinuations from treatment due to infusion site reactions were more common among vaprisol-treated patients (3%) than among placebo-treated patients (0%). Some serious infusion site reactions did occur.
- The adverse reactions presented in Table 1 are derived from 72 healthy volunteers and 243 patients with euvolemic or hypervolemic hyponatremia who received vaprisol 20 mg IV as a loading dose followed by 40 mg/day IV for 2 to 4 days, from 37 patients with euvolemic or hypervolemic hyponatremia who received vaprisol 20 mg IV as a loading dose followed by 20 mg/day IV for 2 to 4 days in an open-label study, and from 40 healthy volunteers and 29 patients with euvolemic or hypervolemic hyponatremia who received placebo. The adverse reactions occurred in at least 5% of patients treated with vaprisol and at a higher incidence for vaprisol-treated patients than for placebo-treated patients.
- Although a dose of 80 mg/day of vaprisol was also studied, it was associated with a higher incidence of infusion site reactions and a higher rate of discontinuation for adverse events than was the 40 mg/day vaprisol dose. The maximum recommended daily dose of vaprisol (after the loading dose) is 40 mg/day.
- In clinical trials where vaprisol was administered to 79 hypervolemic hyponatremic patients with underlying heart failure and intravenous placebo administered to 10 patients, adverse cardiac failure events, atrial dysrhythmias, and sepsis occurred more frequently among patients treated with vaprisol (32%, 5% and 8% respectively) than among patients treated with placebo (20%, 0% and 0% respectively).
## Postmarketing Experience
- There is limited information about the post marketing experience.
# Drug Interactions
- CYP3A
- Conivaptan is a sensitive substrate of CYP3A. The effect of ketoconazole, a potent CYP3A inhibitor, on the pharmacokinetics of intravenous conivaptan has not been evaluated. Coadministration of oral conivaptan hydrochloride 10 mg with ketoconazole 200 mg resulted in 4- and 11-fold increases in Cmax and AUC of conivaptan, respectively.
- Conivaptan is a potent mechanism-based inhibitor of CYP3A. The effect of conivaptan on the pharmacokinetics of co-administered CYP3A substrates has been evaluated with the coadministration of conivaptan with midazolam, simvastatin, and amlodipine. vaprisol 40 mg/day increased the mean AUC values by approximately 2- and 3-fold for 1 mg intravenous or 2 mg oral doses of midazolam, respectively. vaprisol 30 mg/day resulted in a 3-fold increase in the AUC of simvastatin. Oral conivaptan hydrochloride 40 mg twice daily resulted in a 2-fold increase in the AUC and half-life of amlodipine.
- Digoxin
- Coadministration of a 0.5 mg dose of digoxin, a P-glycoprotein substrate, with oral conivaptan hydrochloride 40 mg twice daily resulted in a 30% reduction in clearance and 79% and 43% increases in digoxin Cmax and AUC values, respectively.
- Warfarin
- vaprisol (40 mg/day for 4 days) administered with a single 25 mg dose of warfarin, which undergoes major metabolism by CYP2C9 and minor metabolism by CYP3A, increased the mean S-warfarin AUC and S-warfarin Cmax by 14% and 17%, respectively. The corresponding prothrombin time and international normalized ratio values were unchanged.
- Captopril and Furosemide
- The pharmacokinetics of oral conivaptan (20 - 40 mg/day) were unchanged with coadministration of either captopril 25 mg or furosemide up to 80 mg/day.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Pregnancy Category C. Conivaptan has been shown to have adverse effects on the fetus when given to rats during pregnancy at systemic exposures less than those achieved at the human therapeutic dose based on AUC comparisons '). There are no adequate and well-controlled studies of vaprisol use in pregnant women. vaprisol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The patient should be apprised of the potential hazard to the fetus. Rat fetal tissue levels were < 10% of maternal plasma concentrations while placental levels were 2.2-fold higher than maternal plasma concentrations. Conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Conivaptan in women who are pregnant.
### Labor and Delivery
- The effect of vaprisol on labor and delivery in humans has not been studied. Conivaptan hydrochloride delayed delivery in rats dosed at 10 mg/kg/day by oral gavage (systemic exposure equivalent to the human therapeutic exposure based on AUC comparison). Administration of conivaptan hydrochloride at 2.5 mg/kg/day intravenously increased peripartum pup mortality (systemic exposure less than the human therapeutic exposure based on AUC comparison). These effects may be associated with conivaptan activity on oxytocin receptors in the rat. The relevance to humans is unclear.
### Nursing Mothers
- It is not known whether conivaptan is excreted in human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from vaprisol, a decision should be made to discontinue nursing or vaprisol, taking into consideration the importance of vaprisol to the mother. Conivaptan is excreted in milk and detected in neonates when given by intravenous administration to lactating rats. Milk levels of conivaptan in rats reached maximal levels at 1 hour post dose following intravenous administration and were up to 3 times greater than maternal plasma levels following an intravenous dose of 1 mg/kg (systemic exposure less than human therapeutic exposure based on AUC comparison).
### Pediatric Use
- The safety and effectiveness of vaprisol in pediatric patients have not been studied.
### Geriatic Use
- In clinical studies of vaprisol administered as a 20 mg IV loading dose followed by 20 mg/day or 40 mg/day IV for 2 to 4 days, 89% (20 mg/day regimen) and 60% (40 mg/day regimen) of participants were greater than or equal to 65 years of age and 60% (20 mg/day regimen) and 40% (40 mg/day regimen) were greater than or equal to 75 years of age. In general, the adverse event profile in elderly patients was similar to that seen in the general study population.
### Gender
There is no FDA guidance on the use of Conivaptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Conivaptan with respect to specific racial populations.
### Renal Impairment
- No clinically relevant increase in exposure was observed in subjects with mild and moderate renal impairment (CLcr 30 – 80 mL/min). No dose adjustment of vaprisol is necessary. Because of the high incidence of infusion site phlebitis (which can reduce vascular access sites) and unlikely benefit, use in patients with severe renal impairment (CLcr <30 mL/min) is not recommended.
### Hepatic Impairment
- No clinically relevant increase in exposure was observed in subjects with mild hepatic impairment; therefore no dose adjustment of vaprisol is necessary. The exposure to vaprisol approximately doubles with moderate hepatic impairment. The impact of severe hepatic impairment on the exposure to conivaptan has not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Conivaptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Conivaptan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- vaprisol is for intravenous use only.
- vaprisol is for use in hospitalized patients only.
- Administer vaprisol through large veins and change of the infusion site every 24 hours to minimize the risk of vascular irritation.
### Monitoring
- Patients receiving vaprisol must have frequent monitoring of serum sodium and volume status
- Coadministration of digoxin with oral conivaptan resulted in a 1.8- and 1.4-fold increase in digoxin Cmax and AUC, respectively. Monitor digoxin levels
- In case of overdose, based on expected exaggerated pharmacological activity, symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is recommended.
# IV Compatibility
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter, discoloration or cloudiness is observed, the drug solution should not be used.
- vaprisol is supplied in a single-use 100 mL flexible INTRAVIA Container containing a sterile premixed dilute, ready-to-use, nonpyrogenic solution of conivaptan hydrochloride, 0.2 mg per mL (20 mg/100 mL) in 5% Dextrose. NO FURTHER DILUTION OF THIS PREPARATION IS NECESSARY.
- vaprisol is compatible with 5% Dextrose Injection. vaprisol is physically and chemically compatible with 0.9% Sodium Chloride Injection for up to 48 hours when the two solutions are co-administered via a Y-site connection at a flow rate for vaprisol of 4.2 mL/hour and at flow rates for 0.9% Sodium Chloride Injection of either 2.1 mL/hour or 6.3 mL/hour.
- vaprisol has been shown to be incompatible with both Lactated Ringer's Injection and furosemide injection when these products are mixed in the same container; therefore, do not combine vaprisol with these products in the same intravenous line or container.
- vaprisol should also not be combined with any other product in the same intravenous line or container.
Loading Dose
- Administer the content of a 20 mg/100 mL vaprisol flexible plastic container over 30 minutes.
Continuous Infusion
- For patients requiring 20 mg vaprisol injection per day, administer the content of one 20 mg/100 mL vaprisol flexible plastic container over 24 hours.
For patients requiring 40 mg vaprisol injection per day, administer the content of two consecutive 20 mg/100 mL vaprisol flexible plastic containers over 24 hours.
Since the flexible container is for single-use only, any unused portion should be discarded.
CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.
Do not remove container from overwrap until ready for use. The overwrap is a moisture and light barrier. The inner container maintains the sterility of the product.
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner container firmly. If leaks are found, discard solution as sterility may be impaired. Do not use if the solution is cloudy or a precipitate is present.
DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:
- Suspend container from eyelet support.
- Remove protector from outlet port at bottom of container.
- Attach administration set. Refer to complete directions accompanying set.
# Overdosage
- Although no data on overdosage in humans are available, vaprisol has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of vaprisol, e.g. hypotension and thirst, occurred more frequently at these higher doses.
In case of overdose, based on expected exaggerated pharmacological activity, symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is recommended.
# Pharmacology
## Mechanism of Action
Conivaptan hydrochloride is a dual arginine vasopressin (AVP) antagonist with nanomolar affinity for human V1A and V2 receptors in vitro. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range. The predominant pharmacodynamic effect of conivaptan hydrochloride in the treatment of hyponatremia is through its V2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water.
## Structure
- Conivaptan hydrochloride is chemically -2-carboxamide, N-benzazepin-6(1H)-yl]carbonyl]phenyl]-, monohydrochloride, having a molecular weight of 535.04 and molecular formula C32H26N4O2∙HCl. The structural formula of conivaptan hydrochloride is:
- Conivaptan hydrochloride is a white to off-white or pale orange-white powder that is very slightly soluble in water (0.15 mg/mL at 23° C). Conivaptan hydrochloride injection is supplied as a sterile premixed solution with dextrose in a flexible plastic container.
- Each container contains a clear, colorless, sterile, non-pyrogenic solution of conivaptan hydrochloride in dextrose. Each 100 mL, single-use premixed INTRAVIA Container contains 20 mg of conivaptan hydrochloride and 5 g of Dextrose Hydrous, USP. Lactic Acid, USP is added for pH adjustment to pH 3.4 to 3.8. The flexible plastic container is fabricated from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain of the chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. The flexible container has a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to significantly affect the premixed solution.
## Pharmacodynamics
- The pharmacodynamic effects of conivaptan hydrochloride include increased free water excretion (i.e., effective water clearance ) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. Studies in animal models of hyponatremia showed that conivaptan hydrochloride prevented the occurrence of hyponatremia-related physical signs in rats with the syndrome of inappropriate antidiuretic hormone secretion.
Electrophysiology
- The effect of vaprisol 40 mg IV and 80 mg IV on the QT interval was evaluated after the first dose (Day 1) and at the last day during treatment (Day 4) in a randomized, single-blind, parallel group, placebo- and positive-controlled (moxifloxacin 400 mg IV) study in healthy male and female volunteers aged 18 to 45 years. Digital ECGs were obtained at baseline and on Days 1 and 4. Moxifloxacin elicited placebo-corrected changes from baseline in individualized QT correction (QTcI) of +7 to +10 msec on Days 1 and 4, respectively, indicating that the study had assay sensitivity. The placebo-corrected changes from baseline in QTcI in the vaprisol 40 mg and 80 mg dose groups on Day 1 were -3.5 msec and -2.9 msec, respectively, and -2.1 msec for both dose groups on Day 4. The results suggest that conivaptan has no clinically significant effect on cardiac repolarization.
## Pharmacokinetics
- The pharmacokinetics of conivaptan have been characterized in healthy subjects, special populations and patients following both oral and intravenous dosing regimens. The pharmacokinetics of conivaptan following intravenous infusion (40 mg/day to 80 mg/day) and oral administration are non-linear, and inhibition by conivaptan of its own metabolism seems to be the major factor for the non-linearity. The intersubject variability of conivaptan pharmacokinetics is high (94% CV in CL).
- The pharmacokinetics of conivaptan and its metabolites were characterized in healthy male subjects administered conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 40 mg/day for 3 days. Mean Cmax for conivaptan was 619 ng/mL and occurred at the end of the loading dose. Plasma concentrations reached a minimum at approximately 12 hours after start of the loading dose, then gradually increased over the duration of the infusion to a mean concentration of 188 ng/mL at the end of the infusion. The mean terminal elimination half-life after conivaptan infusion was 5.0 hours, and the mean clearance was 253.3 mL/min.
- In an open-label safety and efficacy study, the pharmacokinetics of conivaptan were characterized in hypervolemic or euvolemic hyponatremia patients (ages 20 - 92 years) receiving conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 20 or 40 mg/day for 4 days. The median-plasma conivaptan concentrations are shown in Figure 1. The median (range) elimination half-life was 5.3 (3.3 - 9.3) or 8.1 (4.1 - 22.5) hours in the 20 mg/day or 40 mg/day group, respectively, based on data from rich PK sampling.
Distribution
- Conivaptan is extensively bound to human plasma proteins, being 99% bound over the concentration range of approximately 10 to 1000 ng/mL.
Metabolism and Excretion
- CYP3A was identified as the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V1A and V2 receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively. The combined exposure of the metabolites following intravenous administration of conivaptan is approximately 7% that of conivaptan and hence, their contribution to the clinical effect of conivaptan is minimal.
- After intravenous (10 mg) or oral (20 mg) administration of conivaptan hydrochloride in a mass balance study, approximately 83% of the dose was excreted in feces as total radioactivity and 12% in urine over several days of collection. Over the first 24 hours after dosing, approximately 1% of the intravenous dose was excreted in urine as intact conivaptan.
Hepatic Impairment
- The systemic exposure to conivaptan is approximately doubled in subjects with moderate hepatic impairment. No clinically relevant increase in exposure was observed in subjects with mild hepatic impairment. The impact of severe hepatic impairment on the exposure to conivaptan has not been studied.
Renal Impairment
- Mild and moderate renal impairment (CLcr 30 - 80 mL/min) do not affect exposure to vaprisol to a clinically relevant extent. Use in patients with severe renal impairment (CLcr < 30 mL/min) is not recommended.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility=
- Standard lifetime (104 week) carcinogenicity bioassays were conducted in mice and rats. Male and female mice were given oral doses of conivaptan hydrochloride up to 30 mg/kg/day and 10 mg/kg/day, respectively, by gavage. Male and female rats were given oral doses of up to 10 mg/kg/day and 30 mg/kg/day, respectively, by gavage. There was no increased incidence of tumors associated with exposure to conivaptan in either species. The 30 mg/kg/day dosage regimen in male mice and female rats was shown to result in a systemic exposure (AUC) about twice the human systemic exposure from an IV bolus of 20 mg on day 1 followed by IV infusion of 40 mg/day for 3 days. The 10 mg/kg/day dosage regimen in female mice and male rats was shown to result in about one-fourth and one-half the human therapeutic exposure, respectively.
Conivaptan was not genotoxic in the bacterial reverse mutation assay, the in vitro human peripheral blood lymphocyte chromosomal aberration assay, or in vivo rat micronucleus assay.
- Fertility of male rats treated with conivaptan hydrochloride by IV bolus doses of up to 2.5 mg/kg/day for the 4 weeks preceding mating and throughout the mating period was unaffected. However, when female rats were given IV bolus conivaptan from 15 days before mating through gestation day 7, there was prolonged diestrus, decreased fertility (decreased numbers of corpora lutea and implantations) and increased post-implantation loss at 2.5 mg/kg/day (systemic exposure less than human exposure at the therapeutic dose).
- When pregnant rats were given intravenous doses of conivaptan hydrochloride up to 2.5 mg/kg/day on gestation days 7 through 17 (systemic exposures less than human therapeutic exposure based on AUC comparisons), no significant maternal or fetal effects were observed.
- When pregnant rats received intravenous conivaptan hydrochloride at a dose of 2.5 mg/kg/day (systemic exposure less than human therapeutic exposure based on AUC comparison) from gestation day 7 through lactation day 20 (weaning), the pups showed decreased neonatal viability and weaning indices, decreased body weight, and delayed reflex and physical development (including sexual maturation). No discernible effects were seen in pups from dams administered conivaptan hydrochloride at 0.5 or 1.25 mg/kg/day during this same period. No maternal adverse effects of conivaptan were seen in this study. When pregnant rabbits were given intravenous doses of conivaptan hydrochloride up to 12 mg/kg/day on gestation days 6 through 18 (about twice the human therapeutic exposure) there were no fetal or maternal findings.
# Clinical Studies
### Hyponatremia=
- The effect on serum sodium of vaprisol was demonstrated in a double-blind, placebo-controlled, randomized, multicenter study conducted in 84 patients with euvolemic (N=56) or hypervolemic (N=28) hyponatremia (serum sodium 115 -130 mEq/L) from a variety of underlying causes (malignant or nonmalignant diseases of the central nervous system, lung, or abdomen; congestive heart failure; hypertension; myocardial infarction; diabetes; osteoarthritis; or idiopathic). Study participants were randomized to receive either placebo IV (N=29), vaprisol 40 mg/day IV (N=29), or vaprisol 80 mg/day IV (N=26). Daily fluid intake was restricted to 2 liters. vaprisol or placebo was administered as a continuous infusion following a 30 minute IV loading dose on the first treatment day and patients were treated for 4 days. Serum or plasma sodium concentrations were assessed pre-dose (Hour 0) and at 4, 6, 10, and 24 hours post-dose on all treatment days.
- Mean serum sodium concentration was 123.3 mEq/L at study entry. The mean change in serum sodium concentration from baseline over the 4-day treatment period is shown in Figure 2.
- Following treatment with 40 mg/day of vaprisol, the mean change from baseline in serum sodium concentration at the end of 2 days of treatment with vaprisol was 5.3 mEq/L (mean concentration 128.6 mEq/L). At the end of the 4-day treatment period, the mean change from baseline was 6.5 mEq/L (mean concentration 129.8 mEq/L). In addition, after 2 days and 4 days of treatment with vaprisol, 41% (after 2 days) and 69% (after 4 days) of patients achieved a ≥ 6 mEq/L increase in serum sodium concentration or a normal serum sodium of ≥ 135 mEq/L. Although 80 mg/day was also studied, it was not significantly more effective than 40 mg/day and was associated with a higher incidence of infusion site reactions and a higher rate of discontinuations for adverse events. Additional efficacy data are summarized in Table 2.
- The aquaretic effect of vaprisol is shown in Figure 3. vaprisol produced a baseline-corrected cumulative increase in effective water clearance of over 3800 mL compared to approximately 1300 mL with placebo by Day 4.
- Where V is urine volume (mL/d), UNa is urine sodium concentration, UK is urine potassium concentration, PNa is plasma/serum sodium concentration, and PK is plasma/serum potassium concentration.
- The effect on serum sodium of vaprisol (administered as a 20 or 40 mg/day IV continuous infusion for 4 days following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day) was also evaluated in an open-label study of 251 patients with euvolemic or hypervolemic hyponatremia. The results are shown in Table 3.
- The effectiveness of vaprisol for the treatment of congestive heart failure has not been established. In ten Phase 2/pilot heart failure studies, vaprisol did not show statistically significant improvement for heart failure outcomes, including such measures as length of hospital stay, changes in categorized physical findings of heart failure, change in ejection fraction, change in exercise tolerance, change in functional status, or change in heart failure symptoms, compared to placebo. In these studies, the changes in the physical findings and heart failure symptoms were no worse in the vaprisol-treated group (N=818) compared to the placebo group (N=290).
# How Supplied
- vaprisol (conivaptan hydrochloride) Injection is supplied as a single-use, premixed solution, containing 20 mg of conivaptan hydrochloride in 5% Dextrose in 100 mL INTRAVIA Plastic Containers.
- 1 container/carton (NDC 0469-1602-10)
## Storage
- vaprisol in INTRAVIA Plastic Containers should be stored at 25°C (77°F); however, brief exposure up to 40°C (104°F) does not adversely affect the product. Avoid excessive heat. Protect from freezing. Protect from light until ready to use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients about the common adverse effects of vaprisol including infusion site effects (edema, erythema, pain, and phlebitis), pyrexia, hypokalemia, headache, orthostatic hypotension and potential for overly rapid increase in serum sodium which can cause serious neurologic sequelae. Instruct patients to inform their healthcare provider if they develop any unusual symptoms, or if any known symptom persists or worsens, with special attention to potential manifestations of osmotic demyelination syndrome.
- Ask patients about what other medications they are currently taking with vaprisol, including over-the-counter medications.
- Ask patients if they have allergies to corn or corn products.
# Precautions with Alcohol
- Alcohol-Conivaptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VAPRISOL DEXTROSE IN PLASTIC CONTAINER
# Look-Alike Drug Names
- There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price | Conivaptan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Overview
Conivaptan is a Vasopressin antagonist that is FDA approved for the treatment of raising serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia.. Common adverse reactions include hypertension, orthostatic hypotension, peripheral edema, phlebitis, injection site reaction, hypokalemia, increased thirst, constipation, diarrhea, vomiting, headache, increased frequency of urination, polyuria, fever.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Euvolemic and Hypervolemic Hyponatremia
- Dosing Information
- Treatment for the 1st day:
- Initial loading dosage:20 mg IV over 30 min
- Followed treatment: 20 mg IV continuously over 24 hours
- Treatment for 2nd-4th day:20 mg/day IV continuously
- If serum sodium is not rising at the desired rate, vaprisol may be titrated upward to a dose of 40 mg daily, administered in a continuous intravenous infusion.
- The total duration of infusion of vaprisol (after the loading dose) should not exceed 4 days. The maximum daily dose of vaprisol (after the loading dose) is 40 mg/day.
- vaprisol is for intravenous use only.
- vaprisol is for use in hospitalized patients only.
- Administer vaprisol through large veins and change of the infusion site every 24 hours to minimize the risk of vascular irritation.
- Patients receiving vaprisol must have frequent monitoring of serum sodium and volume status. An overly rapid rise in serum sodium (> 12 mEq/L/24 hours) may result in serious neurologic sequelae. For patients who develop an undesirably rapid rate of rise of serum sodium, vaprisol should be discontinued, and serum sodium and neurologic status should be carefully monitored. If the serum sodium continues to rise, vaprisol should not be resumed. If hyponatremia persists or recurs, and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, vaprisol may be resumed at a reduced dose. For patients who develop hypovolemia or hypotension while receiving vaprisol, vaprisol should be discontinued, and volume status and vital signs should be frequently monitored. Once the patient is again euvolemic and is no longer hypotensive, vaprisol may be resumed at a reduced dose if the patient remains hyponatremic.
### Hepatic Impairment
- In patients with moderate hepatic impairment, initiate vaprisol with a loading dose of 10 mg over 30 minutes followed by 10 mg per day as a continuous infusion for 2 to 4 days. If serum sodium is not rising at the desired rate, vaprisol may be titrated upward to 20 mg per dayand .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Conivaptan in adult patients.
### Non–Guideline-Supported Use
### Heart Failure
- Dosing information
- 10, 20 , 40 mg IV [1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- FDA Package Insert for Conivaptan contains no information regarding Pediatric Indications and Dosage.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information about Off-Label Guideline-Supported Use of Conivaptan in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information about the non–guideline-supported off-label use.
# Contraindications
- Hypovolemic Hyponatremia
- vaprisol is contraindicated in patients with hypovolemic hyponatremia.
- Coadministration with Potent CYP3A Inhibitors
- The coadministration of vaprisol with potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated.
- Anuric Patients
- In patients unable to make urine, no benefit can be expected.
- Known Allergy to Corn or Corn Products
- Solutions containing dextrose are contraindicated in patients with known allergy to corn or corn products.
# Warnings
- Hypovolemic hyponatremia
- vaprisol is contraindicated in patients with hypovolemic hyponatremia.
- Coadministration with Potent CYP3A Inhibitors
- The coadministration of vaprisol with potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated.
- Anuric Patients
- In patients unable to make urine, no benefit can be expected.
- Known Allergy to Corn or Corn Products
- Solutions containing dextrose are contraindicated in patients with known allergy to corn or corn products.
- Hyponatremia Associated with Heart Failure
- The amount of safety data on the use of vaprisol in patients with hypervolemic hyponatremia associated with heart failure is limited. vaprisol should be used to raise serum sodium in such patients only after consideration of other treatment options.
- Overly Rapid Correction of Serum Sodium
- Osmotic demyelination syndrome is a risk associated with overly rapid correction of hyponatremia (i.e., > 12 mEq/L/24 hours). Osmotic demyelination results in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma or death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, use slower rates of correction. In controlled clinical trials of vaprisol, about 9% of patients who received vaprisol in doses of 20-40 mg/day IV had rises of serum sodium >12 mEq/L/24 hours, but none of these patients had evidence of osmotic demyelination or permanent neurologic sequelae. Serum sodium concentration and neurologic status should be monitored appropriately during vaprisol administration, and vaprisol administration should be discontinued if the patient develops an undesirably rapid rate of rise of serum sodium. If the serum sodium concentration continues to rise, vaprisol should not be resumed. If hyponatremia persists or recurs (after initial discontinuation of vaprisol for an undesirably rapid rate of rise of serum sodium concentration), and the patient has had no evidence of neurologic sequelae of rapid rise in serum sodium, vaprisol may be resumed at a reduced dose.
- Coadministration of vaprisol and Drugs Eliminated Primarily by CYP3A Mediated Metabolism
- In clinical trials of oral conivaptan, two cases of rhabdomyolysis occurred in patients who were also receiving a CYP3A-metabolized HMG-CoA reductase inhibitor. Avoid concomitant use of vaprisol with drugs eliminated primarily by CYP3A-mediated metabolism. Subsequent treatment with CYP3A substrate drugs may be initiated no sooner than 1 week after the infusion of vaprisol is completed.
- Coadministration of vaprisol and digoxin
- Coadministration of digoxin with oral conivaptan resulted in a 1.8- and 1.4-fold increase in digoxin Cmax and AUC, respectively. Monitor digoxin levels .
- Infusion Site Reactions
- Infusion site reactions are common and can include serious reactions, even with proper infusion rates . Administer vaprisol via large veins, and rotate the infusion site every 24 hours.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reactions 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 adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
- The most common adverse reactions reported with vaprisol administration were infusion site reactions. In studies in patients and healthy volunteers, infusion site reactions occurred in 73% and 63% of subjects treated with vaprisol 20 mg/day and 40 mg/day, respectively, compared to 4% in the placebo group. Infusion site reactions were the most common type of adverse event leading to discontinuation of vaprisol. Discontinuations from treatment due to infusion site reactions were more common among vaprisol-treated patients (3%) than among placebo-treated patients (0%). Some serious infusion site reactions did occur.
- The adverse reactions presented in Table 1 are derived from 72 healthy volunteers and 243 patients with euvolemic or hypervolemic hyponatremia who received vaprisol 20 mg IV as a loading dose followed by 40 mg/day IV for 2 to 4 days, from 37 patients with euvolemic or hypervolemic hyponatremia who received vaprisol 20 mg IV as a loading dose followed by 20 mg/day IV for 2 to 4 days in an open-label study, and from 40 healthy volunteers and 29 patients with euvolemic or hypervolemic hyponatremia who received placebo. The adverse reactions occurred in at least 5% of patients treated with vaprisol and at a higher incidence for vaprisol-treated patients than for placebo-treated patients.
- Although a dose of 80 mg/day of vaprisol was also studied, it was associated with a higher incidence of infusion site reactions and a higher rate of discontinuation for adverse events than was the 40 mg/day vaprisol dose. The maximum recommended daily dose of vaprisol (after the loading dose) is 40 mg/day.
- In clinical trials where vaprisol was administered to 79 hypervolemic hyponatremic patients with underlying heart failure and intravenous placebo administered to 10 patients, adverse cardiac failure events, atrial dysrhythmias, and sepsis occurred more frequently among patients treated with vaprisol (32%, 5% and 8% respectively) than among patients treated with placebo (20%, 0% and 0% respectively).
## Postmarketing Experience
- There is limited information about the post marketing experience.
# Drug Interactions
- CYP3A
- Conivaptan is a sensitive substrate of CYP3A. The effect of ketoconazole, a potent CYP3A inhibitor, on the pharmacokinetics of intravenous conivaptan has not been evaluated. Coadministration of oral conivaptan hydrochloride 10 mg with ketoconazole 200 mg resulted in 4- and 11-fold increases in Cmax and AUC of conivaptan, respectively.
- Conivaptan is a potent mechanism-based inhibitor of CYP3A. The effect of conivaptan on the pharmacokinetics of co-administered CYP3A substrates has been evaluated with the coadministration of conivaptan with midazolam, simvastatin, and amlodipine. vaprisol 40 mg/day increased the mean AUC values by approximately 2- and 3-fold for 1 mg intravenous or 2 mg oral doses of midazolam, respectively. vaprisol 30 mg/day resulted in a 3-fold increase in the AUC of simvastatin. Oral conivaptan hydrochloride 40 mg twice daily resulted in a 2-fold increase in the AUC and half-life of amlodipine.
- Digoxin
- Coadministration of a 0.5 mg dose of digoxin, a P-glycoprotein substrate, with oral conivaptan hydrochloride 40 mg twice daily resulted in a 30% reduction in clearance and 79% and 43% increases in digoxin Cmax and AUC values, respectively.
- Warfarin
- vaprisol (40 mg/day for 4 days) administered with a single 25 mg dose of warfarin, which undergoes major metabolism by CYP2C9 and minor metabolism by CYP3A, increased the mean S-warfarin AUC and S-warfarin Cmax by 14% and 17%, respectively. The corresponding prothrombin time and international normalized ratio values were unchanged.
- Captopril and Furosemide
- The pharmacokinetics of oral conivaptan (20 - 40 mg/day) were unchanged with coadministration of either captopril 25 mg or furosemide up to 80 mg/day.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Pregnancy Category C. Conivaptan has been shown to have adverse effects on the fetus when given to rats during pregnancy at systemic exposures less than those achieved at the human therapeutic dose based on AUC comparisons '). There are no adequate and well-controlled studies of vaprisol use in pregnant women. vaprisol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The patient should be apprised of the potential hazard to the fetus. Rat fetal tissue levels were < 10% of maternal plasma concentrations while placental levels were 2.2-fold higher than maternal plasma concentrations. Conivaptan that is taken up by fetal tissue is slowly cleared, suggesting that fetal accumulation is possible.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Conivaptan in women who are pregnant.
### Labor and Delivery
- The effect of vaprisol on labor and delivery in humans has not been studied. Conivaptan hydrochloride delayed delivery in rats dosed at 10 mg/kg/day by oral gavage (systemic exposure equivalent to the human therapeutic exposure based on AUC comparison). Administration of conivaptan hydrochloride at 2.5 mg/kg/day intravenously increased peripartum pup mortality (systemic exposure less than the human therapeutic exposure based on AUC comparison). These effects may be associated with conivaptan activity on oxytocin receptors in the rat. The relevance to humans is unclear.
### Nursing Mothers
- It is not known whether conivaptan is excreted in human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from vaprisol, a decision should be made to discontinue nursing or vaprisol, taking into consideration the importance of vaprisol to the mother. Conivaptan is excreted in milk and detected in neonates when given by intravenous administration to lactating rats. Milk levels of conivaptan in rats reached maximal levels at 1 hour post dose following intravenous administration and were up to 3 times greater than maternal plasma levels following an intravenous dose of 1 mg/kg (systemic exposure less than human therapeutic exposure based on AUC comparison).
### Pediatric Use
- The safety and effectiveness of vaprisol in pediatric patients have not been studied.
### Geriatic Use
- In clinical studies of vaprisol administered as a 20 mg IV loading dose followed by 20 mg/day or 40 mg/day IV for 2 to 4 days, 89% (20 mg/day regimen) and 60% (40 mg/day regimen) of participants were greater than or equal to 65 years of age and 60% (20 mg/day regimen) and 40% (40 mg/day regimen) were greater than or equal to 75 years of age. In general, the adverse event profile in elderly patients was similar to that seen in the general study population.
### Gender
There is no FDA guidance on the use of Conivaptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Conivaptan with respect to specific racial populations.
### Renal Impairment
- No clinically relevant increase in exposure was observed in subjects with mild and moderate renal impairment (CLcr 30 – 80 mL/min). No dose adjustment of vaprisol is necessary. Because of the high incidence of infusion site phlebitis (which can reduce vascular access sites) and unlikely benefit, use in patients with severe renal impairment (CLcr <30 mL/min) is not recommended.
### Hepatic Impairment
- No clinically relevant increase in exposure was observed in subjects with mild hepatic impairment; therefore no dose adjustment of vaprisol is necessary. The exposure to vaprisol approximately doubles with moderate hepatic impairment. The impact of severe hepatic impairment on the exposure to conivaptan has not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Conivaptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Conivaptan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- vaprisol is for intravenous use only.
- vaprisol is for use in hospitalized patients only.
- Administer vaprisol through large veins and change of the infusion site every 24 hours to minimize the risk of vascular irritation.
### Monitoring
- Patients receiving vaprisol must have frequent monitoring of serum sodium and volume status
- Coadministration of digoxin with oral conivaptan resulted in a 1.8- and 1.4-fold increase in digoxin Cmax and AUC, respectively. Monitor digoxin levels
- In case of overdose, based on expected exaggerated pharmacological activity, symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is recommended.
# IV Compatibility
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter, discoloration or cloudiness is observed, the drug solution should not be used.
- vaprisol is supplied in a single-use 100 mL flexible INTRAVIA Container containing a sterile premixed dilute, ready-to-use, nonpyrogenic solution of conivaptan hydrochloride, 0.2 mg per mL (20 mg/100 mL) in 5% Dextrose. NO FURTHER DILUTION OF THIS PREPARATION IS NECESSARY.
- vaprisol is compatible with 5% Dextrose Injection. vaprisol is physically and chemically compatible with 0.9% Sodium Chloride Injection for up to 48 hours when the two solutions are co-administered via a Y-site connection at a flow rate for vaprisol of 4.2 mL/hour and at flow rates for 0.9% Sodium Chloride Injection of either 2.1 mL/hour or 6.3 mL/hour.
- vaprisol has been shown to be incompatible with both Lactated Ringer's Injection and furosemide injection when these products are mixed in the same container; therefore, do not combine vaprisol with these products in the same intravenous line or container.
- vaprisol should also not be combined with any other product in the same intravenous line or container.
Loading Dose
- Administer the content of a 20 mg/100 mL vaprisol flexible plastic container over 30 minutes.
Continuous Infusion
- For patients requiring 20 mg vaprisol injection per day, administer the content of one 20 mg/100 mL vaprisol flexible plastic container over 24 hours.
For patients requiring 40 mg vaprisol injection per day, administer the content of two consecutive 20 mg/100 mL vaprisol flexible plastic containers over 24 hours.
Since the flexible container is for single-use only, any unused portion should be discarded.
CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.
Do not remove container from overwrap until ready for use. The overwrap is a moisture and light barrier. The inner container maintains the sterility of the product.
Tear overwrap down side at slit and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. After removing overwrap, check for minute leaks by squeezing inner container firmly. If leaks are found, discard solution as sterility may be impaired. Do not use if the solution is cloudy or a precipitate is present.
DO NOT ADD SUPPLEMENTARY MEDICATION.
Preparation for Administration:
- Suspend container from eyelet support.
- Remove protector from outlet port at bottom of container.
- Attach administration set. Refer to complete directions accompanying set.
# Overdosage
- Although no data on overdosage in humans are available, vaprisol has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of vaprisol, e.g. hypotension and thirst, occurred more frequently at these higher doses.
In case of overdose, based on expected exaggerated pharmacological activity, symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is recommended.
# Pharmacology
## Mechanism of Action
Conivaptan hydrochloride is a dual arginine vasopressin (AVP) antagonist with nanomolar affinity for human V1A and V2 receptors in vitro. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range. The predominant pharmacodynamic effect of conivaptan hydrochloride in the treatment of hyponatremia is through its V2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water.
## Structure
- Conivaptan hydrochloride is chemically [1,1’-biphenyl]-2-carboxamide, N-[4-[(4,5-dihydro-2-methylimidazo[4,5-d][1]benzazepin-6(1H)-yl]carbonyl]phenyl]-, monohydrochloride, having a molecular weight of 535.04 and molecular formula C32H26N4O2∙HCl. The structural formula of conivaptan hydrochloride is:
- Conivaptan hydrochloride is a white to off-white or pale orange-white powder that is very slightly soluble in water (0.15 mg/mL at 23° C). Conivaptan hydrochloride injection is supplied as a sterile premixed solution with dextrose in a flexible plastic container.
- Each container contains a clear, colorless, sterile, non-pyrogenic solution of conivaptan hydrochloride in dextrose. Each 100 mL, single-use premixed INTRAVIA Container contains 20 mg of conivaptan hydrochloride and 5 g of Dextrose Hydrous, USP. Lactic Acid, USP is added for pH adjustment to pH 3.4 to 3.8. The flexible plastic container is fabricated from a specially designed multilayer plastic (PL 2408). Solutions in contact with the plastic container leach out certain of the chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. The flexible container has a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to significantly affect the premixed solution.
## Pharmacodynamics
- The pharmacodynamic effects of conivaptan hydrochloride include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. Studies in animal models of hyponatremia showed that conivaptan hydrochloride prevented the occurrence of hyponatremia-related physical signs in rats with the syndrome of inappropriate antidiuretic hormone secretion.
Electrophysiology
- The effect of vaprisol 40 mg IV and 80 mg IV on the QT interval was evaluated after the first dose (Day 1) and at the last day during treatment (Day 4) in a randomized, single-blind, parallel group, placebo- and positive-controlled (moxifloxacin 400 mg IV) study in healthy male and female volunteers aged 18 to 45 years. Digital ECGs were obtained at baseline and on Days 1 and 4. Moxifloxacin elicited placebo-corrected changes from baseline in individualized QT correction (QTcI) of +7 to +10 msec on Days 1 and 4, respectively, indicating that the study had assay sensitivity. The placebo-corrected changes from baseline in QTcI in the vaprisol 40 mg and 80 mg dose groups on Day 1 were -3.5 msec and -2.9 msec, respectively, and -2.1 msec for both dose groups on Day 4. The results suggest that conivaptan has no clinically significant effect on cardiac repolarization.
## Pharmacokinetics
- The pharmacokinetics of conivaptan have been characterized in healthy subjects, special populations and patients following both oral and intravenous dosing regimens. The pharmacokinetics of conivaptan following intravenous infusion (40 mg/day to 80 mg/day) and oral administration are non-linear, and inhibition by conivaptan of its own metabolism seems to be the major factor for the non-linearity. The intersubject variability of conivaptan pharmacokinetics is high (94% CV in CL).
- The pharmacokinetics of conivaptan and its metabolites were characterized in healthy male subjects administered conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 40 mg/day for 3 days. Mean Cmax for conivaptan was 619 ng/mL and occurred at the end of the loading dose. Plasma concentrations reached a minimum at approximately 12 hours after start of the loading dose, then gradually increased over the duration of the infusion to a mean concentration of 188 ng/mL at the end of the infusion. The mean terminal elimination half-life after conivaptan infusion was 5.0 hours, and the mean clearance was 253.3 mL/min.
- In an open-label safety and efficacy study, the pharmacokinetics of conivaptan were characterized in hypervolemic or euvolemic hyponatremia patients (ages 20 - 92 years) receiving conivaptan hydrochloride as a 20 mg loading dose (infused over 30 minutes) followed by a continuous infusion of 20 or 40 mg/day for 4 days. The median-plasma conivaptan concentrations are shown in Figure 1. The median (range) elimination half-life was 5.3 (3.3 - 9.3) or 8.1 (4.1 - 22.5) hours in the 20 mg/day or 40 mg/day group, respectively, based on data from rich PK sampling.
Distribution
- Conivaptan is extensively bound to human plasma proteins, being 99% bound over the concentration range of approximately 10 to 1000 ng/mL.
Metabolism and Excretion
- CYP3A was identified as the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V1A and V2 receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively. The combined exposure of the metabolites following intravenous administration of conivaptan is approximately 7% that of conivaptan and hence, their contribution to the clinical effect of conivaptan is minimal.
- After intravenous (10 mg) or oral (20 mg) administration of conivaptan hydrochloride in a mass balance study, approximately 83% of the dose was excreted in feces as total radioactivity and 12% in urine over several days of collection. Over the first 24 hours after dosing, approximately 1% of the intravenous dose was excreted in urine as intact conivaptan.
Hepatic Impairment
- The systemic exposure to conivaptan is approximately doubled in subjects with moderate hepatic impairment. No clinically relevant increase in exposure was observed in subjects with mild hepatic impairment. The impact of severe hepatic impairment on the exposure to conivaptan has not been studied.
Renal Impairment
- Mild and moderate renal impairment (CLcr 30 - 80 mL/min) do not affect exposure to vaprisol to a clinically relevant extent. Use in patients with severe renal impairment (CLcr < 30 mL/min) is not recommended.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility=
- Standard lifetime (104 week) carcinogenicity bioassays were conducted in mice and rats. Male and female mice were given oral doses of conivaptan hydrochloride up to 30 mg/kg/day and 10 mg/kg/day, respectively, by gavage. Male and female rats were given oral doses of up to 10 mg/kg/day and 30 mg/kg/day, respectively, by gavage. There was no increased incidence of tumors associated with exposure to conivaptan in either species. The 30 mg/kg/day dosage regimen in male mice and female rats was shown to result in a systemic exposure (AUC) about twice the human systemic exposure from an IV bolus of 20 mg on day 1 followed by IV infusion of 40 mg/day for 3 days. The 10 mg/kg/day dosage regimen in female mice and male rats was shown to result in about one-fourth and one-half the human therapeutic exposure, respectively.
Conivaptan was not genotoxic in the bacterial reverse mutation assay, the in vitro human peripheral blood lymphocyte chromosomal aberration assay, or in vivo rat micronucleus assay.
- Fertility of male rats treated with conivaptan hydrochloride by IV bolus doses of up to 2.5 mg/kg/day for the 4 weeks preceding mating and throughout the mating period was unaffected. However, when female rats were given IV bolus conivaptan from 15 days before mating through gestation day 7, there was prolonged diestrus, decreased fertility (decreased numbers of corpora lutea and implantations) and increased post-implantation loss at 2.5 mg/kg/day (systemic exposure less than human exposure at the therapeutic dose).
- When pregnant rats were given intravenous doses of conivaptan hydrochloride up to 2.5 mg/kg/day on gestation days 7 through 17 (systemic exposures less than human therapeutic exposure based on AUC comparisons), no significant maternal or fetal effects were observed.
- When pregnant rats received intravenous conivaptan hydrochloride at a dose of 2.5 mg/kg/day (systemic exposure less than human therapeutic exposure based on AUC comparison) from gestation day 7 through lactation day 20 (weaning), the pups showed decreased neonatal viability and weaning indices, decreased body weight, and delayed reflex and physical development (including sexual maturation). No discernible effects were seen in pups from dams administered conivaptan hydrochloride at 0.5 or 1.25 mg/kg/day during this same period. No maternal adverse effects of conivaptan were seen in this study. When pregnant rabbits were given intravenous doses of conivaptan hydrochloride up to 12 mg/kg/day on gestation days 6 through 18 (about twice the human therapeutic exposure) there were no fetal or maternal findings.
# Clinical Studies
### Hyponatremia=
- The effect on serum sodium of vaprisol was demonstrated in a double-blind, placebo-controlled, randomized, multicenter study conducted in 84 patients with euvolemic (N=56) or hypervolemic (N=28) hyponatremia (serum sodium 115 -130 mEq/L) from a variety of underlying causes (malignant or nonmalignant diseases of the central nervous system, lung, or abdomen; congestive heart failure; hypertension; myocardial infarction; diabetes; osteoarthritis; or idiopathic). Study participants were randomized to receive either placebo IV (N=29), vaprisol 40 mg/day IV (N=29), or vaprisol 80 mg/day IV (N=26). Daily fluid intake was restricted to 2 liters. vaprisol or placebo was administered as a continuous infusion following a 30 minute IV loading dose on the first treatment day and patients were treated for 4 days. Serum or plasma sodium concentrations were assessed pre-dose (Hour 0) and at 4, 6, 10, and 24 hours post-dose on all treatment days.
- Mean serum sodium concentration was 123.3 mEq/L at study entry. The mean change in serum sodium concentration from baseline over the 4-day treatment period is shown in Figure 2.
- Following treatment with 40 mg/day of vaprisol, the mean change from baseline in serum sodium concentration at the end of 2 days of treatment with vaprisol was 5.3 mEq/L (mean concentration 128.6 mEq/L). At the end of the 4-day treatment period, the mean change from baseline was 6.5 mEq/L (mean concentration 129.8 mEq/L). In addition, after 2 days and 4 days of treatment with vaprisol, 41% (after 2 days) and 69% (after 4 days) of patients achieved a ≥ 6 mEq/L increase in serum sodium concentration or a normal serum sodium of ≥ 135 mEq/L. Although 80 mg/day was also studied, it was not significantly more effective than 40 mg/day and was associated with a higher incidence of infusion site reactions and a higher rate of discontinuations for adverse events. Additional efficacy data are summarized in Table 2.
- The aquaretic effect of vaprisol is shown in Figure 3. vaprisol produced a baseline-corrected cumulative increase in effective water clearance of over 3800 mL compared to approximately 1300 mL with placebo by Day 4.
- Where V is urine volume (mL/d), UNa is urine sodium concentration, UK is urine potassium concentration, PNa is plasma/serum sodium concentration, and PK is plasma/serum potassium concentration.
- The effect on serum sodium of vaprisol (administered as a 20 or 40 mg/day IV continuous infusion for 4 days following a 30 minute IV infusion of a 20 mg loading dose on the first treatment day) was also evaluated in an open-label study of 251 patients with euvolemic or hypervolemic hyponatremia. The results are shown in Table 3.
- The effectiveness of vaprisol for the treatment of congestive heart failure has not been established. In ten Phase 2/pilot heart failure studies, vaprisol did not show statistically significant improvement for heart failure outcomes, including such measures as length of hospital stay, changes in categorized physical findings of heart failure, change in ejection fraction, change in exercise tolerance, change in functional status, or change in heart failure symptoms, compared to placebo. In these studies, the changes in the physical findings and heart failure symptoms were no worse in the vaprisol-treated group (N=818) compared to the placebo group (N=290).
# How Supplied
- vaprisol (conivaptan hydrochloride) Injection is supplied as a single-use, premixed solution, containing 20 mg of conivaptan hydrochloride in 5% Dextrose in 100 mL INTRAVIA Plastic Containers.
- 1 container/carton (NDC 0469-1602-10)
## Storage
- vaprisol in INTRAVIA Plastic Containers should be stored at 25°C (77°F); however, brief exposure up to 40°C (104°F) does not adversely affect the product. Avoid excessive heat. Protect from freezing. Protect from light until ready to use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients about the common adverse effects of vaprisol including infusion site effects (edema, erythema, pain, and phlebitis), pyrexia, hypokalemia, headache, orthostatic hypotension and potential for overly rapid increase in serum sodium which can cause serious neurologic sequelae. Instruct patients to inform their healthcare provider if they develop any unusual symptoms, or if any known symptom persists or worsens, with special attention to potential manifestations of osmotic demyelination syndrome.
- Ask patients about what other medications they are currently taking with vaprisol, including over-the-counter medications.
- Ask patients if they have allergies to corn or corn products.
# Precautions with Alcohol
- Alcohol-Conivaptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VAPRISOL DEXTROSE IN PLASTIC CONTAINER
# Look-Alike Drug Names
- There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Conivaptan | |
ece10a64d58c6cffa708582727197eb0b6231c06 | wikidoc | Convection | Convection
Convection in the most general terms refers to the movement of currents within fluids (i.e. liquids, gases and rheids)
Convection is one of the major modes of Heat transfer and mass transfer. In fluids, convective heat and mass transfer take place through both diffusion – the random Brownian motion of individual particles in the fluid – and by advection, in which matter or heat is transported by the larger-scale motion of currents in the fluid. In the context of heat and mass transfer, the term "convection" is used to refer to the sum of advective and diffusive transfer.
A common use of the term convection relates to the special case in which heat is advected (carried). In this case, the heat itself often causes the fluid motion, while also being transported by it. In this case, the problem of heat transport (and related transport of other substances in the fluid due to it) may be more complicated.
# Natural convective heat transfer
When heat is carried by the circulation of fluids due to this effect, the process is known as natural convective heat transfer.
Familiar examples are the upward flow of air due to a fire or hot object and the circulation of water in a pot that is heated from below.
For a visual experience of convection, heat up a glass full of water and put red food dye in it. Fill a fish tank with cold, clear water. Then place the glass of the hot red-dyed water in the tank. The convection currents of the red liquid rise and fall, then eventually settle; showing you the process.
# Forced convection
Natural heat convection (also called free convection) is distinguished from various types of forced heat convection, which refer to heat advection by a fluid which is not due to the natural forces of buoyancy induced by heating. In forced heat convection, transfer of heat is due to movement in the fluid which results from many other forces, such as (for example) a fan or pump. A convection oven thus works by forced convection, as a fan which rapidly circulates hot air forces heat into food faster than would naturally happen due to simple heating without the fan. Aerodynamic heating is a form of forced convection. Common fluid heat-radiator systems, and also heating and cooling of parts of the body by blood circulation, are other familiar examples of forced convection.
# Buoyancy induced convection not due to heat
Buoyancy forces which cause convection in gravity fields may result from sources of density variations in fluids other than those produced by heat, such as variable composition. For example, variable salinity in water and variable water content in air masses, are frequent causes of convection in the oceans and atmosphere, which do not involve heat (see thermohaline circulation). Similarly variable composition within the Earth's interior which has not yet achieved maximal stability and minimal energy (densest parts deepest) continues to cause a fraction of the convection of fluid rock and molten metal within the Earth's interior (see below).
# Oceanic convection
Solar radiation also affects the oceans. Warm water from the Equator tends to circulate toward the poles, while cold polar water heads towards the Equator. Oceanic convection is also frequently driven by density differences due to varying salinity, known as thermohaline convection, and is of crucial importance in the global thermohaline circulation. In this case it is quite possible for relatively warm, saline water to sink, and colder, fresher water to rise, reversing the normal transport of heat.
# Mantle convection
Convection within Earth's mantle is the driving force for plate tectonics. There are actually two convection currents occurring within the Earth. The outer core experiences convective turnover of fluid metals (primarily iron and nickel) which are responsible for the Earth's magnetic field. The movement of metals forms electrical currents, which in turn generate magnetic fields.
As heat from the inner and outer core heat the lower portion of the mantle, a second set of convective currents form. This mantle convection is extremely slow, as the mantle is a thick semi-solid with the consistency of a very thick paste. This slow convection can take millions of years to complete one cycle.
Neutrino flux measurements from the Earth's core (see kamLAND) show the source of about two-thirds of the heat in the inner core is the radioactive decay of 40K, uranium and thorium. This has allowed plate tectonics on Earth to continue far longer than it would have if it were simply driven by heat left over from Earth's formation; or with heat produced by rearrangement of denser portions to the centre of the earth.
# Vibration convection in gravity fields
Vibration-induced convection occurs in powders and granulated materials in containers subject to vibration, in a gravity field. When the container accelerates upward, the bottom of the container pushes the entire contents upward. In contrast, when the container accelerates downward, the sides of the container push the adjacent material downward by friction, but the material more remote from the sides is less affected. The net result is a slow circulation of particles downward at the sides, and upward in the middle.
If the container contains particles of different sizes, the downward-moving region at the sides is often narrower than the larger particles. Thus, larger particles tend to become sorted to the top of such a mixture.
# Scale and rate of convection
Convection may happen in fluids at all scales larger than a few atoms. Convection occurs on a large scale in atmospheres, oceans, and planetary mantles. Current movement during convection may be invisibly slow, or it may be obvious and rapid, as in a hurricane. On astronomical scales, convection of gas and dust is thought to occur in the accretion disks of black holes, at speeds which may closely approach that of light.
# Pattern formation
Convection, especially Rayleigh-Bénard convection, where the convecting fluid is contained by two rigid horizontal plates, is a convenient example of a pattern forming system.
When heat is fed into the system from one direction (usually below), at small values it merely diffuses (conducts) from below upward, without causing fluid flow. As the heat flow is increased, above a critical value of the Rayleigh number, the system undergoes a bifurcation from the stable conducting state to the convecting state, where bulk motion of the fluid due to heat begins. If fluid parameters other than density do not depend significantly on temperature, the flow profile is symmetric, with the same volume of fluid rising as falling. This is known as Boussinesq convection.
As the temperature difference between the top and bottom of the fluid becomes higher, significant differences in fluid parameters other than density may develop in the fluid due to temperature. An example of such a parameter is viscosity, which may begin to significantly vary horizontally across layers of fluid. This breaks the symmetry of the system, and generally changes the pattern of up- and down-moving fluid from stripes to hexagons, as seen at right. Such hexagons are one example of a convection cell.
As the Rayleigh number is increased even further above the value where convection cells first appear, the system may undergo other bifurcations, and other more complex patters, such as spirals, may begin to appear. These may be familiar as examples from systems in which viscosity is relatively low and heat through-put high, such as the spiraling upward flow of gases in a fire. | Convection
Convection in the most general terms refers to the movement of currents within fluids (i.e. liquids, gases and rheids)
Convection is one of the major modes of Heat transfer and mass transfer. In fluids, convective heat and mass transfer take place through both diffusion – the random Brownian motion of individual particles in the fluid – and by advection, in which matter or heat is transported by the larger-scale motion of currents in the fluid. In the context of heat and mass transfer, the term "convection" is used to refer to the sum of advective and diffusive transfer.[1]
A common use of the term convection relates to the special case in which heat is advected (carried). In this case, the heat itself often causes the fluid motion, while also being transported by it. In this case, the problem of heat transport (and related transport of other substances in the fluid due to it) may be more complicated.
# Natural convective heat transfer
When heat is carried by the circulation of fluids due to this effect, the process is known as natural convective heat transfer.
Familiar examples are the upward flow of air due to a fire or hot object and the circulation of water in a pot that is heated from below.
For a visual experience of convection, heat up a glass full of water and put red food dye in it. Fill a fish tank with cold, clear water. Then place the glass of the hot red-dyed water in the tank. The convection currents of the red liquid rise and fall, then eventually settle; showing you the process.
# Forced convection
Natural heat convection (also called free convection) is distinguished from various types of forced heat convection, which refer to heat advection by a fluid which is not due to the natural forces of buoyancy induced by heating. In forced heat convection, transfer of heat is due to movement in the fluid which results from many other forces, such as (for example) a fan or pump. A convection oven thus works by forced convection, as a fan which rapidly circulates hot air forces heat into food faster than would naturally happen due to simple heating without the fan. Aerodynamic heating is a form of forced convection. Common fluid heat-radiator systems, and also heating and cooling of parts of the body by blood circulation, are other familiar examples of forced convection.
# Buoyancy induced convection not due to heat
Buoyancy forces which cause convection in gravity fields may result from sources of density variations in fluids other than those produced by heat, such as variable composition. For example, variable salinity in water and variable water content in air masses, are frequent causes of convection in the oceans and atmosphere, which do not involve heat (see thermohaline circulation). Similarly variable composition within the Earth's interior which has not yet achieved maximal stability and minimal energy (densest parts deepest) continues to cause a fraction of the convection of fluid rock and molten metal within the Earth's interior (see below).
# Oceanic convection
Solar radiation also affects the oceans. Warm water from the Equator tends to circulate toward the poles, while cold polar water heads towards the Equator. Oceanic convection is also frequently driven by density differences due to varying salinity, known as thermohaline convection, and is of crucial importance in the global thermohaline circulation. In this case it is quite possible for relatively warm, saline water to sink, and colder, fresher water to rise, reversing the normal transport of heat.
# Mantle convection
Convection within Earth's mantle is the driving force for plate tectonics. There are actually two convection currents occurring within the Earth. The outer core experiences convective turnover of fluid metals (primarily iron and nickel) which are responsible for the Earth's magnetic field. The movement of metals forms electrical currents, which in turn generate magnetic fields.
As heat from the inner and outer core heat the lower portion of the mantle, a second set of convective currents form. This mantle convection is extremely slow, as the mantle is a thick semi-solid with the consistency of a very thick paste. This slow convection can take millions of years to complete one cycle.
Neutrino flux measurements from the Earth's core (see kamLAND) show the source of about two-thirds of the heat in the inner core is the radioactive decay of 40K, uranium and thorium. This has allowed plate tectonics on Earth to continue far longer than it would have if it were simply driven by heat left over from Earth's formation; or with heat produced by rearrangement of denser portions to the centre of the earth.
# Vibration convection in gravity fields
Vibration-induced convection occurs in powders and granulated materials in containers subject to vibration, in a gravity field. When the container accelerates upward, the bottom of the container pushes the entire contents upward. In contrast, when the container accelerates downward, the sides of the container push the adjacent material downward by friction, but the material more remote from the sides is less affected. The net result is a slow circulation of particles downward at the sides, and upward in the middle.
If the container contains particles of different sizes, the downward-moving region at the sides is often narrower than the larger particles. Thus, larger particles tend to become sorted to the top of such a mixture.
# Scale and rate of convection
Convection may happen in fluids at all scales larger than a few atoms. Convection occurs on a large scale in atmospheres, oceans, and planetary mantles. Current movement during convection may be invisibly slow, or it may be obvious and rapid, as in a hurricane. On astronomical scales, convection of gas and dust is thought to occur in the accretion disks of black holes, at speeds which may closely approach that of light.
# Pattern formation
Convection, especially Rayleigh-Bénard convection, where the convecting fluid is contained by two rigid horizontal plates, is a convenient example of a pattern forming system.
When heat is fed into the system from one direction (usually below), at small values it merely diffuses (conducts) from below upward, without causing fluid flow. As the heat flow is increased, above a critical value of the Rayleigh number, the system undergoes a bifurcation from the stable conducting state to the convecting state, where bulk motion of the fluid due to heat begins. If fluid parameters other than density do not depend significantly on temperature, the flow profile is symmetric, with the same volume of fluid rising as falling. This is known as Boussinesq convection.
As the temperature difference between the top and bottom of the fluid becomes higher, significant differences in fluid parameters other than density may develop in the fluid due to temperature. An example of such a parameter is viscosity, which may begin to significantly vary horizontally across layers of fluid. This breaks the symmetry of the system, and generally changes the pattern of up- and down-moving fluid from stripes to hexagons, as seen at right. Such hexagons are one example of a convection cell.
As the Rayleigh number is increased even further above the value where convection cells first appear, the system may undergo other bifurcations, and other more complex patters, such as spirals, may begin to appear. These may be familiar as examples from systems in which viscosity is relatively low and heat through-put high, such as the spiraling upward flow of gases in a fire. | https://www.wikidoc.org/index.php/Convection | |
876c04f2d6083d9148dc6b9a5edf52ec789a345d | wikidoc | Copanlisib | Copanlisib
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# Overview
Copanlisib is a kinase inhibitor that is FDA approved for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Common adverse reactions include hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Copanlisib is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.
- Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- The recommended dose of Copanlisib is 60 mg administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Continue treatment until disease progression or unacceptable toxicity
- Manage toxicities per Table 1 with dose reduction, treatment delay, or discontinuation of Copanlisib. Discontinue Copanlisib if life-threatening Copanlisib-related toxicity occurs.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Copanlisib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Copanlisib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Copanlisib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Copanlisib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Copanlisib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- Serious, including fatal, infections occurred in 19% of 317 patients treated with Copanlisib monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold Copanlisib for Grade 3 and higher infection.
- Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with Copanlisib monotherapy. Before initiating treatment with Copanlisib, consider PJP prophylaxis for populations at risk. Withhold Copanlisib in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume Copanlisib at previous dose with concomitant PJP prophylaxis.
- Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with Copanlisib monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with Copanlisib may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after Copanlisib infusion. Of 155 patients with baseline HbA1c 6.5% at the end of treatment.
- Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with Copanlisib following adequate glucose control and should be monitored closely.
- Achieve optimal blood glucose control before starting each Copanlisib infusion. Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of hyperglycemia.
- Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with Copanlisib monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with Copanlisib may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the Copanlisib infusion. Optimal BP control should be achieved before starting each Copanlisib infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of hypertension.
- Non-infectious pneumonitis occurred in 5% of 317 patients treated with Copanlisib monotherapy. Withhold Copanlisib and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by Copanlisib have been managed by withholding Copanlisib and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of non-infectious pneumonitis.
- Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with Copanlisib monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with Copanlisib. Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of neutropenia.
- Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with Copanlisib monotherapy, respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of severe cutaneous reactions.
- Based on findings in animals and its mechanism of action, Copanlisib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of Copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. 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 one month after the last dose.
# 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 the general patient population.
- The safety data reflect exposure to Copanlisib in 168 adults with follicular lymphoma and other hematologic malignancies treated with Copanlisib 60 mg or 0.8 mg/kg equivalent in clinical trials. The median duration of treatment was 22 weeks (range 1 to 206 weeks).
- Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). The most common adverse reactions (≥20%) were hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia.
- Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most common reasons for dose reduction were hyperglycemia (7%), neutropenia (5%), and hypertension (5%). The most common reasons for drug discontinuation were pneumonitis (2%) and hyperglycemia (2%).
- Table 2 provides the adverse reactions occurring in at least 10% of patients receiving Copanlisib monotherapy, and Table 3 provides the treatment-emergent laboratory abnormalities in ≥20% of patients and ≥4% of Grade ≥3 treated with Copanlisib.
## Postmarketing Experience
There is limited information regarding Copanlisib Postmarketing Experience in the drug label.
# Drug Interactions
- Strong CYP3A Inducers
- Strong CYP3A Inhibitors
- Avoid concomitant use of Copanlisib with strong CYP3A inducers. Concomitant use of Copanlisib with strong CYP3A inducers may decrease Copanlisib AUC and Cmax
- Examplesa of strong CYP3A inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wortb.
- Concomitant use of Copanlisib with strong CYP3A inhibitors increases the Copanlisib AUC. If concomitant use with strong CYP3A inhibitors cannot be avoided, reduce the Copanlisib dose to 45 mg. An increase in the Copanlisib AUC may increase the risk of adverse reactions.
- Examplesa of strong CYP3A inhibitors include: boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juicec, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Based on findings from animal studies and the mechanism of action, Copanlisib 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 Copanlisib to pregnant rats during organogenesis resulted in embryo-fetal death and fetal abnormalities at maternal doses approximately 12% of the recommended dose for patients. Advise pregnant women of the potential risk to a fetus.
- Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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.
- In an embryo-fetal development study in rats, pregnant animals received intravenous doses of Copanlisib of 0, 0.75, or 3 mg/kg/day during the period of organogenesis. Administration of Copanlisib at the dose of 3 mg/kg/day resulted in maternal toxicity and no live fetuses. Copanlisib administration at the dose of 0.75 mg/kg/day was maternally toxic and resulted in embryo-fetal death (increased resorptions, increased post-implantation loss, and decreased numbers of fetuses/dam). The dose of 0.75 mg/kg/day also resulted in increased incidence of fetal gross external (domed head, malformed eyeballs or eyeholes), soft tissue (hydrocephalus internus, ventricular septal defects, major vessel malformations), and skeletal (dysplastic forelimb bones, malformed ribs and vertebrae, and pelvis shift) abnormalities. The dose of 0.75 mg/kg/day (4.5 mg/m2 body surface area) in rats is approximately 12% of the recommended dose for patients.
- Following administration of radiolabeled Copanlisib to pregnant rats approximately 1.5% of the radioactivity (Copanlisib and metabolites) reached the fetal compartment.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Copanlisib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Copanlisib during labor and delivery.
### Nursing Mothers
- There are no data on the presence of Copanlisib and/or metabolites in human milk, the effects on the breastfed child, or on milk production. Following administration of radiolabeled Copanlisib to lactating rats, approximately 2% of the radioactivity was secreted into milk; the milk to plasma ratio of radioactivity was 25-fold. Because of the potential for serious adverse reactions in a breastfed child from Copanlisib, advise a lactating woman not to breastfeed during treatment with Copanlisib and for at least 1 month after the last dose.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
- No dose adjustment is necessary in patients ≥65 years of age. Of 168 patients with follicular lymphoma and other hematologic malignancies treated with Copanlisib, 48% were age 65 or older while 16% were age 75 or older. No clinically relevant differences in efficacy were observed between elderly and younger patients. In patients ≥65 years of age, 30% experienced serious adverse reactions and 21% experienced adverse reactions leading to discontinuation. In the patients <65 years of age, 23% experienced serious adverse reactions and 11% experienced adverse reactions leading to discontinuation.
### Gender
There is no FDA guidance on the use of Copanlisib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Copanlisib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Copanlisib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Copanlisib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Copanlisib can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing prior to initiation of Copanlisib treatment.
Females
- Advise female patients of reproductive potential to use highly effective contraception (contraception with a failure rate <1% per year) during treatment with Copanlisib and for at least one month after the last dose.
Males
- Advise male patients with female partners of reproductive potential to use highly effective contraception during treatment with Copanlisib and for at least one month after the last dose.
- There are no data on the effect of Copanlisib on human fertility. Due to the mechanism of action of Copanlisib, and findings in animal studies, adverse effects on reproduction, including fertility, are expected.
### Immunocompromised Patients
There is no FDA guidance one the use of Copanlisib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- For intravenous infusion only.
- Administer Copanlisib as a single agent, following reconstitution and dilution. Mix only with 0.9% sodium chloride (NaCl) solution. Do not mix or inject Copanlisib with other drugs or other diluents.
- Reconstitute Copanlisib with 4.4 mL of sterile 0.9% NaCl solution leading to a concentration of 15 mg/mL.
- Withdraw 4.4 mL of sterile 0.9% NaCl solution by using a 5 mL sterile syringe with needle.
- Inject the measured volume through the disinfected stopper surface into the vial of ALIQOPA.
- Dissolve the lyophilized solid by gently shaking the injection vial for 30 seconds.
- Allow to stand for one minute to let bubbles rise to the surface.
- Check if any undissolved substance is still seen. If yes, repeat the gentle shaking and settling procedure.
- Inspect visually for discoloration and particulate matter. After reconstitution, the solution should be colorless to slightly yellowish.
- Once the solution is free of visible particles, withdraw the reconstituted solution for further dilution.
- Further dilute the reconstituted solution in 100 mL sterile 0.9% NaCl solution for injection. With a sterile syringe, withdraw the required amount of the reconstituted solution for the desired dosage:
- 60 mg: Withdraw 4 mL of the reconstituted solution with a sterile syringe.
- 45 mg: Withdraw 3 mL of the reconstituted solution with a sterile syringe.
- 30 mg: Withdraw 2 mL of the reconstituted solution with a sterile syringe.
- Inject the contents of the syringe into the patient infusion bag of 100 mL sterile 0.9% NaCl solution. Mix the dose well by inverting.
- Discard any unused reconstituted or diluted solution appropriately.
- Use reconstituted and diluted Copanlisib immediately or store the reconstituted solution in the vial or diluted solution in the infusion bag at 2°C to 8°C (36°F to 46°F) for up to 24 hours before use. Allow the product to adapt to room temperature before use following refrigeration. Avoid exposure of the diluted solution to direct sunlight.
### Monitoring
- Evidence of disease response or stabilization is indicative of efficacy
- CBC: Including absolute neutrophil count, at least weekly during treatment
- Blood pressure (BP): Pre- and post-infusion; in clinical trials BP remained elevated for 6 to 8 hours after the start of the infusion and started decreasing approximately 2 hours post-infusion
- Glucose control: Closely in patients with diabetes mellitus
- Signs or symptoms of infection
# IV Compatibility
There is limited information regarding the compatibility of Copanlisib and IV administrations.
# Overdosage
There is limited information regarding Copanlisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.
## Structure
## Pharmacodynamics
- At 60 mg (or 0.8 mg/kg) of Copanlisib dose, the elevation of plasma glucose was associated with higher Copanlisib exposure.
## Pharmacokinetics
- The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of Copanlisib increase dose-proportionally over 5 to 93 mg (0.08 to 1.55 times the approved recommended dose) absolute dose range and exhibit linear pharmacokinetics. There is no time-dependency and no accumulation in the pharmacokinetics of Copanlisib.
- The geometric mean (range) steady state Copanlisib exposure at 0.8 mg/kg (approximately the approved recommended dose of 60 mg) are 463 (range: 105 to 1670; SD: 584) ng/mL for Cmax and 1570 (range: 536 to 3410; SD: 338) ng.hr/mL for AUC0-25h.
- The in vitro human plasma protein binding of Copanlisib is 84.2%. Albumin is the main binding protein. The in vitro mean blood-to-plasma ratio is 1.7 (range: 1.5 to 2.1). The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L.
- The geometric mean terminal elimination half-life of Copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours. The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr.
- Approximately >90% of Copanlisib metabolism is mediated by CYP3A and <10% by CYP1A1. The M-1 metabolite accounts for 5% of total radioactivity AUC and its pharmacological activity is comparable to the parent compound Copanlisib for the tested kinases PI3KandPI3K.
- Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. Following a single intravenous dose of 12 mg (0.2 times the recommended approved dose) radiolabeled Copanlisib, approximately 64% of the administered dose was recovered in feces and 22% in urine within 20 to 34 days. Unchanged Copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation metabolism accounted for 41% of the administered dose.
- Copanlisib pharmacokinetic differences in the subpopulations listed below are assessed using population pharmacokinetic analyses.
- Age (20 to 90 years), gender, race (White, Asian, Hispanic, and Black), smoking status, body weight (41 to 130 kg), mild hepatic impairment , and mild to moderate renal impairment had no clinically significant effect on the pharmacokinetics of Copanlisib. The pharmacokinetics of Copanlisib in patients with moderate to severe hepatic impairment (TB ≥ 1.5 x ULN, any AST), severe renal impairment (CLcr = 15-29 mL/min by C-G equation), or end stage renal disease (CLcr < 15 mL/min by C-G equation) with or without dialysis is unknown.
Effect of CYP3A and P-gp Inducers on Copanlisib
- Rifampin, a strong CYP3A and a P-glycoprotein (P-gp) transporter inducer, administered at a dose of 600 mg once daily for 12 days with a single intravenous dose of 60 mg Copanlisib in patients with cancer resulted in a 63% decrease in the mean AUC and a 15% decrease in Cmax of Copanlisib.
Effect of CYP3A, P-gp and BCRP Inhibitors on Copanlisib
- Itraconazole, a strong CYP3A inhibitor and a P-gp and Breast Cancer Resistance Protein (BCRP) transporter inhibitor, administered at a dose of 200 mg once daily for 10 days increased the mean AUC of a single intravenous dose of 60 mg Copanlisib by 53% (or 1.53-fold) with no effect on Cmax (1.03-fold) in patients with cancer.
Effect of Transporters on Copanlisib:
- Copanlisib is a substrate of P-gp and BCRP, but not a substrate for organic cation transporter (OCT) 1, OCT2, and OCT3, organic anion transporter (OAT) 1 and OAT3, organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3, multidrug and toxin extrusion protein 1(MATE1) or MATE2-K.
Effect of Copanlisib on CYP and non-CYP Enzymes
- Copanlisib is not an inhibitor of the metabolism of drugs that are substrates of the major CYP isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or uridine diphosphate-glucuronosyltransferase isoforms (UGT) or dihydropyrimidine dehydrogenase (DPD) at therapeutic 60 mg dose plasma concentrations. Copanlisib is not an inducer of CYP1A2, CYP2B6 and CYP3A.
Effect of Copanlisib on Drug Transporter Substrates
- Copanlisib is not an inhibitor of P-gp, BCRP, multi-drug resistance-associated protein (MRP2), bile salt export pump (BSEP), OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, and MATE1 at therapeutic 60 mg dose plasma concentrations.
- Copanlisib is an inhibitor of MATE2-K (IC50: 0.09 μM). Based on the PK of Copanlisib,inhibition may occur after Copanlisib infusion at approved recommended dosage. The clinical significance of this potential inhibition on plasma concentrations of concomitantly administered drugs that are MATE2-K substrates is unknown.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with Copanlisib.
- Copanlisib did not cause genetic damage in in vitro or in vivo assays.
- Fertility studies with Copanlisib were not conducted; however, adverse findings in male and female reproductive systems were observed in the repeat dose toxicity studies. Findings in the male rats and/or dogs included effects on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Findings in female rats included effects on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus.
# Clinical Studies
- The efficacy of Copanlisib was evaluated in a single-arm, multicenter, phase 2 clinical trial (NCT 01660451) CHRONOS-1 in a total of 142 subjects, which included 104 subjects with follicular B-cell non-Hodgkin lymphoma who had relapsed disease following at least two prior treatments. Patients must have received rituximab and an alkylating agent. Baseline patient characteristics are summarized in Table 4. The most common prior systemic therapies were chemotherapy in combination with anti-CD20 immunotherapy (89%), chemotherapy alone (41%), and anti-CD20 immunotherapy alone (37%). In CHRONOS-1, 34% of patients received two prior lines of therapy and 36% received three prior lines of therapy.
- Refractory: No response or progression of disease within six months of last treatment.
- One hundred forty-two patients received 60 mg Copanlisib; 130 patients received fixed dose 60 mg Copanlisib and 12 patients received 0.8 mg/kg equivalent Copanlisib administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Treatment continued until disease progression or unacceptable toxicity. Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. Efficacy based on overall response rate (ORR) was assessed by an Independent Review Committee. Efficacy results from CHRONOS-1 are summarized in Table 5.
# How Supplied
- Copanlisib is contained in a colorless glass vial closed with bromobutyl stopper with a flanged closure. Each vial of Copanlisib contains Copanlisib as a lyophilized solid.
## Storage
- Copanlisib vials must be refrigerated at 2°C to 8°C (36°F to 46°F).
- Administer reconstituted and diluted solution immediately. If not, refrigerate at 2°C to 8°C (36°F to 46°F) and use within 24 hours. After refrigeration, allow the product to adapt to room temperature before use. Avoid exposure of the diluted solution to direct sunlight.
- Mix only with 0.9% NaCl solution. Do not mix or inject Copanlisib with other drugs or other diluents.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Infections – Advise patients that Copanlisib can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection
- Hyperglycemia – Advise patients that an infusion-related increase in blood glucose may occur, and to notify their healthcare provider of any symptoms such as pronounced hunger, excessive thirst, headaches, or frequently urinating. Blood glucose levels should be well controlled prior to infusion
- Hypertension – Advise patients that an infusion-related increase in blood pressure may occur, and to notify their healthcare provider of any symptoms such as dizziness, passing out, headache, and/or a pounding heart. Blood pressure should be normal or well controlled prior to infusion
- Non-infectious pneumonitis – Advise patients of the possibility of pneumonitis, and to report any new or worsening respiratory symptoms including cough or difficulty breathing
- Neutropenia – Advise patients of the need for periodic monitoring of blood counts and to notify their healthcare provider immediately if they develop a fever or any signs of infection
- Severe cutaneous reactions – Advise patients that a severe cutaneous reaction may occur, and to notify their healthcare provider if they develop skin reactions (rash, redness, swelling, itching or peeling of the skin)
- Pregnancy – Advise females of reproductive potential to use effective contraceptive methods and to avoid becoming pregnant during treatment with Copanlisib and for at least one month after the last dose. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during Copanlisib treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Copanlisib and for at least one month after the last dose
- Lactation – Advise women not to breastfeed during treatment with Copanlisib and for at least 1 month after the last dose
# Precautions with Alcohol
Alcohol-Copanlisib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Aliqopa
# Look-Alike Drug Names
There is limited information regarding Copanlisib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Copanlisib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand, Anmol Pitliya, M.B.B.S. M.D.[2]
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# Overview
Copanlisib is a kinase inhibitor that is FDA approved for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Common adverse reactions include hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Copanlisib is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.
- Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
- The recommended dose of Copanlisib is 60 mg administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Continue treatment until disease progression or unacceptable toxicity
- Manage toxicities per Table 1 with dose reduction, treatment delay, or discontinuation of Copanlisib. Discontinue Copanlisib if life-threatening Copanlisib-related toxicity occurs.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Copanlisib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Copanlisib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Copanlisib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Copanlisib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Copanlisib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- Serious, including fatal, infections occurred in 19% of 317 patients treated with Copanlisib monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold Copanlisib for Grade 3 and higher infection.
- Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with Copanlisib monotherapy. Before initiating treatment with Copanlisib, consider PJP prophylaxis for populations at risk. Withhold Copanlisib in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume Copanlisib at previous dose with concomitant PJP prophylaxis.
- Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with Copanlisib monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with Copanlisib may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after Copanlisib infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.
- Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with Copanlisib following adequate glucose control and should be monitored closely.
- Achieve optimal blood glucose control before starting each Copanlisib infusion. Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of hyperglycemia.
- Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with Copanlisib monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with Copanlisib may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the Copanlisib infusion. Optimal BP control should be achieved before starting each Copanlisib infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of hypertension.
- Non-infectious pneumonitis occurred in 5% of 317 patients treated with Copanlisib monotherapy. Withhold Copanlisib and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by Copanlisib have been managed by withholding Copanlisib and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of non-infectious pneumonitis.
- Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with Copanlisib monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with Copanlisib. Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of neutropenia.
- Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with Copanlisib monotherapy, respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue Copanlisib depending on the severity and persistence of severe cutaneous reactions.
- Based on findings in animals and its mechanism of action, Copanlisib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of Copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. 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 one month after the last dose.
# 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 the general patient population.
- The safety data reflect exposure to Copanlisib in 168 adults with follicular lymphoma and other hematologic malignancies treated with Copanlisib 60 mg or 0.8 mg/kg equivalent in clinical trials. The median duration of treatment was 22 weeks (range 1 to 206 weeks).
- Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). The most common adverse reactions (≥20%) were hyperglycemia, diarrhea, decreased general strength and energy, hypertension, leukopenia, neutropenia, nausea, lower respiratory tract infections, and thrombocytopenia.
- Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most common reasons for dose reduction were hyperglycemia (7%), neutropenia (5%), and hypertension (5%). The most common reasons for drug discontinuation were pneumonitis (2%) and hyperglycemia (2%).
- Table 2 provides the adverse reactions occurring in at least 10% of patients receiving Copanlisib monotherapy, and Table 3 provides the treatment-emergent laboratory abnormalities in ≥20% of patients and ≥4% of Grade ≥3 treated with Copanlisib.
## Postmarketing Experience
There is limited information regarding Copanlisib Postmarketing Experience in the drug label.
# Drug Interactions
- Strong CYP3A Inducers
- Strong CYP3A Inhibitors
- Avoid concomitant use of Copanlisib with strong CYP3A inducers. Concomitant use of Copanlisib with strong CYP3A inducers may decrease Copanlisib AUC and Cmax
- Examplesa of strong CYP3A inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wortb.
- Concomitant use of Copanlisib with strong CYP3A inhibitors increases the Copanlisib AUC. If concomitant use with strong CYP3A inhibitors cannot be avoided, reduce the Copanlisib dose to 45 mg. An increase in the Copanlisib AUC may increase the risk of adverse reactions.
- Examplesa of strong CYP3A inhibitors include: boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juicec, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Based on findings from animal studies and the mechanism of action, Copanlisib 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 Copanlisib to pregnant rats during organogenesis resulted in embryo-fetal death and fetal abnormalities at maternal doses approximately 12% of the recommended dose for patients. Advise pregnant women of the potential risk to a fetus.
- Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population are unknown. 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.
- In an embryo-fetal development study in rats, pregnant animals received intravenous doses of Copanlisib of 0, 0.75, or 3 mg/kg/day during the period of organogenesis. Administration of Copanlisib at the dose of 3 mg/kg/day resulted in maternal toxicity and no live fetuses. Copanlisib administration at the dose of 0.75 mg/kg/day was maternally toxic and resulted in embryo-fetal death (increased resorptions, increased post-implantation loss, and decreased numbers of fetuses/dam). The dose of 0.75 mg/kg/day also resulted in increased incidence of fetal gross external (domed head, malformed eyeballs or eyeholes), soft tissue (hydrocephalus internus, ventricular septal defects, major vessel malformations), and skeletal (dysplastic forelimb bones, malformed ribs and vertebrae, and pelvis shift) abnormalities. The dose of 0.75 mg/kg/day (4.5 mg/m2 body surface area) in rats is approximately 12% of the recommended dose for patients.
- Following administration of radiolabeled Copanlisib to pregnant rats approximately 1.5% of the radioactivity (Copanlisib and metabolites) reached the fetal compartment.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Copanlisib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Copanlisib during labor and delivery.
### Nursing Mothers
- There are no data on the presence of Copanlisib and/or metabolites in human milk, the effects on the breastfed child, or on milk production. Following administration of radiolabeled Copanlisib to lactating rats, approximately 2% of the radioactivity was secreted into milk; the milk to plasma ratio of radioactivity was 25-fold. Because of the potential for serious adverse reactions in a breastfed child from Copanlisib, advise a lactating woman not to breastfeed during treatment with Copanlisib and for at least 1 month after the last dose.
### Pediatric Use
- Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
- No dose adjustment is necessary in patients ≥65 years of age. Of 168 patients with follicular lymphoma and other hematologic malignancies treated with Copanlisib, 48% were age 65 or older while 16% were age 75 or older. No clinically relevant differences in efficacy were observed between elderly and younger patients. In patients ≥65 years of age, 30% experienced serious adverse reactions and 21% experienced adverse reactions leading to discontinuation. In the patients <65 years of age, 23% experienced serious adverse reactions and 11% experienced adverse reactions leading to discontinuation.
### Gender
There is no FDA guidance on the use of Copanlisib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Copanlisib with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Copanlisib in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Copanlisib in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Copanlisib can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing prior to initiation of Copanlisib treatment.
Females
- Advise female patients of reproductive potential to use highly effective contraception (contraception with a failure rate <1% per year) during treatment with Copanlisib and for at least one month after the last dose.
Males
- Advise male patients with female partners of reproductive potential to use highly effective contraception during treatment with Copanlisib and for at least one month after the last dose.
- There are no data on the effect of Copanlisib on human fertility. Due to the mechanism of action of Copanlisib, and findings in animal studies, adverse effects on reproduction, including fertility, are expected.
### Immunocompromised Patients
There is no FDA guidance one the use of Copanlisib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- For intravenous infusion only.
- Administer Copanlisib as a single agent, following reconstitution and dilution. Mix only with 0.9% sodium chloride (NaCl) solution. Do not mix or inject Copanlisib with other drugs or other diluents.
- Reconstitute Copanlisib with 4.4 mL of sterile 0.9% NaCl solution leading to a concentration of 15 mg/mL.
- Withdraw 4.4 mL of sterile 0.9% NaCl solution by using a 5 mL sterile syringe with needle.
- Inject the measured volume through the disinfected stopper surface into the vial of ALIQOPA.
- Dissolve the lyophilized solid by gently shaking the injection vial for 30 seconds.
- Allow to stand for one minute to let bubbles rise to the surface.
- Check if any undissolved substance is still seen. If yes, repeat the gentle shaking and settling procedure.
- Inspect visually for discoloration and particulate matter. After reconstitution, the solution should be colorless to slightly yellowish.
- Once the solution is free of visible particles, withdraw the reconstituted solution for further dilution.
- Further dilute the reconstituted solution in 100 mL sterile 0.9% NaCl solution for injection. With a sterile syringe, withdraw the required amount of the reconstituted solution for the desired dosage:
- 60 mg: Withdraw 4 mL of the reconstituted solution with a sterile syringe.
- 45 mg: Withdraw 3 mL of the reconstituted solution with a sterile syringe.
- 30 mg: Withdraw 2 mL of the reconstituted solution with a sterile syringe.
- Inject the contents of the syringe into the patient infusion bag of 100 mL sterile 0.9% NaCl solution. Mix the dose well by inverting.
- Discard any unused reconstituted or diluted solution appropriately.
- Use reconstituted and diluted Copanlisib immediately or store the reconstituted solution in the vial or diluted solution in the infusion bag at 2°C to 8°C (36°F to 46°F) for up to 24 hours before use. Allow the product to adapt to room temperature before use following refrigeration. Avoid exposure of the diluted solution to direct sunlight.
### Monitoring
- Evidence of disease response or stabilization is indicative of efficacy
- CBC: Including absolute neutrophil count, at least weekly during treatment
- Blood pressure (BP): Pre- and post-infusion; in clinical trials BP remained elevated for 6 to 8 hours after the start of the infusion and started decreasing approximately 2 hours post-infusion
- Glucose control: Closely in patients with diabetes mellitus
- Signs or symptoms of infection
# IV Compatibility
There is limited information regarding the compatibility of Copanlisib and IV administrations.
# Overdosage
There is limited information regarding Copanlisib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Copanlisib has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.
## Structure
## Pharmacodynamics
- At 60 mg (or 0.8 mg/kg) of Copanlisib dose, the elevation of plasma glucose was associated with higher Copanlisib exposure.
## Pharmacokinetics
- The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of Copanlisib increase dose-proportionally over 5 to 93 mg (0.08 to 1.55 times the approved recommended dose) absolute dose range and exhibit linear pharmacokinetics. There is no time-dependency and no accumulation in the pharmacokinetics of Copanlisib.
- The geometric mean (range) steady state Copanlisib exposure at 0.8 mg/kg (approximately the approved recommended dose of 60 mg) are 463 (range: 105 to 1670; SD: 584) ng/mL for Cmax and 1570 (range: 536 to 3410; SD: 338) ng.hr/mL for AUC0-25h.
- The in vitro human plasma protein binding of Copanlisib is 84.2%. Albumin is the main binding protein. The in vitro mean blood-to-plasma ratio is 1.7 (range: 1.5 to 2.1). The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L.
- The geometric mean terminal elimination half-life of Copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours. The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr.
- Approximately >90% of Copanlisib metabolism is mediated by CYP3A and <10% by CYP1A1. The M-1 metabolite accounts for 5% of total radioactivity AUC and its pharmacological activity is comparable to the parent compound Copanlisib for the tested kinases PI3KandPI3K.
- Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. Following a single intravenous dose of 12 mg (0.2 times the recommended approved dose) radiolabeled Copanlisib, approximately 64% of the administered dose was recovered in feces and 22% in urine within 20 to 34 days. Unchanged Copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation metabolism accounted for 41% of the administered dose.
- Copanlisib pharmacokinetic differences in the subpopulations listed below are assessed using population pharmacokinetic analyses.
- Age (20 to 90 years), gender, race (White, Asian, Hispanic, and Black), smoking status, body weight (41 to 130 kg), mild hepatic impairment [total bilirubin (TB) ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or TB < 1-1.5 x ULN and any AST], and mild to moderate renal impairment [CLcr ≥ 30 mL/min as estimated by Cockcroft-Gault (C-G) equation] had no clinically significant effect on the pharmacokinetics of Copanlisib. The pharmacokinetics of Copanlisib in patients with moderate to severe hepatic impairment (TB ≥ 1.5 x ULN, any AST), severe renal impairment (CLcr = 15-29 mL/min by C-G equation), or end stage renal disease (CLcr < 15 mL/min by C-G equation) with or without dialysis is unknown.
Effect of CYP3A and P-gp Inducers on Copanlisib
- Rifampin, a strong CYP3A and a P-glycoprotein (P-gp) transporter inducer, administered at a dose of 600 mg once daily for 12 days with a single intravenous dose of 60 mg Copanlisib in patients with cancer resulted in a 63% decrease in the mean AUC and a 15% decrease in Cmax of Copanlisib.
Effect of CYP3A, P-gp and BCRP Inhibitors on Copanlisib
- Itraconazole, a strong CYP3A inhibitor and a P-gp and Breast Cancer Resistance Protein (BCRP) transporter inhibitor, administered at a dose of 200 mg once daily for 10 days increased the mean AUC of a single intravenous dose of 60 mg Copanlisib by 53% (or 1.53-fold) with no effect on Cmax (1.03-fold) in patients with cancer.
Effect of Transporters on Copanlisib:
- Copanlisib is a substrate of P-gp and BCRP, but not a substrate for organic cation transporter (OCT) 1, OCT2, and OCT3, organic anion transporter (OAT) 1 and OAT3, organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3, multidrug and toxin extrusion protein 1(MATE1) or MATE2-K.
Effect of Copanlisib on CYP and non-CYP Enzymes
- Copanlisib is not an inhibitor of the metabolism of drugs that are substrates of the major CYP isoforms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or uridine diphosphate-glucuronosyltransferase isoforms (UGT) or dihydropyrimidine dehydrogenase (DPD) at therapeutic 60 mg dose plasma concentrations. Copanlisib is not an inducer of CYP1A2, CYP2B6 and CYP3A.
Effect of Copanlisib on Drug Transporter Substrates
- Copanlisib is not an inhibitor of P-gp, BCRP, multi-drug resistance-associated protein (MRP2), bile salt export pump (BSEP), OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, and MATE1 at therapeutic 60 mg dose plasma concentrations.
- Copanlisib is an inhibitor of MATE2-K (IC50: 0.09 μM). Based on the PK of Copanlisib,inhibition may occur after Copanlisib infusion at approved recommended dosage. The clinical significance of this potential inhibition on plasma concentrations of concomitantly administered drugs that are MATE2-K substrates is unknown.
## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with Copanlisib.
- Copanlisib did not cause genetic damage in in vitro or in vivo assays.
- Fertility studies with Copanlisib were not conducted; however, adverse findings in male and female reproductive systems were observed in the repeat dose toxicity studies. Findings in the male rats and/or dogs included effects on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Findings in female rats included effects on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus.
# Clinical Studies
- The efficacy of Copanlisib was evaluated in a single-arm, multicenter, phase 2 clinical trial (NCT 01660451) CHRONOS-1 in a total of 142 subjects, which included 104 subjects with follicular B-cell non-Hodgkin lymphoma who had relapsed disease following at least two prior treatments. Patients must have received rituximab and an alkylating agent. Baseline patient characteristics are summarized in Table 4. The most common prior systemic therapies were chemotherapy in combination with anti-CD20 immunotherapy (89%), chemotherapy alone (41%), and anti-CD20 immunotherapy alone (37%). In CHRONOS-1, 34% of patients received two prior lines of therapy and 36% received three prior lines of therapy.
- Refractory: No response or progression of disease within six months of last treatment.
- One hundred forty-two patients received 60 mg Copanlisib; 130 patients received fixed dose 60 mg Copanlisib and 12 patients received 0.8 mg/kg equivalent Copanlisib administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle on an intermittent schedule (three weeks on and one week off). Treatment continued until disease progression or unacceptable toxicity. Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. Efficacy based on overall response rate (ORR) was assessed by an Independent Review Committee. Efficacy results from CHRONOS-1 are summarized in Table 5.
# How Supplied
- Copanlisib is contained in a colorless glass vial closed with bromobutyl stopper with a flanged closure. Each vial of Copanlisib contains Copanlisib as a lyophilized solid.
## Storage
- Copanlisib vials must be refrigerated at 2°C to 8°C (36°F to 46°F).
- Administer reconstituted and diluted solution immediately. If not, refrigerate at 2°C to 8°C (36°F to 46°F) and use within 24 hours. After refrigeration, allow the product to adapt to room temperature before use. Avoid exposure of the diluted solution to direct sunlight.
- Mix only with 0.9% NaCl solution. Do not mix or inject Copanlisib with other drugs or other diluents.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Infections – Advise patients that Copanlisib can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection
- Hyperglycemia – Advise patients that an infusion-related increase in blood glucose may occur, and to notify their healthcare provider of any symptoms such as pronounced hunger, excessive thirst, headaches, or frequently urinating. Blood glucose levels should be well controlled prior to infusion
- Hypertension – Advise patients that an infusion-related increase in blood pressure may occur, and to notify their healthcare provider of any symptoms such as dizziness, passing out, headache, and/or a pounding heart. Blood pressure should be normal or well controlled prior to infusion
- Non-infectious pneumonitis – Advise patients of the possibility of pneumonitis, and to report any new or worsening respiratory symptoms including cough or difficulty breathing
- Neutropenia – Advise patients of the need for periodic monitoring of blood counts and to notify their healthcare provider immediately if they develop a fever or any signs of infection
- Severe cutaneous reactions – Advise patients that a severe cutaneous reaction may occur, and to notify their healthcare provider if they develop skin reactions (rash, redness, swelling, itching or peeling of the skin)
- Pregnancy – Advise females of reproductive potential to use effective contraceptive methods and to avoid becoming pregnant during treatment with Copanlisib and for at least one month after the last dose. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during Copanlisib treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Copanlisib and for at least one month after the last dose
- Lactation – Advise women not to breastfeed during treatment with Copanlisib and for at least 1 month after the last dose
# Precautions with Alcohol
Alcohol-Copanlisib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Aliqopa
# Look-Alike Drug Names
There is limited information regarding Copanlisib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Copanlisib | |
aefdc3d5e84c6054ab1c79385bd944bfc490e3d6 | wikidoc | Coprolalia | Coprolalia
# Overview
Coprolalia is involuntary swearing or the involuntary utterance of obscene words or socially inappropriate and derogatory remarks. Coprolalia comes from the Greek κόπρος meaning "feces" and λαλία meaning "babbling, meaningless talk", from lalein, "to talk". The term is often used as a clinomorphism, with 'compulsive profanity' inaccurately referred to as being Tourette syndrome.
Related terms are copropraxia, performing obscene or forbidden gestures, and coprographia, making obscene writings or drawings.
# Characteristics
Coprolalia encompasses words and phrases that are culturally taboo or generally unsuitable for acceptable social use, when used out of context. The term is not used to describe contextual swearing. It is usually expressed out of social or emotional context, and may be spoken in a louder tone or different cadence or pitch than normal conversation. It can be a single word, or complex phrases. A person with coprolalia may repeat the word mentally rather than saying it out loud; these subvocalizations can be very distressing.
Coprolalia is an occasional but rare characteristic of Tourette syndrome, although it is not required for a diagnosis of Tourette's. In Tourette syndrome, compulsive swearing can be uncontrollable and undesired by the person uttering the phrases. Involuntary outbursts, such as racial or ethnic slurs in the company of those most offended by such remarks, can be particularly embarrassing. The phrases uttered by a person with coprolalia do not necessarily reflect the thoughts or opinions of the person.
Coprolalia is also a rare symptom of other psychiatric disorders, such as Lesch-Nyhan syndrome.
# Prevalence
According to the Tourette Syndrome Association, fewer than 15% of Tourette syndrome patients exhibit coprolalia, but it tends to attract more attention than any other symptom. There is a paucity of epidemiological studies of Tourette syndrome; ascertainment bias affects clinical studies. Studies on people with Tourette's often "came from tertiary referral samples, the sickest of the sick". Further, the criteria for a diagnosis of Tourette's were changed in 2000, when the impairment criteria was removed from the DSM-IV-TR for all tic disorders, resulting in increased diagnoses of milder cases. Further, many clinical studies suffer from small sample size. These factors combine to render older estimates of coprolalia—biased towards clinical populations of the more severe cases—outdated. An international, multi-site database of 3,500 individuals with Tourette syndrome drawn from clinical samples found 14% of patients with Tourette's accompanied by comorbid conditions had coprolalia, while only 6% of those with uncomplicated ("pure") Tourette's had coprolalia. The same study found that the chance of having coprolalia increased linearly with the number of comorbid conditions: patients with four or five other conditions—in addition to tics—were four to six times more likely to have coprolalia than persons with only Tourette's. One study of a general pediatric practice found an 8% rate of coprolalia in children with Tourette syndrome, while another study found 60% in a tertiary referral center (where typically more severe cases are referred). A more recent Brazilian study of 44 patients with Tourette syndrome found a 14% rate of coprolalia; a Costa Rican study of 85 subjects found 20% had coprolalia; a Chilean study of 70 patients found an 8.5% rate of coprolalia; older studies in Japan reported a 4% incidence of coprolalia; and a still older clinical study in Brazil found 28% of 32 patients had coprolalia. Considering the methodological issues affecting all of these reports, the consensus of the Tourette Syndrome Association is that the actual number is below 15 percent.
# Treatment
Some patients have been treated by injecting botulinum toxin (botox) near the vocal cords. This does not prevent the vocalizations, but the partial paralysis that results helps to control the volume of any outbursts. Surprisingly, botox injections result in more generalized relief of tics than the focal relief expected. | Coprolalia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Coprolalia is involuntary swearing or the involuntary utterance of obscene words or socially inappropriate and derogatory remarks. Coprolalia comes from the Greek κόπρος meaning "feces" and λαλία meaning "babbling, meaningless talk", from lalein, "to talk".[1] The term is often used as a clinomorphism, with 'compulsive profanity' inaccurately referred to as being Tourette syndrome.
Related terms are copropraxia, performing obscene or forbidden gestures,[2] and coprographia, making obscene writings or drawings.[3]
# Characteristics
Coprolalia encompasses words and phrases that are culturally taboo or generally unsuitable for acceptable social use, when used out of context. The term is not used to describe contextual swearing. It is usually expressed out of social or emotional context, and may be spoken in a louder tone or different cadence or pitch than normal conversation. It can be a single word, or complex phrases. A person with coprolalia may repeat the word mentally rather than saying it out loud; these subvocalizations can be very distressing.[4]
Coprolalia is an occasional but rare characteristic of Tourette syndrome, although it is not required for a diagnosis of Tourette's. In Tourette syndrome, compulsive swearing can be uncontrollable and undesired by the person uttering the phrases. Involuntary outbursts, such as racial or ethnic slurs in the company of those most offended by such remarks, can be particularly embarrassing. The phrases uttered by a person with coprolalia do not necessarily reflect the thoughts or opinions of the person.[4]
Coprolalia is also a rare symptom of other psychiatric disorders,[5] such as Lesch-Nyhan syndrome.[6]
# Prevalence
According to the Tourette Syndrome Association, fewer than 15% of Tourette syndrome patients exhibit coprolalia, but it tends to attract more attention than any other symptom.[7] There is a paucity of epidemiological studies of Tourette syndrome; ascertainment bias affects clinical studies. Studies on people with Tourette's often "came from tertiary referral samples, the sickest of the sick".[8] Further, the criteria for a diagnosis of Tourette's were changed in 2000, when the impairment criteria was removed from the DSM-IV-TR for all tic disorders,[9] resulting in increased diagnoses of milder cases. Further, many clinical studies suffer from small sample size. These factors combine to render older estimates of coprolalia—biased towards clinical populations of the more severe cases—outdated. An international, multi-site database of 3,500 individuals with Tourette syndrome drawn from clinical samples found 14% of patients with Tourette's accompanied by comorbid conditions had coprolalia, while only 6% of those with uncomplicated ("pure") Tourette's had coprolalia. The same study found that the chance of having coprolalia increased linearly with the number of comorbid conditions: patients with four or five other conditions—in addition to tics—were four to six times more likely to have coprolalia than persons with only Tourette's.[10] One study of a general pediatric practice found an 8% rate of coprolalia in children with Tourette syndrome, while another study found 60% in a tertiary referral center (where typically more severe cases are referred).[11] A more recent Brazilian study of 44 patients with Tourette syndrome found a 14% rate of coprolalia;[12] a Costa Rican study of 85 subjects found 20% had coprolalia;[13] a Chilean study of 70 patients found an 8.5% rate of coprolalia;[14] older studies in Japan reported a 4% incidence of coprolalia;[15] and a still older clinical study in Brazil found 28% of 32 patients had coprolalia.[16] Considering the methodological issues affecting all of these reports, the consensus of the Tourette Syndrome Association is that the actual number is below 15 percent.
# Treatment
Some patients have been treated by injecting botulinum toxin (botox) near the vocal cords. This does not prevent the vocalizations, but the partial paralysis that results helps to control the volume of any outbursts.[17][18][19] Surprisingly, botox injections result in more generalized relief of tics than the focal relief expected.[20] | https://www.wikidoc.org/index.php/Coprolalia | |
889eb762af7a05a2778177d4428eb91b15273ed8 | wikidoc | Coq au vin | Coq au vin
Coq au vin (French: "rooster with wine") is a French fricassee of rooster cooked with wine, lardons, mushrooms, and garlic. Older roosters are traditionally used because they contain a lot of connective tissue, which creates a richer broth when cooked.
Many regions of France have variants of coq au vin using the local wine, such as coq au vin jaune (Jura), coq au Champagne, and so on. The most extravagant version is coq au Chambertin, but this generally involves Chambertin more in name than in practice.
# History
Various legends trace coq au vin to ancient Gaul and Julius Caesar, but the food is not documented until the early 20th century, though it no doubt existed as a rustic country dish long before that.
# Preparation
Standard recipes call for chicken, wine (often a full bottle), often brandy, lardons (salt pork), button mushrooms, and usually garlic. Recipes with vin jaune usually specify morels instead of white mushrooms. The preparation is similar in many respects to Beef Bourguignon. The lardons are cut as thin strips and then par-boiled to remove excess salt. They are then sauteed to render out the fat. Additional oil is added if needed in order to brown the chicken pieces. A mirepoix of diced carrots, onions, and celery is added along with minced garlic and allowed to briefly cook. Then the wine and stock are added to cover. The traditional seasonings are salt, pepper, thyme, and bay leaf (usually in the form of a bouquet garni). Mushroom stems and pieces will often be added at the beginning of the dish in order to contribute to the flavor of the sauce. Near the end of the preparation, the sauce may be strained to remove the cooked vegetables. The sauce is then returned to the chicken and the whole mushrooms and sometimes pearl onions are added for the last fifteen minutes of cooking.
The juices are thickened either by making a small roux at the beginning of cooking, or by adding blood at the end.
# Notes
- ↑ Oxford Companion to Food, s.v. cock | Coq au vin
Coq au vin (French: "rooster with wine") is a French fricassee of rooster cooked with wine, lardons, mushrooms, and garlic. Older roosters are traditionally used because they contain a lot of connective tissue, which creates a richer broth when cooked.
Many regions of France have variants of coq au vin using the local wine, such as coq au vin jaune (Jura), coq au Champagne, and so on. The most extravagant version is coq au Chambertin, but this generally involves Chambertin more in name than in practice.
# History
Various legends trace coq au vin to ancient Gaul and Julius Caesar, but the food is not documented until the early 20th century, though it no doubt existed as a rustic country dish long before that.[1]
# Preparation
Standard recipes call for chicken, wine (often a full bottle), often brandy, lardons (salt pork), button mushrooms, and usually garlic. Recipes with vin jaune usually specify morels instead of white mushrooms. The preparation is similar in many respects to Beef Bourguignon. The lardons are cut as thin strips and then par-boiled to remove excess salt. They are then sauteed to render out the fat. Additional oil is added if needed in order to brown the chicken pieces. A mirepoix of diced carrots, onions, and celery is added along with minced garlic and allowed to briefly cook. Then the wine and stock are added to cover. The traditional seasonings are salt, pepper, thyme, and bay leaf (usually in the form of a bouquet garni). Mushroom stems and pieces will often be added at the beginning of the dish in order to contribute to the flavor of the sauce. Near the end of the preparation, the sauce may be strained to remove the cooked vegetables. The sauce is then returned to the chicken and the whole mushrooms and sometimes pearl onions are added for the last fifteen minutes of cooking.
The juices are thickened either by making a small roux at the beginning of cooking, or by adding blood at the end.
# Notes
- ↑ Oxford Companion to Food, s.v. cock
# External links
Template:Cookbook
- Perfect Coq au Vin via The Observer
Template:Cuisine-stub
de:Coq au vin
nl:Coq au vin
no:Coq au vin
sl:Coq au vin
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Coq_au_vin | |
e999922ac97b3a0bee71df0eba8c1cf95dc5974f | wikidoc | Cord blood | Cord blood
# Overview
Umbilical cord blood is human blood from the placenta and umbilical cord, collected after the cord has been detached from the newborn baby. Cord blood is utilized as a source of stem cells for transplantation, being rich in hematopoietic stem cells.
Cord blood is stored by both public and private cord blood banks. Public cord blood banks store cord blood for the benefit of the general public, and most U.S. banks coordinate matching cord blood to patients through the National Marrow Donor Program (NMDP). Private cord blood banks are for-profit organizations which store cord blood for the exclusive use of the donor or donor's relatives.
Public cord blood banking is strongly supported by the medical community. However, private cord blood banking is generally not recommended unless there is a family history of specific genetic diseases. Private banking is unlawful in France and Italy, and opposed by the European Group on Ethics in Science and New Technologies.
# Properties
Cord blood stem cells are more proliferate and have a higher chance of matching family members than stem cells from bone marrow. Parents and siblings match 50% of the genetic markers of the donor's stem cell. However, since many different genetic markers are required for a match, the probability of a potential implant in a parent or sibling is considerably lower.
# Collection, storage and costs
Additional stem cells may be collected from the placenta via Placenta Cord Banking. After the health care provider draws the cord blood from the umbilical cord, the placenta is couriered to the stem cell laboratory where it is processed for additional stem cells. By banking stem cells derived from the placenta as well as umbilical cord blood, families may save as much as twice the number of CD34+ stem cells for use in transplants. Having as many of these stem cells as possible is medically important: published research shows that the size of the stem cell transplant (especially the number of CD34+ cells) is consistently a significant factor in achieving a successful treatment and patient survival.
There are two methods of cord blood collection from the umbilical vein: before the placenta is delivered (in utero), and after (ex utero).
With the ex utero collection method, the cord blood is collected after the placenta is delivered and the umbilical cord is clamped off from the newborn. The placenta is placed in a sterile supporting structure with the umbilical cord hanging through the support. The blood is collected by gravity drainage yielding 40-150 mL of cord blood.
A similar collection method is performed in utero, except that the cord blood is collected after the baby has been delivered but before the delivery of the placenta.
After collection, the cord blood units must be immediately shipped to a cord blood bank facility. At public cord blood banks, this blood is then analyzed for infectious agents and the tissue type is determined. Cord blood is processed and depleted of red blood cells before being stored in liquid nitrogen for later use.
New parents have the option of storing their newborn's cord blood at a private cord blood bank or donating it to a public cord blood bank. The cost of private cord blood banking is approximately $2000 for collection and approximately $125 per year for storage, as of 2007. Donation to a public cord blood bank is not possible everywhere, but availability is increasing. Several local cord blood banks across the United States are now accepting donations from within their own states. The cord blood bank will not charge the donor for the donation; the OB/GYN may still charge a collection fee, although many OB/GYNs choose to donate their time.
After the first sibling-donor cord blood transplant was performed in 1988, the National Institute of Health (NIH) awarded a grant to Dr. Pablo Rubinstein to develop the worlds first cord blood program at the New York Blood Center(NYBC), in order to establish the inventory of non embryonal stem cell units necessary to provide unrelated, matched grafts for patients.
In 2005, University of Toronto researcher Peter Zandstra developed a method to increase the yield of cord blood stem cells to enable their use in treating adults as well as children.
# Usage
When cryopreserved cord blood is needed, it is thawed, washed of the cryoprotectant, and injected through a vein of the patient. This kind of treatment, where the stem cells are collected from another donor, is called allogenetic treatment. When the cells are collected from the same patient on whom they will be used, it is called autologous and when collected from identical individuals, it is referred to as syngenic. Xenogenetic transfer of cells (between different species) is very underdeveloped and is said to have little research potential.
# Controversy
While there is general support in the medical community for public banking of cord blood, the question of private banking has raised objections from many governments and nonprofit organizations. The controversy centers on varying assessments of the current and future likelihood of successful uses of the stored blood.
Estimates of the odds that a child will need an autologous stem cell implant by age twenty vary widely. Proponents cite odds of around 1:2,700. The European Union Group on Ethics has cited a paper claiming the odds are 1:20,000. The European Union group went on to conclude that "he legitimacy of commercial cord blood banks for autologous use should be questioned as they sell a service, which has presently, no real use regarding therapeutic options. Thus they promise more than they can deliver. The activities of such banks raise serious ethical criticisms."
In May 2006, The World Marrow Donor Association's Policy Statement for the Utility of Autologous or Family Cord Blood Unit Storage stated that:
- The use of autologous cord blood cells for the treatment of childhood leukemia is contra-indicated because pre-leukemic cells are present at birth. Autologous cord blood carries the same genetic defects as the donor and should not be used to treat genetic diseases.
- There is at present no known protocol where autologous cord blood stem cells are used in therapy.
- If autologous stem cell therapies should become reality in the future, these protocols will probably rely on easily accessible stem cells.
# Diseases treated with cord blood
Beginning in the late 1980s, following a successful sibling-donor transplant, cord blood stem cells have been used to treat a number of blood and immune-system related genetic diseases, cancers, and disorders. Because of medical issues around using one's own cells, in nearly every instance the treatments are done using cells from another donor, with the vast majority being unrelated donors.
In 1993, Dr. Joanne Kurtzberg, of Duke University Medical Center, performed the first two successful unrelated donor cord blood transplants; one of which cured acute lymphoblastic leukemia.
The principal diseases and disorders currently treated are listed at the National Donor Marrow Program website.
# Federal Efforts to Promote Cord Blood Usage and Research
In 2005, U.S. Rep. Chris Smith passed legislation to increase usage and research into cord blood stem cells. Smith's “Stem Cell Therapeutic and Research Act of 2005” (P.L. 109-129), authorized $265 million for stem cell therapy, umbilical cord blood and bone marrow treatments.
The bill, which was signed into law by President George W. Bush in December of 2005, authorizes $79 million for the collection of cord blood stem cells with the goal of building the nation’s public umbilical cord blood supply by adding 150,000 new units to the current inventory. The intention of the law is to collect a genetically diverse cross-section of cord blood units in an effort to make matches available to 90 percent of patients in need.
The law also created a national registry to match cord blood for those in need. All the cord blood banks participating in the inventory program will be linked into a search system that would allow transplant physicians to search for cord blood and bone marrow matches through a single access point. In September 2006, the National Marrow Donor Program (NMDP) was selected by the federal government to perform these duties.
“The Stem Cell Therapeutic and Research Act of 2005” is not only aimed at increasing the medical utilization rate for cord blood stem cells, but is also aimed at increasing cord blood stem cell research. All cord blood collected and deemed unsuitable for transplant is required to be donated for research. | Cord blood
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Umbilical cord blood is human blood from the placenta and umbilical cord, collected after the cord has been detached from the newborn baby. Cord blood is utilized as a source of stem cells for transplantation, being rich in hematopoietic stem cells.
Cord blood is stored by both public and private cord blood banks. Public cord blood banks store cord blood for the benefit of the general public, and most U.S. banks coordinate matching cord blood to patients through the National Marrow Donor Program (NMDP). Private cord blood banks are for-profit organizations which store cord blood for the exclusive use of the donor or donor's relatives.
Public cord blood banking is strongly supported by the medical community. However, private cord blood banking is generally not recommended unless there is a family history of specific genetic diseases. Private banking is unlawful in France and Italy, and opposed by the European Group on Ethics in Science and New Technologies.
# Properties
Cord blood stem cells are more proliferate and have a higher chance of matching family members than stem cells from bone marrow. Parents and siblings match 50% of the genetic markers of the donor's stem cell. However, since many different genetic markers are required for a match, the probability of a potential implant in a parent or sibling is considerably lower.
# Collection, storage and costs
Additional stem cells may be collected from the placenta via Placenta Cord Banking. After the health care provider draws the cord blood from the umbilical cord, the placenta is couriered to the stem cell laboratory where it is processed for additional stem cells. By banking stem cells derived from the placenta as well as umbilical cord blood, families may save as much as twice the number of CD34+ stem cells for use in transplants. Having as many of these stem cells as possible is medically important: published research shows that the size of the stem cell transplant (especially the number of CD34+ cells) is consistently a significant factor in achieving a successful treatment and patient survival.
There are two methods of cord blood collection from the umbilical vein: before the placenta is delivered (in utero), and after (ex utero).
With the ex utero collection method, the cord blood is collected after the placenta is delivered and the umbilical cord is clamped off from the newborn. The placenta is placed in a sterile supporting structure with the umbilical cord hanging through the support. The blood is collected by gravity drainage yielding 40-150 mL of cord blood.
A similar collection method is performed in utero, except that the cord blood is collected after the baby has been delivered but before the delivery of the placenta.
After collection, the cord blood units must be immediately shipped to a cord blood bank facility. At public cord blood banks, this blood is then analyzed for infectious agents and the tissue type is determined. Cord blood is processed and depleted of red blood cells before being stored in liquid nitrogen for later use.
New parents have the option of storing their newborn's cord blood at a private cord blood bank or donating it to a public cord blood bank. The cost of private cord blood banking is approximately $2000 for collection and approximately $125 per year for storage, as of 2007. Donation to a public cord blood bank is not possible everywhere, but availability is increasing. Several local cord blood banks across the United States are now accepting donations from within their own states. The cord blood bank will not charge the donor for the donation; the OB/GYN may still charge a collection fee, although many OB/GYNs choose to donate their time.
After the first sibling-donor cord blood transplant was performed in 1988, the National Institute of Health (NIH) awarded a grant to Dr. Pablo Rubinstein to develop the worlds first cord blood program at the New York Blood Center(NYBC)[1], in order to establish the inventory of non embryonal stem cell units necessary to provide unrelated, matched grafts for patients.
In 2005, University of Toronto researcher Peter Zandstra developed a method to increase the yield of cord blood stem cells to enable their use in treating adults as well as children.[2]
# Usage
When cryopreserved cord blood is needed, it is thawed, washed of the cryoprotectant, and injected through a vein of the patient. This kind of treatment, where the stem cells are collected from another donor, is called allogenetic treatment. When the cells are collected from the same patient on whom they will be used, it is called autologous and when collected from identical individuals, it is referred to as syngenic. Xenogenetic transfer of cells (between different species) is very underdeveloped and is said to have little research potential.[citation needed]
# Controversy
While there is general support in the medical community for public banking of cord blood, the question of private banking has raised objections from many governments and nonprofit organizations. The controversy centers on varying assessments of the current and future likelihood of successful uses of the stored blood.
Estimates of the odds that a child will need an autologous stem cell implant by age twenty vary widely. Proponents cite odds of around 1:2,700.[3] The European Union Group on Ethics[4] has cited a paper[5] claiming the odds are 1:20,000. The European Union group went on to conclude that "[t]he legitimacy of commercial cord blood banks for autologous use should be questioned as they sell a service, which has presently, no real use regarding therapeutic options. Thus they promise more than they can deliver. The activities of such banks raise serious ethical criticisms." [4]
In May 2006, The World Marrow Donor Association's Policy Statement for the Utility of Autologous or Family Cord Blood Unit Storage[6] stated that:
- The use of autologous cord blood cells for the treatment of childhood leukemia is contra-indicated because pre-leukemic cells are present at birth. Autologous cord blood carries the same genetic defects as the donor and should not be used to treat genetic diseases.
- There is at present no known protocol where autologous cord blood stem cells are used in therapy.
- If autologous stem cell therapies should become reality in the future, these protocols will probably rely on easily accessible stem cells.
# Diseases treated with cord blood
Beginning in the late 1980s, following a successful sibling-donor transplant, cord blood stem cells have been used to treat a number of blood and immune-system related genetic diseases, cancers, and disorders. Because of medical issues around using one's own cells, in nearly every instance the treatments are done using cells from another donor, with the vast majority being unrelated donors.
In 1993, Dr. Joanne Kurtzberg, of Duke University Medical Center, performed the first two successful unrelated donor cord blood transplants[7]; one of which cured acute lymphoblastic leukemia.
The principal diseases and disorders currently treated are listed at the National Donor Marrow Program website.
# Federal Efforts to Promote Cord Blood Usage and Research
In 2005, U.S. Rep. Chris Smith passed legislation to increase usage and research into cord blood stem cells. Smith's “Stem Cell Therapeutic and Research Act of 2005” (P.L. 109-129), authorized $265 million for stem cell therapy, umbilical cord blood and bone marrow treatments.
The bill, which was signed into law by President George W. Bush in December of 2005, authorizes $79 million for the collection of cord blood stem cells with the goal of building the nation’s public umbilical cord blood supply by adding 150,000 new units to the current inventory. The intention of the law is to collect a genetically diverse cross-section of cord blood units in an effort to make matches available to 90 percent of patients in need.
The law also created a national registry to match cord blood for those in need. All the cord blood banks participating in the inventory program will be linked into a search system that would allow transplant physicians to search for cord blood and bone marrow matches through a single access point. In September 2006, the National Marrow Donor Program (NMDP) was selected by the federal government to perform these duties.
“The Stem Cell Therapeutic and Research Act of 2005” is not only aimed at increasing the medical utilization rate for cord blood stem cells, but is also aimed at increasing cord blood stem cell research. All cord blood collected and deemed unsuitable for transplant is required to be donated for research. | https://www.wikidoc.org/index.php/Cord_blood |
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