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e0899e944502d538542aaa91b8543ec1eb6784b8 | wikidoc | Myoglobin | Myoglobin
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is distantly related to hemoglobin which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. In humans, myoglobin is only found in the bloodstream after muscle injury. It is an abnormal finding, and can be diagnostically relevant when found in blood.
Myoglobin is the primary oxygen-carrying pigment of muscle tissues. High concentrations of myoglobin in muscle cells allow organisms to hold their breath for a longer period of time. Diving mammals such as whales and seals have muscles with particularly high abundance of myoglobin. Myoglobin is found in Type I muscle, Type II A and Type II B, but most texts consider myoglobin not to be found in smooth muscle.
Myoglobin was the first protein to have its three-dimensional structure revealed by X-ray crystallography. This achievement was reported in 1958 by John Kendrew and associates. For this discovery, John Kendrew shared the 1962 Nobel Prize in chemistry with Max Perutz. Despite being one of the most studied proteins in biology, its physiological function is not yet conclusively established: mice genetically engineered to lack myoglobin can be viable and fertile but show many cellular and physiological adaptations to overcome the loss. Through observing these changes in myoglobin-deplete mice, it is hypothesised that myoglobin function relates to increased oxygen transport to muscle, oxygen storage and as a scavenger of reactive oxygen species.
In humans myoglobin is encoded by the MB gene.
Myoglobin can take the forms oxymyoglobin (MbO2), carboxymyoglobin (MbCO), and metmyoglobin (met-Mb), analogously to hemoglobin taking the forms oxyhemoglobin (HbO2), carboxyhemoglobin (HbCO), and methemoglobin (met-Hb).
# Differences from hemoglobin
Like hemoglobin, myoglobin is a cytoplasmic protein that binds oxygen on a heme group. It harbors only one heme group, whereas hemoglobin has four. Although its heme group is identical to those in Hb, Mb has a higher affinity for oxygen than does hemoglobin. This difference is related to its different role: whereas hemoglobin transports oxygen, myoglobin's function is to store oxygen.
# Meat color
Myoglobin contains hemes, pigments responsible for the colour of red meat. The colour that meat takes is partly determined by the degree of oxidation of the myoglobin. In fresh meat the iron atom is in the ferrous (+2) oxidation state bound to an oxygen molecule (O2). Meat cooked well done is brown because the iron atom is now in the ferric (+3) oxidation state, having lost an electron. If meat has been exposed to nitrites, it will remain pink because the iron atom is bound to NO, nitric oxide (true of, e.g., corned beef or cured hams). Grilled meats can also take on a pink "smoke ring" that comes from the iron binding to a molecule of carbon monoxide. Raw meat packed in a carbon monoxide atmosphere also shows this same pink "smoke ring" due to the same principles. Notably, the surface of this raw meat also displays the pink color, which is usually associated in consumers' minds with fresh meat. This artificially induced pink color can persist, reportedly up to one year. Hormel and Cargill are both reported to use this meat-packing process, and meat treated this way has been in the consumer market since 2003.
# Role in disease
Myoglobin is released from damaged muscle tissue (rhabdomyolysis), which has very high concentrations of myoglobin. The released myoglobin is filtered by the kidneys but is toxic to the renal tubular epithelium and so may cause acute kidney injury. It is not the myoglobin itself that is toxic (it is a protoxin) but the ferrihemate portion that is dissociated from myoglobin in acidic environments (e.g., acidic urine, lysosomes).
Myoglobin is a sensitive marker for muscle injury, making it a potential marker for heart attack in patients with chest pain. However, elevated myoglobin has low specificity for acute myocardial infarction (AMI) and thus CK-MB, cardiac Troponin, ECG, and clinical signs should be taken into account to make the diagnosis.
# Structure and bonding
Myoglobin belongs to the globin superfamily of proteins, and as with other globins, consists of eight alpha helices connected by loops. Myoglobin contains 154 amino acids.
Myoglobin contains a porphyrin ring with an iron at its center. A proximal histidine group (His-93) is attached directly to iron, and a distal histidine group (His-64) hovers near the opposite face. The distal imidazole is not bonded to the iron but is available to interact with the substrate O2. This interaction encourages the binding of O2, but not carbon monoxide (CO), which still binds about 240× more strongly than O2.
The binding of O2 causes substantial structural change at the Fe center, which shrinks in radius and moves into the center of N4 pocket. O2-binding induces "spin-pairing": the five-coordinate ferrous deoxy form is high spin and the six coordinate oxy form is low spin and diamagnetic.
# Synthetic analogues
Many models of myoglobin have been synthesized as part of a broad interest in transition metal dioxygen complexes. A well known example is the picket fence porphyrin, which consists of a ferrous complex of a sterically bulky derivative of tetraphenylporphyrin. In the presence of an imidazole ligand, this ferrous complex reversibly binds O2. The O2 substrate adopts a bent geometry, occupying the sixth position of the iron center. A key property of this model is the slow formation of the μ-oxo dimer, which is an inactive diferric state. In nature, such deactivation pathways are suppressed by protein matrix that prevents close approach of the Fe-porphyrin assemblies. | Myoglobin
Myoglobin (symbol Mb or MB) is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is distantly related to hemoglobin[1] which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. In humans, myoglobin is only found in the bloodstream after muscle injury. It is an abnormal finding, and can be diagnostically relevant when found in blood.[2]
Myoglobin is the primary oxygen-carrying pigment of muscle tissues.[3] High concentrations of myoglobin in muscle cells allow organisms to hold their breath for a longer period of time. Diving mammals such as whales and seals have muscles with particularly high abundance of myoglobin.[2] Myoglobin is found in Type I muscle, Type II A and Type II B, but most texts consider myoglobin not to be found in smooth muscle.
Myoglobin was the first protein to have its three-dimensional structure revealed by X-ray crystallography.[4] This achievement was reported in 1958 by John Kendrew and associates.[5] For this discovery, John Kendrew shared the 1962 Nobel Prize in chemistry with Max Perutz.[6] Despite being one of the most studied proteins in biology, its physiological function is not yet conclusively established: mice genetically engineered to lack myoglobin can be viable and fertile but show many cellular and physiological adaptations to overcome the loss. Through observing these changes in myoglobin-deplete mice, it is hypothesised that myoglobin function relates to increased oxygen transport to muscle, oxygen storage and as a scavenger of reactive oxygen species.[7]
In humans myoglobin is encoded by the MB gene.[8]
Myoglobin can take the forms oxymyoglobin (MbO2), carboxymyoglobin (MbCO), and metmyoglobin (met-Mb), analogously to hemoglobin taking the forms oxyhemoglobin (HbO2), carboxyhemoglobin (HbCO), and methemoglobin (met-Hb).
# Differences from hemoglobin
Like hemoglobin, myoglobin is a cytoplasmic protein that binds oxygen on a heme group. It harbors only one heme group, whereas hemoglobin has four. Although its heme group is identical to those in Hb, Mb has a higher affinity for oxygen than does hemoglobin. This difference is related to its different role: whereas hemoglobin transports oxygen, myoglobin's function is to store oxygen.
# Meat color
Myoglobin contains hemes, pigments responsible for the colour of red meat. The colour that meat takes is partly determined by the degree of oxidation of the myoglobin. In fresh meat the iron atom is in the ferrous (+2) oxidation state bound to an oxygen molecule (O2). Meat cooked well done is brown because the iron atom is now in the ferric (+3) oxidation state, having lost an electron. If meat has been exposed to nitrites, it will remain pink because the iron atom is bound to NO, nitric oxide (true of, e.g., corned beef or cured hams). Grilled meats can also take on a pink "smoke ring" that comes from the iron binding to a molecule of carbon monoxide.[9] Raw meat packed in a carbon monoxide atmosphere also shows this same pink "smoke ring" due to the same principles. Notably, the surface of this raw meat also displays the pink color, which is usually associated in consumers' minds with fresh meat. This artificially induced pink color can persist, reportedly up to one year.[10] Hormel and Cargill are both reported to use this meat-packing process, and meat treated this way has been in the consumer market since 2003.[11]
# Role in disease
Myoglobin is released from damaged muscle tissue (rhabdomyolysis), which has very high concentrations of myoglobin. The released myoglobin is filtered by the kidneys but is toxic to the renal tubular epithelium and so may cause acute kidney injury.[12] It is not the myoglobin itself that is toxic (it is a protoxin) but the ferrihemate portion that is dissociated from myoglobin in acidic environments (e.g., acidic urine, lysosomes).
Myoglobin is a sensitive marker for muscle injury, making it a potential marker for heart attack in patients with chest pain.[13] However, elevated myoglobin has low specificity for acute myocardial infarction (AMI) and thus CK-MB, cardiac Troponin, ECG, and clinical signs should be taken into account to make the diagnosis.
# Structure and bonding
Myoglobin belongs to the globin superfamily of proteins, and as with other globins, consists of eight alpha helices connected by loops. Myoglobin contains 154 amino acids.[15]
Myoglobin contains a porphyrin ring with an iron at its center. A proximal histidine group (His-93) is attached directly to iron, and a distal histidine group (His-64) hovers near the opposite face.[15] The distal imidazole is not bonded to the iron but is available to interact with the substrate O2. This interaction encourages the binding of O2, but not carbon monoxide (CO), which still binds about 240× more strongly than O2.
The binding of O2 causes substantial structural change at the Fe center, which shrinks in radius and moves into the center of N4 pocket. O2-binding induces "spin-pairing": the five-coordinate ferrous deoxy form is high spin and the six coordinate oxy form is low spin and diamagnetic.[citation needed]
# Synthetic analogues
Many models of myoglobin have been synthesized as part of a broad interest in transition metal dioxygen complexes. A well known example is the picket fence porphyrin, which consists of a ferrous complex of a sterically bulky derivative of tetraphenylporphyrin.[16] In the presence of an imidazole ligand, this ferrous complex reversibly binds O2. The O2 substrate adopts a bent geometry, occupying the sixth position of the iron center. A key property of this model is the slow formation of the μ-oxo dimer, which is an inactive diferric state. In nature, such deactivation pathways are suppressed by protein matrix that prevents close approach of the Fe-porphyrin assemblies.[17] | https://www.wikidoc.org/index.php/Ddx:Myoglobin | |
8a9518b028c3bbcb4f169aa42ce36a635dce534d | wikidoc | Nystagmus | Nystagmus
# Overview
Nystagmus is involuntary eye movement that can be part of either the vestibulo-ocular reflex (VOR) or a pathological process. It is characterized by alternating smooth pursuit in one direction and saccadic movement in the other direction.
# Pathophysiology
Nystagmus can be caused by subsequent foveation of moving objects, pathology, sustained rotation or substance abuse.
The direction of nystagmus is defined by the direction of its quick phase (e.g. a right-beating nystagmus is characterized by a rightward-moving quick phase). The oscillations may occur in the vertical, horizontal or torsional planes, or in any combination. The resulting nystagmus is often named as a gross description of the movement, e.g. downbeat nystagmus, upbeat nystagmus, seesaw nystagmus, periodic alternating nystagmus.
These descriptive names can be misleading however, as many were assigned historically, solely on the basis of subjective clinical examination, which is not sufficient to determine the eyes' true trajectory.
Over the past forty years, however, objective eye movement recording techniques have been applied to the study of nystagmus, and the results have led to a greater accuracy and understanding of the condition.
Nystagmus is not to be confused with other superficially similar-appearing disorders of eye movements (saccadic oscillations) such as opsoclonus or ocular flutter that are composed purely of fast-phase (saccadic) eye movements, while nystagmus is characterised by the combination of a smooth pursuit, which usually acts to take the eye off the point of regard, interspersed with the saccadic movement that serves to bring the eye back on target. Without the use of objective recording techniques, it may be very difficult to distinguish between these conditions.
In medicine, the presence of nystagmus can be benign, or it can indicate an underlying visual or neurological problem. Over forty types of nystagmus have been classified.
# Nystagmus and alcohol
In police work, testing for horizontal gaze nystagmus is one of a battery of field sobriety tests used by officers in the field to determine whether a suspect is driving under the influence of alcohol. The test involves observation of the suspect's pupil as it follows a moving object, noting (1) lack of smooth pursuit, (2) distinct and sustained nystagmus at maximum deviation, and (3) the onset of nystagmus prior to 45 degrees. As a rule of thumb, a person's blood alcohol concentration can be estimated by subtracting the angle of onset from 50 degrees. Therefore, a person with an angle of onset of nystagmus at 35 degrees has a blood alcohol concentration of approximately 0.15%.
# Pathological nystagmus
When nystagmus occurs without filling its normal function, it is pathologic (deviating from the healthy or normal condition). Pathological nystagmus is the result of damage to one or more components of the vestibular system, including the semicircular canals, otolith organs, and the vestibulocerebellum.
Pathological nystagmus generally causes a degree of vision impairment, although the severity of such impairment varies widely. Sometimes it is the other way around — many blind people have nystagmus, which is one reason that some wear dark glasses.
## Prevalence
Nystagmus is a relatively common clinical condition, affecting one in every 5,000 to 10,000 individuals. One survey in Oxfordshire, England identified one in every 670 children by the age of two as manifesting nystagmus.
## Variations
- Peripheral nystagmus occurs as a result of either normal or diseased functional states of the vestibular system and may combine a rotational component with vertical or horizontal eye movements and may be spontaneous, positional or evoked.
Positional nystagmus occurs when a persons head is in a specific position. An example of disease state in which this occurs is Benign paroxysmal positional vertigo (BPPV).
Gaze Induced nystagmus occurs or is exacerbated as a result of changing one's gaze toward or away from a particular side which has an affected vestibular apparatus.
Post Head Shake nystagmus occurs after an imbalance is created between a normal side and a diseased side by stimulation of the vestibular system by rapid shaking of the head.
Spontaneous nystagmus is nystagmus that occurs randomly, regardless of the position of the patient's head.
- Positional nystagmus occurs when a persons head is in a specific position. An example of disease state in which this occurs is Benign paroxysmal positional vertigo (BPPV).
- Gaze Induced nystagmus occurs or is exacerbated as a result of changing one's gaze toward or away from a particular side which has an affected vestibular apparatus.
- Post Head Shake nystagmus occurs after an imbalance is created between a normal side and a diseased side by stimulation of the vestibular system by rapid shaking of the head.
- Spontaneous nystagmus is nystagmus that occurs randomly, regardless of the position of the patient's head.
- Central nystagmus occurs as a result of either normal or abnormal processes not related to the vestibular organ. For example lesions of the midbrain or cerebellum can results in up and down-beat nystagmus.
## Causes
The cause for pathological nystagmus may be congenital, idiopathic, secondary to a pre-existing neurological disorder or may be induced temporarily by disorientation (such as on roller coaster rides) or certain drugs (alcohol and other central nervous system depressants and stimulants, such as lithium salts, phenytoin and ecstasy).
### Congenital
Congenital nystagmus occurs more frequently than acquired nystagmus. It can be insular or accompany other disorders (such as micro-ophthalmic anomalies or Down's Syndrome). Congential nystagmus itself and is usually mild and non-progressive. The affected persons are not normally aware of their spontaneous eye movements but vision can be impaired depending on the severity of the movements.
- Infantile:
- Idiopathic
- Albinism
- Aniridia
- Leber's congenital amaurosis
- Bilateral optic nerve hypoplasia
- Bilateral congenital cataracts
- Rod monochromatism
- Optic nerve or macular disease
- Persistent tunica vasculosa lentis
- Latent nystagmus
- Nystagmus blockage syndrome
### Acquired
Some of the diseases which present nystagmus as a pathological sign are:
- Benign Paroxysmal Positional Vertigo
- Head trauma
- Stroke (the most common cause in older people)
- Ménière's disease and other balance disorders
- Multiple sclerosis
- Brain tumors
- Wernicke-Korsakoff syndrome
- Encephalopathy
- Lateral medullary syndrome
- Aniridia
- Optic nerve hypoplasia
- Albinism
- Noonan syndrome
- Pelizaeus-Merzbacher disease
- Superior canal dehiscence syndrome
- Tullio phenomenon
- Horner's Syndrome
Nystagmus from toxic or metabolic reasons could be the result of e.g.:
- Alcohol intoxication (see above)
- Lithium
- Barbiturates
- Phenytoin (Dilantin)
- Salicylates
- Benzodiazepines
- Lysergic acid diethylamide (LSD)
- Phencyclidine (PCP)
- Ketamine
- Other anticonvulsants or sedatives
- Methylenedioxymethamphetamine
- Wernicke's encephalopathy
- Thiamine deficiency
- Cytarabine
If the pathologic nystagmus is based in the central nervous system (CNS), such as with a cerebellar problem, the nystagmus can be in any direction including horizontal. Purely vertical nystagmus is usually central in origin.
Causes include e.g.:
- Thalamic hemorrhage
- Tumor
- Stroke
- Trauma
- Multiple sclerosis
- Vestibular Pathology (Ménière's disease, SCDS (superior canal dehiscence syndrome), BPPV, Labyrinthitis)
- Trochlear nerve malfunction
- Non-physiologic
## Complete Differential Diagnosis of the Causes of Nystagmus
(By organ system)
## Complete list of differential diagnosis of Nystagmus
# Diagnosis
## Physical Examination
### HEENT
Nystagmus can be clinically investigated by using a number of non-invasive standard tests. The simplest one is Caloric reflex test. In a caloric reflex test, one external auditory meatus is irrigated with warm or cold water. The temperature gradient provokes the stimulation of the vestibulocochlear nerve and the consequent nystagmus.
The resulting movement of the eyes may be recorded and quantified by special devices called electronystagmograph (ENG), which is a form of electrooculography (an electrical method of measuring eye movements using external electrodes) or even less invasive devices called videoonystagmograph (VNG), which is a form of videooculography(VOG) (a video-based method of measuring eye movements using external small cameras built into head masks). Special swinging chairs with electrical controls are also used in this test to induce rotatory nystagmus.
## Laboratory Findings
Suggested laboratory studies to order include a toxicology screen.
# Treatment
Congenital nystagmus has traditionally been viewed as non-treatable, but medications have been discovered in recent years that show promise in some patients. In 1980, researchers discovered that a drug called baclofen could effectively stop periodic alternating nystagmus. Subsequently, gabapentin, an anticonvulsant, was found to cause improvement in about half the patients who received it to relieve symptoms of nystagmus. Other drugs found to be effective against nystagmus in some patients include memantine, levetiracetam, 3,4-diaminopyridine, 4-aminopyridine, and acetazolamide. Several therapeutic approaches, such as contact lenses, drugs, surgery, and low vision rehabilitation can also be used in order to improve visual function.
Clinical trials of a surgery to treat nystagmus (known as tenotomy) concluded in 2001. Tenotomy is being performed regularly at the University of Pittsburgh Children's Hospital and by a handful of surgeons around the world. The surgery developed by Louis F. Dell'Osso Ph.D aims to reduce the eye shaking (oscillations) which in turn tends to improve visual acuity.
## Surgery and Device Based Therapy
- Otolith repositioning maneuvers
- Refractive lenses to treat amblyopia | Nystagmus
Template:SignSymptom infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Shankar Kumar, M.B.B.S. [3]]
# Overview
Nystagmus is involuntary eye movement that can be part of either the vestibulo-ocular reflex (VOR) or a pathological process. It is characterized by alternating smooth pursuit in one direction and saccadic movement in the other direction.
# Pathophysiology
Nystagmus can be caused by subsequent foveation of moving objects, pathology, sustained rotation or substance abuse.
The direction of nystagmus is defined by the direction of its quick phase (e.g. a right-beating nystagmus is characterized by a rightward-moving quick phase). The oscillations may occur in the vertical, horizontal or torsional planes, or in any combination. The resulting nystagmus is often named as a gross description of the movement, e.g. downbeat nystagmus, upbeat nystagmus, seesaw nystagmus, periodic alternating nystagmus.
These descriptive names can be misleading however, as many were assigned historically, solely on the basis of subjective clinical examination, which is not sufficient to determine the eyes' true trajectory.
Over the past forty years, however, objective eye movement recording techniques have been applied to the study of nystagmus, and the results have led to a greater accuracy and understanding of the condition.
Nystagmus is not to be confused with other superficially similar-appearing disorders of eye movements (saccadic oscillations) such as opsoclonus or ocular flutter that are composed purely of fast-phase (saccadic) eye movements, while nystagmus is characterised by the combination of a smooth pursuit, which usually acts to take the eye off the point of regard, interspersed with the saccadic movement that serves to bring the eye back on target. Without the use of objective recording techniques, it may be very difficult to distinguish between these conditions.
In medicine, the presence of nystagmus can be benign, or it can indicate an underlying visual or neurological problem. Over forty types of nystagmus have been classified.
# Nystagmus and alcohol
In police work, testing for horizontal gaze nystagmus is one of a battery of field sobriety tests used by officers in the field to determine whether a suspect is driving under the influence of alcohol. The test involves observation of the suspect's pupil as it follows a moving object, noting (1) lack of smooth pursuit, (2) distinct and sustained nystagmus at maximum deviation, and (3) the onset of nystagmus prior to 45 degrees. As a rule of thumb, a person's blood alcohol concentration can be estimated by subtracting the angle of onset from 50 degrees. Therefore, a person with an angle of onset of nystagmus at 35 degrees has a blood alcohol concentration of approximately 0.15%.
# Pathological nystagmus
When nystagmus occurs without filling its normal function, it is pathologic (deviating from the healthy or normal condition). Pathological nystagmus is the result of damage to one or more components of the vestibular system, including the semicircular canals, otolith organs, and the vestibulocerebellum.
Pathological nystagmus generally causes a degree of vision impairment, although the severity of such impairment varies widely. Sometimes it is the other way around — many blind people have nystagmus, which is one reason that some wear dark glasses.[1]
## Prevalence
Nystagmus is a relatively common clinical condition, affecting one in every 5,000 to 10,000 individuals. One survey in Oxfordshire, England identified one in every 670 children by the age of two as manifesting nystagmus. [2]
## Variations
- Peripheral nystagmus occurs as a result of either normal or diseased functional states of the vestibular system and may combine a rotational component with vertical or horizontal eye movements and may be spontaneous, positional or evoked.
Positional nystagmus occurs when a persons head is in a specific position. An example of disease state in which this occurs is Benign paroxysmal positional vertigo (BPPV).
Gaze Induced nystagmus occurs or is exacerbated as a result of changing one's gaze toward or away from a particular side which has an affected vestibular apparatus.
Post Head Shake nystagmus occurs after an imbalance is created between a normal side and a diseased side by stimulation of the vestibular system by rapid shaking of the head.
Spontaneous nystagmus is nystagmus that occurs randomly, regardless of the position of the patient's head.
- Positional nystagmus occurs when a persons head is in a specific position. An example of disease state in which this occurs is Benign paroxysmal positional vertigo (BPPV).
- Gaze Induced nystagmus occurs or is exacerbated as a result of changing one's gaze toward or away from a particular side which has an affected vestibular apparatus.
- Post Head Shake nystagmus occurs after an imbalance is created between a normal side and a diseased side by stimulation of the vestibular system by rapid shaking of the head.
- Spontaneous nystagmus is nystagmus that occurs randomly, regardless of the position of the patient's head.
- Central nystagmus occurs as a result of either normal or abnormal processes not related to the vestibular organ. For example lesions of the midbrain or cerebellum can results in up and down-beat nystagmus.
## Causes
The cause for pathological nystagmus may be congenital, idiopathic, secondary to a pre-existing neurological disorder or may be induced temporarily by disorientation (such as on roller coaster rides) or certain drugs (alcohol and other central nervous system depressants and stimulants, such as lithium salts, phenytoin and ecstasy).
### Congenital
Congenital nystagmus occurs more frequently than acquired nystagmus. It can be insular or accompany other disorders (such as micro-ophthalmic anomalies or Down's Syndrome). Congential nystagmus itself and is usually mild and non-progressive. The affected persons are not normally aware of their spontaneous eye movements but vision can be impaired depending on the severity of the movements.
- Infantile:
- Idiopathic
- Albinism
- Aniridia
- Leber's congenital amaurosis
- Bilateral optic nerve hypoplasia
- Bilateral congenital cataracts
- Rod monochromatism
- Optic nerve or macular disease
- Persistent tunica vasculosa lentis
- Latent nystagmus
- Nystagmus blockage syndrome
### Acquired
Some of the diseases which present nystagmus as a pathological sign are:
- Benign Paroxysmal Positional Vertigo
- Head trauma
- Stroke (the most common cause in older people)
- Ménière's disease and other balance disorders
- Multiple sclerosis
- Brain tumors
- Wernicke-Korsakoff syndrome
- Encephalopathy
- Lateral medullary syndrome
- Aniridia
- Optic nerve hypoplasia
- Albinism
- Noonan syndrome
- Pelizaeus-Merzbacher disease
- Superior canal dehiscence syndrome
- Tullio phenomenon
- Horner's Syndrome
Nystagmus from toxic or metabolic reasons could be the result of e.g.:
- Alcohol intoxication (see above)
- Lithium
- Barbiturates
- Phenytoin (Dilantin)
- Salicylates
- Benzodiazepines
- Lysergic acid diethylamide (LSD)
- Phencyclidine (PCP)
- Ketamine
- Other anticonvulsants or sedatives
- Methylenedioxymethamphetamine
- Wernicke's encephalopathy
- Thiamine deficiency
- Cytarabine
If the pathologic nystagmus is based in the central nervous system (CNS), such as with a cerebellar problem, the nystagmus can be in any direction including horizontal. Purely vertical nystagmus is usually central in origin.
Causes include e.g.:
- Thalamic hemorrhage
- Tumor
- Stroke
- Trauma
- Multiple sclerosis
- Vestibular Pathology (Ménière's disease, SCDS (superior canal dehiscence syndrome), BPPV, Labyrinthitis)
- Trochlear nerve malfunction[3]
- Non-physiologic
## Complete Differential Diagnosis of the Causes of Nystagmus
(By organ system)
## Complete list of differential diagnosis of Nystagmus
# Diagnosis
## Physical Examination
### HEENT
Nystagmus can be clinically investigated by using a number of non-invasive standard tests. The simplest one is Caloric reflex test. In a caloric reflex test, one external auditory meatus is irrigated with warm or cold water. The temperature gradient provokes the stimulation of the vestibulocochlear nerve and the consequent nystagmus.
The resulting movement of the eyes may be recorded and quantified by special devices called electronystagmograph (ENG), which is a form of electrooculography (an electrical method of measuring eye movements using external electrodes) or even less invasive devices called videoonystagmograph (VNG), which is a form of videooculography(VOG) (a video-based method of measuring eye movements using external small cameras built into head masks). Special swinging chairs with electrical controls are also used in this test to induce rotatory nystagmus.
## Laboratory Findings
Suggested laboratory studies to order include a toxicology screen.
# Treatment
Congenital nystagmus has traditionally been viewed as non-treatable, but medications have been discovered in recent years that show promise in some patients. In 1980, researchers discovered that a drug called baclofen could effectively stop periodic alternating nystagmus. Subsequently, gabapentin, an anticonvulsant, was found to cause improvement in about half the patients who received it to relieve symptoms of nystagmus. Other drugs found to be effective against nystagmus in some patients include memantine, levetiracetam, 3,4-diaminopyridine, 4-aminopyridine, and acetazolamide.[4] Several therapeutic approaches, such as contact lenses, drugs, surgery, and low vision rehabilitation can also be used in order to improve visual function.
Clinical trials of a surgery to treat nystagmus (known as tenotomy) concluded in 2001. Tenotomy is being performed regularly at the University of Pittsburgh Children's Hospital and by a handful of surgeons around the world. The surgery developed by Louis F. Dell'Osso Ph.D aims to reduce the eye shaking (oscillations) which in turn tends to improve visual acuity.
## Surgery and Device Based Therapy
- Otolith repositioning maneuvers
- Refractive lenses to treat amblyopia | https://www.wikidoc.org/index.php/Ddx:Nystagmus | |
697636176dab6759926d5af13cd394de8076e130 | wikidoc | Phosphate | Phosphate
# Overview
A phosphate, in inorganic chemistry, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Phosphates are important in biochemistry and biogeochemistry or ecology.
# Chemical properties
The phosphate ion is a polyatomic ion with the empirical formula PO43− and a molar mass of 94.97 g/mol; it consists of one central phosphorus atom surrounded by four identical oxygen atoms in a tetrahedral arrangement. The phosphate ion carries a negative three formal charge and is the conjugate base of the hydrogenphosphate ion, HPO42−, which is the conjugate base of H2PO4−, the dihydrogen phosphate ion, which in turn is the conjugate base of H3PO4, phosphoric acid. It is a hypervalent molecule (the phosphorus atom has 10 electrons in its valence shell). Phosphate is also an organophosphorus compound with the formula OP(OR)3.
A phosphate salt forms when a positively charged ion attaches to the negatively charged oxygen atoms of the ion, forming an ionic compound. Many phosphates are insoluble in water at standard temperature and pressure, except for the alkali metal salts.
In dilute aqueous solution, phosphate exists in four forms. In strongly basic conditions, the phosphate ion (PO43−) predominates, while in weakly basic conditions, the hydrogen phosphate ion (HPO42−) is prevalent. In weakly acid conditions, the dihydrogen phosphate ion (H2PO4−) is most common. In strongly acid conditions, aqueous phosphoric acid (H3PO4) is the main form.
- H3PO4
- H2PO4−
- HPO42−
- PO43−
More precisely, considering the following three equilibrium reactions:
the corresponding constants at 25°C (in mol/L) are (see phosphoric acid):
K_{a1}=\frac{}{}\simeq 7.5\times10^{-3}
K_{a2}=\frac{}{}\simeq 6.2\times10^{-8}
K_{a3}=\frac{}{}\simeq 2.14\times10^{-13}
For a strongly basic pH (pH=13), we find
\frac{}{}\simeq 7.5\times10^{10} \mbox{ , }\frac{}{}\simeq 6.2\times10^5 \mbox{ , } \frac{}{}\simeq 2.14
showing that only PO43− and HPO42− are in significant amounts.
For a neutral pH (for example the cytosol pH=7.0), we find
\frac{}{}\simeq 7.5\times10^4 \mbox{ , }\frac{}{}\simeq 0.62 \mbox{ , } \frac{}{}\simeq 2.14\times10^{-6}
so that only H2PO4− and HPO42− ions are in significant amounts (62% H2PO4−, 38% HPO42−). Note that in the extracellular fluid (pH=7.4), this proportion is inverted (61% HPO42−, 39% H2PO4−).
For a strongly acid pH (pH=1), we find
\frac{}{}\simeq 0.075 \mbox{ , }\frac{}{}\simeq 6.2\times10^{-7} \mbox{ , } \frac{}{}\simeq 2.14\times10^{-12}
showing that H3PO4 is dominant with respect to H2PO4−. HPO42− and PO43− are practically absent.
Phosphate can form many polymeric ions, diphosphate (also pyrophosphate), P2O74−, triphosphate, P3O105−, et cetera. The various metaphosphate ions have an empirical formula of PO3− and are found in many compounds.
Phosphate deposits can contain significant amounts of naturally occurring uranium. Subsequent uptake of such soil amendments can lead to crops containing uranium concentrations.
# Occurrence
Elemental phosphorus and phosphides are not found (rare phosphide minerals may be found in meteorites).
## Geochemistry
Phosphates are the naturally occurring form of the element phosphorus, found in many phosphate minerals. In mineralogy and geology, phosphate refers to a rock or ore containing phosphate ions.
The largest rock phosphate deposits in North America lie in the Bone Valley region of central Florida, United States, the Soda Springs region of Idaho, and the coast of North Carolina. Smaller deposits are located in Montana, Tennessee, Georgia and South Carolina near Charleston along Ashley Phosphate road. The small island nation of Nauru and its neighbor Banaba Island, which used to have massive phosphate deposits of the best quality, have been mined excessively. Rock phosphate can also be found on Egypt, Israel, Morocco, Navassa Island, Tunisia, Togo and Jordan have large phosphate mining industries as well.
## Biochemistry
In biological systems, phosphorus is found as a free phosphate ion in solution and is called inorganic phosphate, to distinguish it from phosphates bound in various phosphate esters. Inorganic phosphate is generally denoted Pi and can be created by the hydrolysis of pyrophosphate, which is denoted PPi:
However, phosphates are most commonly found in the form of adenosine phosphates, (AMP, ADP and ATP) and in DNA and RNA and can be released by the hydrolysis of ATP or ADP. Similar reactions exist for the other nucleoside diphosphates and triphosphates. Phosphoanhydride bonds in ADP and ATP, or other nucleoside diphosphates and triphosphates, contain high amounts of energy which give them their vital role in all living organisms. They are generally referred to as high energy phosphate, as are the phosphagens in muscle tissue. Compounds such as substituted phosphines, have uses in organic chemistry but do not seem to have any natural counterparts.
## Ecology of phosphates
In ecological terms, because of its important role in biological systems, phosphate is a highly sought after resource. Consequently, it is often a limiting reagent in environments, and its availability may govern the rate of growth of organisms. Addition of high levels of phosphate to environments and to micro-environments in which it is typically rare can have significant ecological consequences. For example, booms in the populations of some organisms at the expense of others, and the collapse of populations deprived of resources such as oxygen (see eutrophication). In the context of pollution, phosphates are a principal component of total dissolved solids, a major indicator of water quality.
Calcium hydroxyapatite and calcite precipitates can be found around bacteria in alluvial topsoil. As clay minerals promote biomineralization, the presence of bacteria and clay minerals resulted in calcium hydroxyapatite and calcite precipitates.
Phosphate deposits can contain significant amounts of naturally occurring heavy metals such as uranium. Mining operations processing phosphate rock can leave tailings piles containing elevated levels of cadmium, lead, nickel, copper, chromium, and uranium. Unless carefully managed, these waste products can leach heavy metals into groundwater or nearby estuaries. Uptake of these substances by plants and marine life can lead to concentration of toxic heavy metals in food products.
# Uses
Phosphates were once commonly used in laundry detergent in the form trisodium phosphate (TSP), but because of algae boom-bust cycles tied to emission of phosphates into watersheds, phosphate detergent sale or usage is restricted in some areas.
In agriculture phosphate is one of the three primary plant nutrients, and it is a component of fertilizers. Rock phosphate is quarried from phosphate beds in sedimentary rocks. In former times it was simply crushed and used as is, but the crude form is now used only in organic farming. Normally it is chemically treated to make superphosphate, triple superphosphate, or ammonium phosphates, which have higher concentration of phosphate and are also more soluble, therefore more quickly usable by plants.
Fertilizer grades normally have three numbers; the first is the available nitrogen, the second is the available phosphate (expressed on a P2O5 basis), and the third is the available potash (expressed on a K2O basis). Thus a 10-10-10 fertilizer would contain ten percent of each, with the remainder being filler.
Surface runoff of phosphates from excessively fertilized farmland can be a cause of phosphate pollution leading to eutrophication (nutrient enrichment), algal bloom and consequent oxygen deficit. This can lead to anoxia for fish and other aquatic organisms in the same manner as phosphate-based detergents.
Phosphate compounds are occasionally added to the public drinking water supply to counter plumbosolvency.
The food industry uses phosphates to perform several different functions. For example, in meat products, it solubilizes the protein. This improves its water-holding ability and increases its moistness and succulence. In baked products, such as cookies and crackers, phosphate compounds can act as part of the leavening system when it reacts with an alkalai, usually sodium bicarbonate (baking soda). | Phosphate
Editor-In-Chief: Henry A. Hoff
# Overview
A phosphate, in inorganic chemistry, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Phosphates are important in biochemistry and biogeochemistry or ecology.
# Chemical properties
The phosphate ion is a polyatomic ion with the empirical formula PO43− and a molar mass of 94.97 g/mol; it consists of one central phosphorus atom surrounded by four identical oxygen atoms in a tetrahedral arrangement. The phosphate ion carries a negative three formal charge and is the conjugate base of the hydrogenphosphate ion, HPO42−, which is the conjugate base of H2PO4−, the dihydrogen phosphate ion, which in turn is the conjugate base of H3PO4, phosphoric acid. It is a hypervalent molecule (the phosphorus atom has 10 electrons in its valence shell). Phosphate is also an organophosphorus compound with the formula OP(OR)3.
A phosphate salt forms when a positively charged ion attaches to the negatively charged oxygen atoms of the ion, forming an ionic compound. Many phosphates are insoluble in water at standard temperature and pressure, except for the alkali metal salts.
In dilute aqueous solution, phosphate exists in four forms. In strongly basic conditions, the phosphate ion (PO43−) predominates, while in weakly basic conditions, the hydrogen phosphate ion (HPO42−) is prevalent. In weakly acid conditions, the dihydrogen phosphate ion (H2PO4−) is most common. In strongly acid conditions, aqueous phosphoric acid (H3PO4) is the main form.
- H3PO4
- H2PO4−
- HPO42−
- PO43−
More precisely, considering the following three equilibrium reactions:
the corresponding constants at 25°C (in mol/L) are (see phosphoric acid):
<math> K_{a1}=\frac{[\mbox{H}^+][\mbox{H}_2\mbox{PO}_4^-]}{[\mbox{H}_3\mbox{PO}_4]}\simeq 7.5\times10^{-3}</math>
<math>K_{a2}=\frac{[\mbox{H}^+][\mbox{HPO}_4^{2-}]}{[\mbox{H}_2\mbox{PO}_4^-]}\simeq 6.2\times10^{-8}</math>
<math> K_{a3}=\frac{[\mbox{H}^+][\mbox{PO}_4^{3-}]}{[\mbox{HPO}_4^{2-}]}\simeq 2.14\times10^{-13}</math>
For a strongly basic pH (pH=13), we find
<math>\frac{[\mbox{H}_2\mbox{PO}_4^-]}{[\mbox{H}_3\mbox{PO}_4]}\simeq 7.5\times10^{10} \mbox{ , }\frac{[\mbox{HPO}_4^{2-}]}{[\mbox{H}_2\mbox{PO}_4^-]}\simeq 6.2\times10^5 \mbox{ , } \frac{[\mbox{PO}_4^{3-}]}{[\mbox{HPO}_4^{2-}]}\simeq 2.14</math>
showing that only PO43− and HPO42− are in significant amounts.
For a neutral pH (for example the cytosol pH=7.0), we find
<math> \frac{[\mbox{H}_2\mbox{PO}_4^-]}{[\mbox{H}_3\mbox{PO}_4]}\simeq 7.5\times10^4 \mbox{ , }\frac{[\mbox{HPO}_4^{2-}]}{[\mbox{H}_2\mbox{PO}_4^-]}\simeq 0.62 \mbox{ , } \frac{[\mbox{PO}_4^{3-}]}{[\mbox{HPO}_4^{2-}]}\simeq 2.14\times10^{-6}</math>
so that only H2PO4− and HPO42− ions are in significant amounts (62% H2PO4−, 38% HPO42−). Note that in the extracellular fluid (pH=7.4), this proportion is inverted (61% HPO42−, 39% H2PO4−).
For a strongly acid pH (pH=1), we find
<math>\frac{[\mbox{H}_2\mbox{PO}_4^-]}{[\mbox{H}_3\mbox{PO}_4]}\simeq 0.075 \mbox{ , }\frac{[\mbox{HPO}_4^{2-}]}{[\mbox{H}_2\mbox{PO}_4^-]}\simeq 6.2\times10^{-7} \mbox{ , } \frac{[\mbox{PO}_4^{3-}]}{[\mbox{HPO}_4^{2-}]}\simeq 2.14\times10^{-12}</math>
showing that H3PO4 is dominant with respect to H2PO4−. HPO42− and PO43− are practically absent.
Phosphate can form many polymeric ions, diphosphate (also pyrophosphate), P2O74−, triphosphate, P3O105−, et cetera. The various metaphosphate ions have an empirical formula of PO3− and are found in many compounds.
Phosphate deposits can contain significant amounts of naturally occurring uranium. Subsequent uptake of such soil amendments can lead to crops containing uranium concentrations.
# Occurrence
Elemental phosphorus and phosphides are not found (rare phosphide minerals may be found in meteorites).
## Geochemistry
Phosphates are the naturally occurring form of the element phosphorus, found in many phosphate minerals. In mineralogy and geology, phosphate refers to a rock or ore containing phosphate ions.
The largest rock phosphate deposits in North America lie in the Bone Valley region of central Florida, United States, the Soda Springs region of Idaho, and the coast of North Carolina. Smaller deposits are located in Montana, Tennessee, Georgia and South Carolina near Charleston along Ashley Phosphate road. The small island nation of Nauru and its neighbor Banaba Island, which used to have massive phosphate deposits of the best quality, have been mined excessively. Rock phosphate can also be found on Egypt, Israel, Morocco, Navassa Island, Tunisia, Togo and Jordan have large phosphate mining industries as well.
## Biochemistry
In biological systems, phosphorus is found as a free phosphate ion in solution and is called inorganic phosphate, to distinguish it from phosphates bound in various phosphate esters. Inorganic phosphate is generally denoted Pi and can be created by the hydrolysis of pyrophosphate, which is denoted PPi:
However, phosphates are most commonly found in the form of adenosine phosphates, (AMP, ADP and ATP) and in DNA and RNA and can be released by the hydrolysis of ATP or ADP. Similar reactions exist for the other nucleoside diphosphates and triphosphates. Phosphoanhydride bonds in ADP and ATP, or other nucleoside diphosphates and triphosphates, contain high amounts of energy which give them their vital role in all living organisms. They are generally referred to as high energy phosphate, as are the phosphagens in muscle tissue. Compounds such as substituted phosphines, have uses in organic chemistry but do not seem to have any natural counterparts.
## Ecology of phosphates
In ecological terms, because of its important role in biological systems, phosphate is a highly sought after resource. Consequently, it is often a limiting reagent in environments, and its availability may govern the rate of growth of organisms. Addition of high levels of phosphate to environments and to micro-environments in which it is typically rare can have significant ecological consequences. For example, booms in the populations of some organisms at the expense of others, and the collapse of populations deprived of resources such as oxygen (see eutrophication). In the context of pollution, phosphates are a principal component of total dissolved solids, a major indicator of water quality.
Calcium hydroxyapatite and calcite precipitates can be found around bacteria in alluvial topsoil.[2] As clay minerals promote biomineralization, the presence of bacteria and clay minerals resulted in calcium hydroxyapatite and calcite precipitates.[2]
Phosphate deposits can contain significant amounts of naturally occurring heavy metals such as uranium. Mining operations processing phosphate rock can leave tailings piles containing elevated levels of cadmium, lead, nickel, copper, chromium, and uranium. Unless carefully managed, these waste products can leach heavy metals into groundwater or nearby estuaries. Uptake of these substances by plants and marine life can lead to concentration of toxic heavy metals in food products.[3]
# Uses
Phosphates were once commonly used in laundry detergent in the form trisodium phosphate (TSP), but because of algae boom-bust cycles tied to emission of phosphates into watersheds, phosphate detergent sale or usage is restricted in some areas.
In agriculture phosphate is one of the three primary plant nutrients, and it is a component of fertilizers. Rock phosphate is quarried from phosphate beds in sedimentary rocks. In former times it was simply crushed and used as is, but the crude form is now used only in organic farming. Normally it is chemically treated to make superphosphate, triple superphosphate, or ammonium phosphates, which have higher concentration of phosphate and are also more soluble, therefore more quickly usable by plants.
Fertilizer grades normally have three numbers; the first is the available nitrogen, the second is the available phosphate (expressed on a P2O5 basis), and the third is the available potash (expressed on a K2O basis). Thus a 10-10-10 fertilizer would contain ten percent of each, with the remainder being filler.
Surface runoff of phosphates from excessively fertilized farmland can be a cause of phosphate pollution leading to eutrophication (nutrient enrichment), algal bloom and consequent oxygen deficit. This can lead to anoxia for fish and other aquatic organisms in the same manner as phosphate-based detergents.
Phosphate compounds are occasionally added to the public drinking water supply to counter plumbosolvency.
The food industry uses phosphates to perform several different functions. For example, in meat products, it solubilizes the protein. This improves its water-holding ability and increases its moistness and succulence. In baked products, such as cookies and crackers, phosphate compounds can act as part of the leavening system when it reacts with an alkalai, usually sodium bicarbonate (baking soda).[4][5] | https://www.wikidoc.org/index.php/Ddx:Phosphate | |
005b36dd76ea449dee8806a4a054ed7598a68c36 | wikidoc | Prolactin | Prolactin
Prolactin (PRL), also known as luteotropic hormone or luteotropin, is a protein that is best known for its role in enabling mammals, usually females, to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pituitary gland in response to eating, mating, estrogen treatment, ovulation and nursing. Prolactin is secreted in pulses in between these events. Prolactin plays an essential role in metabolism, regulation of the immune system and pancreatic development.
Discovered in non-human animals around 1930 by Oscar Riddle and confirmed in humans in 1970 by Henry Friesen prolactin is a peptide hormone, encoded by the PRL gene.
In mammals, prolactin is associated with milk production; in fish it is thought to be related to the control of water and salt balance. Prolactin also acts in a cytokine-like manner and as an important regulator of the immune system. It has important cell cycle-related functions as a growth-, differentiating- and anti-apoptotic factor. As a growth factor, binding to cytokine-like receptors, it influences hematopoiesis, angiogenesis and is involved in the regulation of blood clotting through several pathways. The hormone acts in endocrine, autocrine and paracrine manner through the prolactin receptor and a large number of cytokine receptors.
Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus. The most important of these are the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus that secrete dopamine (aka Prolactin Inhibitory Hormone) to act on the D2 receptors of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing factor (thyrotropin-releasing hormone) has a stimulatory effect on prolactin release, however prolactin is the only adenohypophyseal hormone whose principal control is inhibitory.
Several variants and forms are known per species. Many fish have variants prolactin A and prolactin B. Most vertebrates including humans also have the closely related somatolactin. In humans, three smaller (4, 16 and 22 kDa) and several larger (so called big and big-big) variants exist.
# Functions
Prolactin has a wide variety of effects. It stimulates the mammary glands to produce milk (lactation): increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands and prepare for milk production, which normally starts when levels of progesterone fall by the end of pregnancy and a suckling stimulus is present. Prolactin plays an important role in maternal behavior.
The hormone counteracts the effect of dopamine.
Elevated levels of prolactin decrease the levels of sex hormones — estrogen in women and testosterone in men. The effects of mildly elevated levels of prolactin are much more variable, in women, substantially increasing or decreasing estrogen levels.
Prolactin is sometimes classified as a gonadotropin although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important. Prolactin within the normal reference ranges can act as a weak gonadotropin, but at the same time suppresses GnRH secretion. The exact mechanism by which it inhibits GnRH is poorly understood. Although expression of prolactin receptors (PRL-R) have been demonstrated in rat hypothalamus, the same has not been observed in GnRH neurons. Physiologic levels of prolactin in males enhance luteinizing hormone-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis.
Prolactin also stimulates proliferation of oligodendrocyte precursor cells. These cells differentiate into oligodendrocytes, the cells responsible for the formation of myelin coatings on axons in the central nervous system.
Other actions include contributing to pulmonary surfactant synthesis of the fetal lungs at the end of the pregnancy and immune tolerance of the fetus by the maternal organism during pregnancy. Prolactin promotes neurogenesis in maternal and fetal brains.
## Functions in other vertebrate species
The primary function of prolactin in fish is osmoregulation, i.e., controlling the movement of water and salts between the tissues of the fish and the surrounding water. Like mammals, however, prolactin in fish also has reproductive functions, including promoting sexual maturation and inducing breeding cycles, as well as brooding and parental care. In the South American discus, prolactin may also regulate the production of a skin secretion that provides food for larval fry. An increase in brooding behaviour caused by prolactin has been reported in hens.
Prolactin and its receptor are expressed in the skin, specifically in the hair follicles, where they regulate hair growth and moulting in an autocrine fashion. Elevated levels of prolactin can inhibit hair growth, and knock-out mutations in the prolactin gene cause increased hair length in cattle and mice. Conversely, mutations in the prolactin receptor can cause reduced hair growth, resulting in the "slick" phenotype in cattle. Additionally, prolactin delays hair regrowth in mice.
Analogous to its effects on hair growth and shedding in mammals, prolactin in birds controls the moulting of feathers, as well as the age at onset of feathering in both turkeys and chickens.
# Regulation
In humans, prolactin is produced at least in the anterior pituitary, decidua, myometrium, breast, lymphocytes, leukocytes and prostate.
Pituitary PRL is controlled by the Pit-1 transcription factor that binds to the prolactin gene at several sites. Ultimately dopamine, extrapituitary PRL is controlled by a superdistal promoter and apparently unaffected by dopamine. The thyrotropin-releasing hormone and the vasoactive intestinal peptide stimulate the secretion of prolactin in experimental settings, however their physiological influence is unclear. The main stimulus for prolactin secretion is suckling, the effect of which is neuronally mediated. A key regulator of prolactin production is estrogens that enhance growth of prolactin-producing cells and stimulate prolactin production directly, as well as suppressing dopamine.
In decidual cells and in lymphocytes the distal promoter and thus prolactin expression is stimulated by cAMP. Responsivness to cAMP is mediated by an imperfect cAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP). Progesterone upregulates prolactin synthesis in the endometrium and decreases it in myometrium and breast glandular tissue. Breast and other tissues may express the Pit-1 promoter in addition to the distal promoter.
Extrapituitary production of prolactin is thought to be special to humans and primates and may serve mostly tissue-specific paracrine and autocrine purposes. It has been hypothesized that in vertebrates such as mice a similar tissue-specific effect is achieved by a large family of prolactin-like proteins controlled by at least 26 paralogous PRL genes not present in primates.
Vasoactive intestinal peptide and peptide histidine isoleucine help to regulate prolactin secretion in humans, but the functions of these hormones in birds can be quite different.
Prolactin follows diurnal and ovulatory cycles. Prolactin levels peak during REM sleep and in the early morning. Many mammals experience a seasonal cycle.
During pregnancy, high circulating concentrations of estrogen and progesterone increase prolactin levels by 10- to 20-fold. Estrogen and progesterone inhibit the stimulatory effects of prolactin on milk production. The abrupt drop of estrogen and progesterone levels following delivery allow prolactin—which temporarily remains high—to induce lactation.
Sucking on the nipple offsets the fall in prolactin as the internal stimulus for them is removed. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland increase prolactin secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milk-ejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed.
In usual circumstances, in the absence of galactorrhea, lactation ceases within one or two weeks following the end of breastfeeding.
Levels can rise after exercise, high-protein meals, minor surgical procedures, following epileptic seizures or due to physical or emotional stress. In a study on female volunteers under hypnosis, prolactin surges resulted from the evocation, with rage, of humiliating experiences, but not from the fantasy of nursing.
Prolactin levels have also been found to rise with use of the drug MDMA.
Hypersecretion is more common than hyposecretion. Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors, termed prolactinomas. Prolactinomas may disrupt the hypothalamic-pituitary-gonadal axis as prolactin tends to suppress the secretion of GnRH from the hypothalamus and in turn decreases the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, therefore disrupting the ovulatory cycle. Such hormonal changes may manifest as amenorrhea and infertility in females as well as impotence in males. Inappropriate lactation (galactorrhoea) is another important clinical sign of prolactinomas.
# Structure and isoforms
The structure of prolactin is similar to that of growth hormone and placental lactogen. The molecule is folded due to the activity of three disulfide bonds. Significant heterogeneity of the molecule has been described, thus bioassays and immunoassays can give different results due to differing glycosylation, phosphorylation and sulfation, as well as degradation. The non-glycosylated form of prolactin is the dominant form that is secreted by the pituitary gland.
The three different sizes of prolactin are:
- Little prolactin—the predominant form. It has a molecular weight of appxoximately 22-kDa. It is a single-chain polypeptide of 198 amino acids and is apparently the result of removal of some amino acids.
- Big prolactin—approximately 48 kDa. It may be the product of interaction of several prolactin molecules. It appears to have little, if any, biological activity.
- Big big prolactin—approximately 150 kDa. It appears to have a low biological activity.
The levels of larger ones are somewhat higher during the early postpartum period.
# Prolactin receptor
Prolactin receptors are present in the mammillary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the central nervous system. When prolactin binds to the receptor, it causes it to dimerize with another prolactin receptor. This results in the activation of Janus kinase 2, a tyrosine kinase that initiates the JAK-STAT pathway. Activation also results in the activation of mitogen-activated protein kinases and Src kinase.
Human prolactin receptors are insensitive to mouse prolactin.
# Diagnostic use
Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of FSH and GnRH, leading to hypogonadism and sometimes causing erectile dysfunction.
Prolactin levels may be of some use in distinguishing epileptic seizures from psychogenic non-epileptic seizures. The serum prolactin level usually rises following an epileptic seizure.
# Units and unit conversions
The serum concentration of prolactin can be given in mass concentration (µg/L or ng/mL), molar concentration (nmol/L or pmol/L) or in international units (typically mIU/L). The current IU is calibrated against the third International Standard for Prolactin, IS 84/500. Reference ampoules of IS 84/500 contain 2.5 µg of lyophilized human prolactin and have been assigned an activity of .053 International Units. Measurements that are calibrated against the current international standard can be converted into mass units using this ratio of grams to IUs; prolactin concentrations expressed in mIU/L can be converted to µg/L by dividing by 21.2. Previous standards use other ratios.
The first International Reference Preparation (or IRP) of human Prolactin for Immunoassay was established in 1978 (75/504 1st IRP for human Prolactin) at a time when purified human prolactin was in short supply. Previous standards relied on prolactin from animal sources. Purified human prolactin was scarce, heterogeneous, unstable and difficult to characterize. A preparation labelled 81/541 was distributed by the WHO Expert Committee on Biological Standardization without official status and given the assigned value of 50 mIU/ampoule based on an earlier collaborative study. It was determined that this preparation behaved anomalously in certain immunoassays and was not suitable as an IS.
Three different human pituitary extracts containing prolactin were subsequently obtained as candidates for an IS. These were distributed into ampoules coded 83/562, 83/573 and 84/500. Collaborative studies involving 20 different laboratories found little difference between these three preparations. 83/562 appeared to be the most stable. This preparation was largely free of dimers and polymers of prolactin. On the basis of these investigations 83/562 was established as the Second IS for human Prolactin. Once stocks of these ampoules were depleted, 84/500 was established as the Third IS for human Prolactin.
# Reference ranges
General guidelines for diagnosing prolactin excess (hyperprolactinemia) define the upper threshold of normal prolactin at 25 µg/L for women and 20 µg/L for men. Similarly, guidelines for diagnosing prolactin deficiency (hypoprolactinemia) are defined as prolactin levels below 3 µg/L in women and 5 µg/L in men. However, different assays and methods for measuring prolactin are employed by different laboratories and as such the serum reference range for prolactin is often determined by the laboratory performing the measurement. Furthermore, prolactin levels also vary factors including age, sex, menstrual cycle stage and pregnancy. The circumstances surrounding a given prolactin measurement (assay, patient condition, etc.) must therefore be considered before the measurement can be accurately interpreted.
The following chart illustrates the variations seen in normal prolactin measurements across different populations. Prolactin values were obtained from specific control groups of varying sizes using the IMMULITE assay.
## Inter-method variability
The following table illustrates variability in reference ranges of serum prolactin between some commonly used assay methods (as of 2008), using a control group of healthy health care professionals (53 males, age 20–64 years, median 28 years; 97 females, age 19–59 years, median 29 years) in Essex, England:
An example usage of table above is, if using the Centaur assay to estimate prolactin values in µg/L for females, the mean is 7.92 µg/L and the reference range is 3.35–16.4 µg/L.
# Conditions
## Elevated levels
Hyperprolactinaemia, or excess serum prolactin, is associated with hypoestrogenism, anovulatory infertility, oligomenorrhoea, amenorrhoea, unexpected lactation and loss of libido in women and erectile dysfunction and loss of libido in men.
## Decreased levels
Hypoprolactinemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women, and arteriogenic erectile dysfunction, premature ejaculation, oligozoospermia, asthenospermia, hypofunction of seminal vesicles and hypoandrogenism in men. In one study, normal sperm characteristics were restored when prolactin levels were raised to normal values in hypoprolactinemic men.
Hypoprolactinemia can result from hypopituitarism, excessive dopaminergic action in the tuberoinfundibular pathway and ingestion of D2 receptor agonists such as bromocriptine.
While there is evidence that women who smoke tend to breast feed for shorter periods, there is a wide variation of breast-feeding rates in women who do smoke. This suggest that psychosocial factors rather than physiological mechanisms (e.g., nicotine suppressing prolactin levels) are responsible for the lower rates of breast feeding in women who do smoke.
# In medicine
Prolactin is available commercially for use in animals, but not in humans. It is used to stimulate lactation in animals. The biological half-life of prolactin in humans is around 15–20 minutes. The D2 receptor is involved in the regulation of prolactin secretion, and agonists of the receptor such as bromocriptine and cabergoline decrease prolactin levels while antagonists of the receptor such as domperidone, metoclopramide, haloperidol, risperidone, and sulpiride increase prolactin levels. D2 receptor antagonists like domperidone, metoclopramide, and sulpiride are used as galactogogues to increase prolatin secretion in pituitary gland and induce lactation in humans. | Prolactin
Prolactin (PRL), also known as luteotropic hormone or luteotropin, is a protein that is best known for its role in enabling mammals, usually females, to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans.[1] Prolactin is secreted from the pituitary gland in response to eating, mating, estrogen treatment, ovulation and nursing. Prolactin is secreted in pulses in between these events. Prolactin plays an essential role in metabolism, regulation of the immune system and pancreatic development.
Discovered in non-human animals around 1930 by Oscar Riddle[2] and confirmed in humans in 1970 by Henry Friesen[3] prolactin is a peptide hormone, encoded by the PRL gene.[4]
In mammals, prolactin is associated with milk production; in fish it is thought to be related to the control of water and salt balance. Prolactin also acts in a cytokine-like manner and as an important regulator of the immune system. It has important cell cycle-related functions as a growth-, differentiating- and anti-apoptotic factor. As a growth factor, binding to cytokine-like receptors, it influences hematopoiesis, angiogenesis and is involved in the regulation of blood clotting through several pathways. The hormone acts in endocrine, autocrine and paracrine manner through the prolactin receptor and a large number of cytokine receptors.[1]
Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus. The most important of these are the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus that secrete dopamine (aka Prolactin Inhibitory Hormone) to act on the D2 receptors of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing factor (thyrotropin-releasing hormone) has a stimulatory effect on prolactin release, however prolactin is the only adenohypophyseal hormone whose principal control is inhibitory.
Several variants and forms are known per species. Many fish have variants prolactin A and prolactin B. Most vertebrates including humans also have the closely related somatolactin. In humans, three smaller (4, 16 and 22 kDa) and several larger (so called big and big-big) variants exist.[not verified in body]
# Functions
Prolactin has a wide variety of effects. It stimulates the mammary glands to produce milk (lactation): increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands and prepare for milk production, which normally starts when levels of progesterone fall by the end of pregnancy and a suckling stimulus is present. Prolactin plays an important role in maternal behavior.[5]
The hormone counteracts the effect of dopamine.[citation needed]
Elevated levels of prolactin decrease the levels of sex hormones — estrogen in women and testosterone in men.[6] The effects of mildly elevated levels of prolactin are much more variable, in women, substantially increasing or decreasing estrogen levels.
Prolactin is sometimes classified as a gonadotropin[7] although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important.[8] Prolactin within the normal reference ranges can act as a weak gonadotropin, but at the same time suppresses GnRH secretion. The exact mechanism by which it inhibits GnRH is poorly understood. Although expression of prolactin receptors (PRL-R) have been demonstrated in rat hypothalamus, the same has not been observed in GnRH neurons.[9] Physiologic levels of prolactin in males enhance luteinizing hormone-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis.[10]
Prolactin also stimulates proliferation of oligodendrocyte precursor cells. These cells differentiate into oligodendrocytes, the cells responsible for the formation of myelin coatings on axons in the central nervous system.[11]
Other actions include contributing to pulmonary surfactant synthesis of the fetal lungs at the end of the pregnancy and immune tolerance of the fetus by the maternal organism during pregnancy. Prolactin promotes neurogenesis in maternal and fetal brains.[12][13]
## Functions in other vertebrate species
The primary function of prolactin in fish is osmoregulation[14], i.e., controlling the movement of water and salts between the tissues of the fish and the surrounding water. Like mammals, however, prolactin in fish also has reproductive functions, including promoting sexual maturation and inducing breeding cycles, as well as brooding and parental care.[15] In the South American discus, prolactin may also regulate the production of a skin secretion that provides food for larval fry.[16] An increase in brooding behaviour caused by prolactin has been reported in hens.[17]
Prolactin and its receptor are expressed in the skin, specifically in the hair follicles, where they regulate hair growth and moulting in an autocrine fashion.[18][19] Elevated levels of prolactin can inhibit hair growth[20], and knock-out mutations in the prolactin gene cause increased hair length in cattle[21] and mice.[19] Conversely, mutations in the prolactin receptor can cause reduced hair growth, resulting in the "slick" phenotype in cattle.[21][22] Additionally, prolactin delays hair regrowth in mice.[23]
Analogous to its effects on hair growth and shedding in mammals, prolactin in birds controls the moulting of feathers,[24] as well as the age at onset of feathering in both turkeys and chickens.[25]
# Regulation
In humans, prolactin is produced at least in the anterior pituitary, decidua, myometrium, breast, lymphocytes, leukocytes and prostate.[26][27]
Pituitary PRL is controlled by the Pit-1 transcription factor that binds to the prolactin gene at several sites. Ultimately dopamine, extrapituitary PRL is controlled by a superdistal promoter and apparently unaffected by dopamine.[27] The thyrotropin-releasing hormone and the vasoactive intestinal peptide stimulate the secretion of prolactin in experimental settings, however their physiological influence is unclear. The main stimulus for prolactin secretion is suckling, the effect of which is neuronally mediated.[28] A key regulator of prolactin production is estrogens that enhance growth of prolactin-producing cells and stimulate prolactin production directly, as well as suppressing dopamine.
In decidual cells and in lymphocytes the distal promoter and thus prolactin expression is stimulated by cAMP. Responsivness to cAMP is mediated by an imperfect cAMP–responsive element and two CAAT/enhancer binding proteins (C/EBP).[27] Progesterone upregulates prolactin synthesis in the endometrium and decreases it in myometrium and breast glandular tissue.[29] Breast and other tissues may express the Pit-1 promoter in addition to the distal promoter.
Extrapituitary production of prolactin is thought to be special to humans and primates and may serve mostly tissue-specific paracrine and autocrine purposes. It has been hypothesized that in vertebrates such as mice a similar tissue-specific effect is achieved by a large family of prolactin-like proteins controlled by at least 26 paralogous PRL genes not present in primates.[27]
Vasoactive intestinal peptide and peptide histidine isoleucine help to regulate prolactin secretion in humans, but the functions of these hormones in birds can be quite different.[30]
Prolactin follows diurnal and ovulatory cycles. Prolactin levels peak during REM sleep and in the early morning. Many mammals experience a seasonal cycle.
During pregnancy, high circulating concentrations of estrogen and progesterone increase prolactin levels by 10- to 20-fold. Estrogen and progesterone inhibit the stimulatory effects of prolactin on milk production. The abrupt drop of estrogen and progesterone levels following delivery allow prolactin—which temporarily remains high—to induce lactation.[verification needed]
Sucking on the nipple offsets the fall in prolactin as the internal stimulus for them is removed. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland increase prolactin secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milk-ejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed.
In usual circumstances, in the absence of galactorrhea, lactation ceases within one or two weeks following the end of breastfeeding.
Levels can rise after exercise, high-protein meals, minor surgical procedures,[31] following epileptic seizures[32] or due to physical or emotional stress.[33][34] In a study on female volunteers under hypnosis, prolactin surges resulted from the evocation, with rage, of humiliating experiences, but not from the fantasy of nursing.[34]
Prolactin levels have also been found to rise with use of the drug MDMA.[35]
Hypersecretion is more common than hyposecretion. Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors, termed prolactinomas. Prolactinomas may disrupt the hypothalamic-pituitary-gonadal axis as prolactin tends to suppress the secretion of GnRH from the hypothalamus and in turn decreases the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, therefore disrupting the ovulatory cycle.[36] Such hormonal changes may manifest as amenorrhea and infertility in females as well as impotence in males. Inappropriate lactation (galactorrhoea) is another important clinical sign of prolactinomas.
# Structure and isoforms
The structure of prolactin is similar to that of growth hormone and placental lactogen. The molecule is folded due to the activity of three disulfide bonds. Significant heterogeneity of the molecule has been described, thus bioassays and immunoassays can give different results due to differing glycosylation, phosphorylation and sulfation, as well as degradation. The non-glycosylated form of prolactin is the dominant form that is secreted by the pituitary gland.
The three different sizes of prolactin are:
- Little prolactin—the predominant form.[37] It has a molecular weight of appxoximately 22-kDa.[37] It is a single-chain polypeptide of 198 amino acids and is apparently the result of removal of some amino acids.
- Big prolactin—approximately 48 kDa.[37] It may be the product of interaction of several prolactin molecules. It appears to have little, if any, biological activity.[38]
- Big big prolactin—approximately 150 kDa.[37] It appears to have a low biological activity.[39]
The levels of larger ones are somewhat higher during the early postpartum period.[40]
# Prolactin receptor
Prolactin receptors are present in the mammillary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the central nervous system.[41] When prolactin binds to the receptor, it causes it to dimerize with another prolactin receptor. This results in the activation of Janus kinase 2, a tyrosine kinase that initiates the JAK-STAT pathway. Activation also results in the activation of mitogen-activated protein kinases and Src kinase.[41]
Human prolactin receptors are insensitive to mouse prolactin.[42]
# Diagnostic use
Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of FSH and GnRH, leading to hypogonadism and sometimes causing erectile dysfunction.
Prolactin levels may be of some use in distinguishing epileptic seizures from psychogenic non-epileptic seizures. The serum prolactin level usually rises following an epileptic seizure.[43]
# Units and unit conversions
The serum concentration of prolactin can be given in mass concentration (µg/L or ng/mL), molar concentration (nmol/L or pmol/L) or in international units (typically mIU/L). The current IU is calibrated against the third International Standard for Prolactin, IS 84/500.[44][45] Reference ampoules of IS 84/500 contain 2.5 µg of lyophilized human prolactin[46] and have been assigned an activity of .053 International Units.[44][45] Measurements that are calibrated against the current international standard can be converted into mass units using this ratio of grams to IUs;[47] prolactin concentrations expressed in mIU/L can be converted to µg/L by dividing by 21.2. Previous standards use other ratios.[48][49][50][51]
The first International Reference Preparation (or IRP) of human Prolactin for Immunoassay was established in 1978 (75/504 1st IRP for human Prolactin) at a time when purified human prolactin was in short supply.[47][48] Previous standards relied on prolactin from animal sources.[51] Purified human prolactin was scarce, heterogeneous, unstable and difficult to characterize. A preparation labelled 81/541 was distributed by the WHO Expert Committee on Biological Standardization without official status and given the assigned value of 50 mIU/ampoule based on an earlier collaborative study.[47][49] It was determined that this preparation behaved anomalously in certain immunoassays and was not suitable as an IS.[47]
Three different human pituitary extracts containing prolactin were subsequently obtained as candidates for an IS. These were distributed into ampoules coded 83/562, 83/573 and 84/500.[44][45][47][50] Collaborative studies involving 20 different laboratories found little difference between these three preparations. 83/562 appeared to be the most stable. This preparation was largely free of dimers and polymers of prolactin. On the basis of these investigations 83/562 was established as the Second IS for human Prolactin.[50] Once stocks of these ampoules were depleted, 84/500 was established as the Third IS for human Prolactin.[44][47]
# Reference ranges
General guidelines for diagnosing prolactin excess (hyperprolactinemia) define the upper threshold of normal prolactin at 25 µg/L for women and 20 µg/L for men.[41] Similarly, guidelines for diagnosing prolactin deficiency (hypoprolactinemia) are defined as prolactin levels below 3 µg/L in women[52][53] and 5 µg/L in men.[54][55][56] However, different assays and methods for measuring prolactin are employed by different laboratories and as such the serum reference range for prolactin is often determined by the laboratory performing the measurement.[41][57] Furthermore, prolactin levels also vary factors including age,[58] sex,[58] menstrual cycle stage[58] and pregnancy.[58] The circumstances surrounding a given prolactin measurement (assay, patient condition, etc.) must therefore be considered before the measurement can be accurately interpreted.[41]
The following chart illustrates the variations seen in normal prolactin measurements across different populations. Prolactin values were obtained from specific control groups of varying sizes using the IMMULITE assay.[58]
## Inter-method variability
The following table illustrates variability in reference ranges of serum prolactin between some commonly used assay methods (as of 2008), using a control group of healthy health care professionals (53 males, age 20–64 years, median 28 years; 97 females, age 19–59 years, median 29 years) in Essex, England:[57]
An example usage of table above is, if using the Centaur assay to estimate prolactin values in µg/L for females, the mean is 7.92 µg/L and the reference range is 3.35–16.4 µg/L.
# Conditions
## Elevated levels
Hyperprolactinaemia, or excess serum prolactin, is associated with hypoestrogenism, anovulatory infertility, oligomenorrhoea, amenorrhoea, unexpected lactation and loss of libido in women and erectile dysfunction and loss of libido in men.[60]
## Decreased levels
Hypoprolactinemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women,[52][53] and arteriogenic erectile dysfunction, premature ejaculation,[54] oligozoospermia, asthenospermia, hypofunction of seminal vesicles and hypoandrogenism[55] in men. In one study, normal sperm characteristics were restored when prolactin levels were raised to normal values in hypoprolactinemic men.[56]
Hypoprolactinemia can result from hypopituitarism, excessive dopaminergic action in the tuberoinfundibular pathway and ingestion of D2 receptor agonists such as bromocriptine.
While there is evidence that women who smoke tend to breast feed for shorter periods, there is a wide variation of breast-feeding rates in women who do smoke. This suggest that psychosocial factors rather than physiological mechanisms (e.g., nicotine suppressing prolactin levels) are responsible for the lower rates of breast feeding in women who do smoke.[61][62]
# In medicine
Prolactin is available commercially for use in animals, but not in humans.[63] It is used to stimulate lactation in animals.[63] The biological half-life of prolactin in humans is around 15–20 minutes.[64] The D2 receptor is involved in the regulation of prolactin secretion, and agonists of the receptor such as bromocriptine and cabergoline decrease prolactin levels while antagonists of the receptor such as domperidone, metoclopramide, haloperidol, risperidone, and sulpiride increase prolactin levels.[65] D2 receptor antagonists like domperidone, metoclopramide, and sulpiride are used as galactogogues to increase prolatin secretion in pituitary gland and induce lactation in humans.[66] | https://www.wikidoc.org/index.php/Ddx:Prolactin | |
3815f04307dd8028bbef1b48710f8fe40298bc98 | wikidoc | Toothache | Toothache
Irritation at the nerve root of a tooth is characterized as toothache. Dental pain is caused primarily by injury, decay, infection or tooth loss. Pain that is believed to be in the tooth could actually be from the temporomandibular joint, cardiac or ear problems.
# Diagnosis
# Physical Examination
- Tooth mobility
- using the back ends of two mouth mirrors, test the tooth’s mobility
## Other (Teeth)
- mobility tests
- percussion
- electric pulp tests
- thermal tests
## Chest X Ray
- test for sinusitis
## Other Imaging Findings
- Transillumination can be used to show fractures in tooth structure
- Dental radiographs
# Differential Diagnosis of Causes of Toothache
In alphabetical order.
- Angina Pectoris
- Barodontalgia from high altitudes
- "Dental Migrane"
- Dry Socket (osteitis)
- Headache
- Otitis Media and /or mastoiditis
- Periradicular or periapical pain
- Pulpaglia
- Salivary gland disorders
- Sinusitis
- Temporomadibular Joint Syndrome pain (TMJ)
- Traumatic occlusion
- Traumatic tooth injury
- Trigeminal neuralgia
# Treatment
## Acute Pharmacotherapies
- Penicillin for infections
- other oral antibiotics for sinusitis
- Pain relief for migranes/migrane specific medications
# Surgery and Device Based Therapy
## Abscess
- incision and drainage will relieve pain immediately
## Irreversible pulpitis
- root canal/tooth extraction
## Reversible pulpitis
- filling or crown
# Primary Prevention
## TMJ
- avoid to gum disorders and bruxing use a bite blocker
## Brush and floss teeth | Toothache
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Irritation at the nerve root of a tooth is characterized as toothache. Dental pain is caused primarily by injury, decay, infection or tooth loss. Pain that is believed to be in the tooth could actually be from the temporomandibular joint, cardiac or ear problems.
# Diagnosis
# Physical Examination
- Tooth mobility
- using the back ends of two mouth mirrors, test the tooth’s mobility
## Other (Teeth)
- mobility tests
- percussion
- electric pulp tests
- thermal tests
## Chest X Ray
- test for sinusitis
## Other Imaging Findings
- Transillumination can be used to show fractures in tooth structure
- Dental radiographs
# Differential Diagnosis of Causes of Toothache
In alphabetical order. [1] [2]
- Angina Pectoris
- Barodontalgia from high altitudes
- "Dental Migrane"
- Dry Socket (osteitis)
- Headache
- Otitis Media and /or mastoiditis
- Periradicular or periapical pain
- Pulpaglia
- Salivary gland disorders
- Sinusitis
- Temporomadibular Joint Syndrome pain (TMJ)
- Traumatic occlusion
- Traumatic tooth injury
- Trigeminal neuralgia
# Treatment
## Acute Pharmacotherapies
- Penicillin for infections
- other oral antibiotics for sinusitis
- Pain relief for migranes/migrane specific medications
# Surgery and Device Based Therapy
## Abscess
- incision and drainage will relieve pain immediately
## Irreversible pulpitis
- root canal/tooth extraction
## Reversible pulpitis
- filling or crown
# Primary Prevention
## TMJ
- avoid to gum disorders and bruxing use a bite blocker
## Brush and floss teeth
-
-
-
-
-
- | https://www.wikidoc.org/index.php/Ddx:Toothache | |
c4528fce1eca156e576b362fe2ea444707ccae14 | wikidoc | Deaf-mute | Deaf-mute
# Overview
Deaf-mute was a term historically used by hearing people to identify a person who was deaf and could not speak. In the past "deaf-mute" was socially acceptable, usually to describe deaf people who use a signed language, but is now considered offensive (similar to the way that "colored" was once used to describe African Americans but is now looked upon as derogatory). The preferred term today is simply "deaf". The term "deaf-mute" first appears in the Code of Hammurabi, an ancient set of laws from the near east, in 1700 BC. It is also referenced in ancient Greek writing of the 7th century BC. It continues to be used to refer to deaf people, mainly within a historical context, to indicate deaf people who cannot speak, or have some degree of speaking ability, but choose not to speak because of the negative or unwanted attention atypical voices sometimes attract.
Additionally, it is sometimes used to refer to other hearing people in jest, to chide, or to invoke an image of someone who refuses to employ common sense or who is unreliable. "Deaf and dumb," "semi-deaf" and "semi-mute" are other historic references to deaf people. Of these latter examples, only "deaf and dumb" prevails as a reference.
There are connotations of insensitivity to deaf people concerning these terms of reference and for this reason the prevailing terms are generally looked upon as insulting, inaccurate or socially and politically incorrect. From antiquity (as noted in the Code of Hammurabi) until recent (and less enlightened) times , the terms "deaf-mute" and "deaf and dumb" were even considered analogous to "idiot" by some hearing people.
In Europe and western society, most deaf people are taught to speak with varying outcomes of ability or degrees of fluency. The simple identity of "deaf" has been embraced by the community of signing deaf people since the foundations of public deaf education in the 18th century and remains the preferred term of reference or identity for many years.
# Deaf-muteness in art and literature
The phrase is used in the Catcher in the Rye to indicate someone who does not speak their mind, and hears nothing, in effect becoming isolated from the world.
Chief Bromden, in One Flew Over the Cuckoo's Nest, is believed by all to be deaf-mute, but in fact he can hear and speak; he does not let anyone know this because, as he grew up, he was not spoken to (making him "deaf") and ignored (making him "mute").
In the film Babel, the character Chieko Wataya, played by Rinko Kikuchi, is a deaf teenaged girl who is referred to several times in the English subtitles as being a deaf-mute (although it is unclear how accurately the subtitles translate the Japanese reference to the deaf character).
The character Singer in the novel The Heart Is a Lonely Hunter, written in 1940, is referred to as a deaf-mute multiple times.
de:Taubstummheit
it:Sordomuto | Deaf-mute
# Overview
Deaf-mute was a term historically used by hearing people to identify a person who was deaf and could not speak. In the past "deaf-mute" was socially acceptable, usually to describe deaf people who use a signed language, but is now considered offensive (similar to the way that "colored" was once used to describe African Americans but is now looked upon as derogatory). The preferred term today is simply "deaf". The term "deaf-mute" first appears in the Code of Hammurabi, an ancient set of laws from the near east, in 1700 BC. [1] It is also referenced in ancient Greek writing of the 7th century BC. It continues to be used to refer to deaf people, mainly within a historical context, to indicate deaf people who cannot speak, or have some degree of speaking ability, but choose not to speak because of the negative or unwanted attention atypical voices sometimes attract.
Additionally, it is sometimes used to refer to other hearing people in jest, to chide, or to invoke an image of someone who refuses to employ common sense or who is unreliable. "Deaf and dumb," "semi-deaf" and "semi-mute" are other historic references to deaf people. Of these latter examples, only "deaf and dumb" prevails as a reference.
There are connotations of insensitivity to deaf people concerning these terms of reference and for this reason the prevailing terms are generally looked upon as insulting, inaccurate or socially and politically incorrect.[2] From antiquity (as noted in the Code of Hammurabi) until recent (and less enlightened) times [3], the terms "deaf-mute" and "deaf and dumb" were even considered analogous to "idiot" by some hearing people.
In Europe and western society, most deaf people are taught to speak with varying outcomes of ability or degrees of fluency. The simple identity of "deaf" has been embraced by the community of signing deaf people since the foundations of public deaf education in the 18th century and remains the preferred term of reference or identity for many years.
# Deaf-muteness in art and literature
The phrase is used in the Catcher in the Rye to indicate someone who does not speak their mind, and hears nothing, in effect becoming isolated from the world.
Chief Bromden, in One Flew Over the Cuckoo's Nest, is believed by all to be deaf-mute, but in fact he can hear and speak; he does not let anyone know this because, as he grew up, he was not spoken to (making him "deaf") and ignored (making him "mute").
In the film Babel, the character Chieko Wataya, played by Rinko Kikuchi, is a deaf teenaged girl who is referred to several times in the English subtitles as being a deaf-mute (although it is unclear how accurately the subtitles translate the Japanese reference to the deaf character).
The character Singer in the novel The Heart Is a Lonely Hunter, written in 1940, is referred to as a deaf-mute multiple times.
de:Taubstummheit
it:Sordomuto
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Deaf-mute | |
f4b37cf02ae842d080a5e8ad7ff9a4daaa9bb080 | wikidoc | Dean Burk | Dean Burk
Dean Burk (March 21, 1904 - Oct. 6 1988) was a co-discoverer of biotin, medical researcher, and a cancer researcher at the Kaiser Wilhelm Institute and the National Cancer Institute .
He entered the University of California at Davis at the age of 15. A year later, he transferred to the University of California at Berkeley, where he received his B.S. in Entomology in 1923. Four years later he earned a Ph.D. in biochemistry. Burk joined the Department of Agriculture in 1929 working in the Fixed Nitrogen Research Laboratory.
In 1939, he joined the cancer institute as a senior chemist. He was head of the cytochemistry laboratory when he retired in 1974. He also taught biochemistry at the Cornell University medical school from 1939 to 1941. From he was a research master at George Washington University. Burk was a close friend and co-author of papers with Otto Heinrich Warburg.
For his work on photosynthesis, Burk received the Hillebrand Prize in 1952 and the Gerhard Domagk Prize in 1965 for his techniques to distinguish between a normal cell and one damaged by cancer. He was a co-developer of the prototype of the Magnetic Resonance Scanner and a co-discoverer of biotin.
After retiring form the NCI in 1974 he devoted himself to the study and discussion of fluoridation and alternative cancer treatments. A friend of Dean Burk has written that Dean Burk was responsible for convincing the government of the Netherlands to cease adding fluoride to its drinking water.
He published more than 250 scientific articles in his lifetime.
# Publications
- D Burk, H Lineweaver (1930) "The Influence of Fixed Nitrogen on Azobacter," Journal of Bacteriology, Apr;27(4):325-40.
- I Weisman, L. Bennett, L. Maxwell Sr., M. Woods, and D. Burk (1972)"Recognition of Cancer in vivo by Nuclear Magnetic Resonance", Science 178, 1288 - 1290
- J Yiamouyiannis, D Burk "Fluoridation and cancer, age-dependence of cancer mortality related to artificial fluoridation" Fluoride 1977
- Burk D, Schade AL. On respiratory impairment in cancer cells. Science. 1956 Aug 10;124(3215):270-2. | Dean Burk
Template:Infobox Person
Dean Burk (March 21, 1904 - Oct. 6 1988) was a co-discoverer of biotin, medical researcher, and a cancer researcher at the Kaiser Wilhelm Institute and the National Cancer Institute .
He entered the University of California at Davis at the age of 15. A year later, he transferred to the University of California at Berkeley, where he received his B.S. in Entomology in 1923. Four years later he earned a Ph.D. in biochemistry. Burk joined the Department of Agriculture in 1929 working in the Fixed Nitrogen Research Laboratory.
In 1939, he joined the cancer institute as a senior chemist. He was head of the cytochemistry laboratory when he retired in 1974. He also taught biochemistry at the Cornell University medical school from 1939 to 1941. From he was a research master at George Washington University. Burk was a close friend and co-author of papers with Otto Heinrich Warburg.[1]
For his work on photosynthesis, Burk received the Hillebrand Prize in 1952 and the Gerhard Domagk Prize in 1965 for his techniques to distinguish between a normal cell and one damaged by cancer. He was a co-developer of the prototype of the Magnetic Resonance Scanner and a co-discoverer of biotin.
After retiring form the NCI in 1974 he devoted himself to the study and discussion of fluoridation and alternative cancer treatments. A friend of Dean Burk has written that Dean Burk was responsible for convincing the government of the Netherlands to cease adding fluoride to its drinking water. [2]
He published more than 250 scientific articles in his lifetime.
# Publications
- D Burk, H Lineweaver (1930) "The Influence of Fixed Nitrogen on Azobacter," Journal of Bacteriology, Apr;27(4):325-40.
- I Weisman, L. Bennett, L. Maxwell Sr., M. Woods, and D. Burk (1972)"Recognition of Cancer in vivo by Nuclear Magnetic Resonance", Science 178, 1288 - 1290
- J Yiamouyiannis, D Burk "Fluoridation and cancer, age-dependence of cancer mortality related to artificial fluoridation" Fluoride 1977
- Burk D, Schade AL. On respiratory impairment in cancer cells. Science. 1956 Aug 10;124(3215):270-2. | https://www.wikidoc.org/index.php/Dean_Burk | |
3fb50d4eb654aa3ce016833770a5174b402d6d63 | wikidoc | Debulking | Debulking
# Overview
In interventional cardiology, the term debulking refers to the removal of plaque and thrombus from a blockage or lesion. Devices such as directional and rotational atherectomy are debulking devices.
Debulking is the surgical removal of part of a malignant tumour which cannot be completely excised, so as to enhance the effectiveness of radiation or chemotherapy. It is used only in specific malignancies, as generally partial removal of a tumor is not considered a worthwhile intervention. Ovarian carcinoma and some types of brain tumor are debulked prior to commencing radio- or chemotherapy. It is usually a long and often complicated procedure taking several hours or more to perform, depending on internal involvement and location.
Debulking is also known as cytoreduction surgery; "cytoreduction" refers to reducing the number of cancer cells. | Debulking
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
In interventional cardiology, the term debulking refers to the removal of plaque and thrombus from a blockage or lesion. Devices such as directional and rotational atherectomy are debulking devices.
Debulking is the surgical removal of part of a malignant tumour which cannot be completely excised, so as to enhance the effectiveness of radiation or chemotherapy. It is used only in specific malignancies, as generally partial removal of a tumor is not considered a worthwhile intervention. Ovarian carcinoma and some types of brain tumor are debulked prior to commencing radio- or chemotherapy. It is usually a long and often complicated procedure taking several hours or more to perform, depending on internal involvement and location.
Debulking is also known as cytoreduction surgery; "cytoreduction" refers to reducing the number of cancer cells.
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Debulking | |
efd66d7d63a2ff039e58fbd01745fa9c8a51ba3d | wikidoc | Decametre | Decametre
A decametre also dekametre (American spelling: dekameter, earlier decameter symbol dam) is a very rarely used unit of length in the metric system, equal to ten metres, the SI base unit of length. It can be written in scientific notation as 1 E+1 m (exponential notation) — meaning 10 × 1 m.
This measure is included mostly for completeness. One practical use of the decameter is for altitude of geopotential heights (circumscribing equal pressure) in meteorology. Interestingly, meteorologists also use another seldom encountered SI prefix: hecto- in hectopascal (hPa). The volumetric form (see below) cubic decametre is convenient for describing large volumes of water such as in rivers and lakes.
- For surface the square decametre (dam2) is a common unit, be it by the name are (a). The are is a measurement of area the size of 1 decametre by 1 decametre — the square decametre — 10 metres by 10 metres, equalling 100 square metres (100 m2).
- For volumes the cubic decametre (dam3) is also used, 10 m by 10 m by 10 m equalling 1,000 cubic metres (1,000 m3). | Decametre
Template:Unit of length
A decametre also dekametre (American spelling: dekameter, earlier decameter symbol dam) is a very rarely used unit of length in the metric system, equal to ten metres, the SI base unit of length. It can be written in scientific notation as 1 E+1 m (exponential notation) — meaning 10 × 1 m.
This measure is included mostly for completeness. One practical use of the decameter is for altitude of geopotential heights (circumscribing equal pressure) in meteorology. Interestingly, meteorologists also use another seldom encountered SI prefix: hecto- in hectopascal (hPa). The volumetric form (see below) cubic decametre is convenient for describing large volumes of water such as in rivers and lakes.
- For surface the square decametre (dam2) is a common unit, be it by the name are (a). The are is a measurement of area the size of 1 decametre by 1 decametre — the square decametre — 10 metres by 10 metres, equalling 100 square metres (100 m2).
- For volumes the cubic decametre (dam3) is also used, 10 m by 10 m by 10 m equalling 1,000 cubic metres (1,000 m3). | https://www.wikidoc.org/index.php/Decametre | |
18dc782d6b1fa45c411ffe8542347eda56950100 | wikidoc | Decoction | Decoction
A decoction is a method of extraction of herbal or plant material, which includes, but is not limited to: Stems, roots, bark, and rhizomes.
Some teas are decoctions. Likewise, the term is used colloquially in South India to refer to black coffee prepared by the traditional method. Decoctions, however, differ from most teas, infusions, or tisanes, in that decoctions are usually boiled.
Decoction mashing is the traditional method used in many German breweries. It was used out of necessity before the invention of thermometers allowed simpler step mashing. But the practice continues for many traditional beers because of the unique malty flavor it lends to the beer. This is the result of Maillard reactions while boiling part of the grain.
# Process
Decoction involves first mashing, and then boiled in water to extract oils, volatile organic compounds, and other chemical substances.
## In herbalism
In herbalism, decoctions are usually made to extract fluids from hard plant materials such as roots and bark. To achieve this, the plant material is is usually boiled for 8-10 minutes in water. It is then sifted. | Decoction
A decoction is a method of extraction of herbal or plant material, which includes, but is not limited to: Stems, roots, bark, and rhizomes.
Some teas are decoctions. Likewise, the term is used colloquially in South India to refer to black coffee prepared by the traditional method. Decoctions, however, differ from most teas, infusions, or tisanes, in that decoctions are usually boiled.
Decoction mashing is the traditional method used in many German breweries. It was used out of necessity before the invention of thermometers allowed simpler step mashing. But the practice continues for many traditional beers because of the unique malty flavor it lends to the beer. This is the result of Maillard reactions while boiling part of the grain.
# Process
Decoction involves first mashing, and then boiled in water to extract oils, volatile organic compounds, and other chemical substances.
## In herbalism
In herbalism, decoctions are usually made to extract fluids from hard plant materials such as roots and bark. To achieve this, the plant material is is usually boiled for 8-10 minutes in water. It is then sifted. | https://www.wikidoc.org/index.php/Decoction | |
f4363697211a706fb3242884f6dbadc8e3395449 | wikidoc | Deep vein | Deep vein
# Overview
Deep vein is a term used to describe a vein that is deep in the body. It is used to differentiate deep veins from veins which are close to the surface, also known as superficial veins.
Deep veins are almost always beside an artery with the same name (e.g. the femoral vein is beside the femoral artery). Collectively, they carry the vast majority of the blood. Occlusion of a deep vein can be life threatening and is most often caused by thrombosis. Occlusion of a deep vein by thrombosis is called deep vein thrombosis.
# Some named deep veins
- internal jugular vein
### Upper limb
- brachial vein
- radial vein
- ulnar vein
### Lower limb
- femoral vein, sometimes called the superficial femoral vein, which is a source of confusion.
- profunda femoris vein
- popliteal vein
- peroneal vein
- anterior tibial vein
- posterior tibial vein | Deep vein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Deep vein is a term used to describe a vein that is deep in the body. It is used to differentiate deep veins from veins which are close to the surface, also known as superficial veins.
Deep veins are almost always beside an artery with the same name (e.g. the femoral vein is beside the femoral artery). Collectively, they carry the vast majority of the blood. Occlusion of a deep vein can be life threatening and is most often caused by thrombosis. Occlusion of a deep vein by thrombosis is called deep vein thrombosis.
# Some named deep veins
- internal jugular vein
### Upper limb
- brachial vein
- radial vein
- ulnar vein
### Lower limb
- femoral vein, sometimes called the superficial femoral vein, which is a source of confusion.
- profunda femoris vein
- popliteal vein
- peroneal vein
- anterior tibial vein
- posterior tibial vein | https://www.wikidoc.org/index.php/Deep_vein | |
902e62eeda82e34ea3f54ebc40c1bb3cf6bbe3af | wikidoc | Deformity | Deformity
A deformity, dysmorphism, or dysmorphic feature is a major difference in the shape of the body a body part, or a body organ (internal or external) compared to the average shape for the part in question.
Deformity may arise from numerous causes:
- A genetic mutation
- Damage to the fetus or uterus
- Complications at birth
- A growth or hormone disorder
- Reconstructive surgery following a severe injury e.g. burn injury.
- Arthritis and other rheumatoid disorders
Irish Mythology includes the Fomorians, who are almost without exception described as being deformed, possessing only one of what most have two of (eyes, arms, legs, etc.) or having larger than normal limbs. Other mythological creatures may have been created due to a deformative syndrome also, for instance, descriptions of mermaids may be related to the symptoms of sirenomelia.
Deformity can occur in non-humans, as well. Frogs can be mutated due to Ribeiroia (Trematoda) infection.
It is important to note that in many cases, deformed individuals do not survive. For example, in many cases in which a major deformity is present at birth, it is the result of an underlying condition severe enough that the baby does not survive very long. Or, in cases in which an individual becomes deformed due to an event, the event may kill the individual. In some societies, defective babies are abandoned at birth: some are saved by the "kindness of strangers"(See John Boswell). | Deformity
A deformity, dysmorphism, or dysmorphic feature is a major difference in the shape of the body a body part, or a body organ (internal or external) compared to the average shape for the part in question.
Deformity may arise from numerous causes:
- A genetic mutation
- Damage to the fetus or uterus
- Complications at birth
- A growth or hormone disorder
- Reconstructive surgery following a severe injury e.g. burn injury.
- Arthritis and other rheumatoid disorders
Irish Mythology includes the Fomorians, who are almost without exception described as being deformed, possessing only one of what most have two of (eyes, arms, legs, etc.) or having larger than normal limbs. Other mythological creatures may have been created due to a deformative syndrome also, for instance, descriptions of mermaids may be related to the symptoms of sirenomelia.
Deformity can occur in non-humans, as well. Frogs can be mutated due to Ribeiroia (Trematoda) infection.
Template:Commons2
It is important to note that in many cases, deformed individuals do not survive. For example, in many cases in which a major deformity is present at birth, it is the result of an underlying condition severe enough that the baby does not survive very long. Or, in cases in which an individual becomes deformed due to an event, the event may kill the individual. In some societies, defective babies are abandoned at birth: some are saved by the "kindness of strangers"(See John Boswell). | https://www.wikidoc.org/index.php/Deformities | |
8dee91cf77a601bc319f8dd1463fd18eddca0dd9 | wikidoc | Degarelix | Degarelix
# 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
Degarelix is an anti-neoplastic agent that is FDA approved for the treatment of patients with advanced prostate cancer. Common adverse reactions include injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT),asthenia, fever, night sweats, Nausea, Dizziness, headache and insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Degarelix is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer
- Degarelix is for subcutaneous administration only and is not to be administered intravenously.
- Degarelix is administered as a subcutaneous injection in the abdominal region. As with other drugs administered by subcutaneous injection, the injection site should vary periodically. Injections should be given in areas of the abdomen that will not be exposed to pressure, e.g. not close to waistband or belt nor close to the ribs.
- Degarelix is supplied as a powder to be reconstituted with Sterile Water for Injection, USP (WFI). The reconstitution procedure needs to be carefully followed. Administration of other concentrations is not recommended. See Instructions for Proper Use.
- NOTE:
- Gloves should be worn during preparation and administration
- Reconstituted drug must be administered within one hour after addition of Sterile Water for Injection, USP (WFI)
- Keep the vials vertical at all times
- Do not shake the vials
- Follow aseptic technique
- The Treatment Initiation pack contains 2 vials of Degarelix 120 mg that must be prepared for 2 subcutaneous injections. Hence, the instructions here below need to be repeated a second time.
- Prepare Degarelix 120 mg for reconstitution by gathering the following:
- 6 mL of Sterile Water for Injection, USP (WFI); Do not use Bacteriostatic Water for Injection
- 2 reconstitution needles – 21G / 2 inch
- 2 administration needles for subcutaneous injection – 27G / 1-1/4 inch
- 2 injection syringes (5 mL)
- Draw up 3 mL WFI with a reconstitution needle (21G / 2 in).
- Inject the WFI slowly into the Degarelix 120 mg vial. To keep the product and syringe sterile, do not remove the syringe and the needle.
- Keeping the vial in an upright position, swirl it very gently until the liquid looks clear and without undissolved powder or particles. If the powder adheres to the vial over the liquid surface, the vial can be tilted slightly to dissolve powder. Avoid shaking to prevent foam formation. A ring of small air bubbles on the surface of the liquid is acceptable. The reconstitution procedure may take up to 15 minutes.
- Tilt the vial slightly and keep the needle in the lowest part of the vial. Withdraw 3 mL of Degarelix 120 mg without turning the vial upside down.
- Exchange the reconstitution needle with the administration needle for deep subcutaneous injection (27G / 1-1/4 in). Remove any air bubbles.
- Inject 3 mL of Degarelix 120 mg subcutaneously immediately after reconstitution.
- Grasp the skin of the abdomen, elevate the subcutaneous tissue. Insert the needle deeply at an angle of not less than 45 degrees.
- Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, the reconstituted product can no longer be used. Discontinue the procedure and discard the syringe and the needle (reconstitute a new dose for the patient).
- Repeat reconstitution procedure for the second dose. Choose a different injection site and inject 3 mL.
- The Treatment Maintenance pack contains 1 vial of Degarelix 80 mg that must be prepared for subcutaneous injection.
- Prepare Degarelix 80 mg for reconstitution by gathering the following:
- 4.2 mL of Sterile Water for Injection, USP (WFI); Do not use Bacteriostatic Water for Injection
- 1 reconstitution needle – 21G / 2 inch
- 1 administration needle for subcutaneous injection – 27G / 1-1/4 inch
- 1 injection syringe (5 mL)
- Draw up 4.2 mL WFI with the reconstitution needle (21G / 2 in).
- Inject the WFI slowly into the Degarelix 80 mg vial. To keep the product and syringe sterile, do not remove the syringe and the needle.
- Keeping the vial in an upright position, swirl it very gently until the liquid looks clear and without undissolved powder or particles. If the powder adheres to the vial over the liquid surface, the vial can be tilted slightly to dissolve powder. Avoid shaking to prevent foam formation. A ring of small air bubbles on the surface of the liquid is acceptable. The reconstitution procedure may take up to 15 minutes.
- Tilt the vial slightly and keep the needle in the lowest part of the vial. Withdraw 4 mL of Degarelix 80 mg without turning the vial upside down.
- Exchange the reconstitution needle with the administration needle for deep subcutaneous injection (27G / 1-1/4 in). Remove any air bubbles.
- Inject 4 mL of Degarelix 80 mg subcutaneously immediately after reconstitution:
- Grasp the skin of the abdomen, elevate the subcutaneous tissue. Insert the needle deeply at an angle of not less than 45 degrees.
- Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, the reconstituted product can no longer be used. Discontinue the procedure and discard the syringe and the needle (reconstitute a new dose for the patient).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Degarelix in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Degarelix in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Safety and effectiveness in pediatric patients have not been established.
### Non–Guideline-Supported Use
Safety and effectiveness in pediatric patients have not been established.
# Contraindications
- Degarelix is contraindicated in patients with known hypersensitivity to degarelix or to any of the product components.
- Degarelix is contraindicated in women who are or may become pregnant. Degarelix can cause fetal harm when administered to a pregnant woman. Degarelix given to rabbits during organogenesis at doses that were 0.02% of the clinical loading dose (240 mg) on a mg/m2 basis caused embryo/fetal lethality and abortion. When degarelix was given to female rats during organogenesis, at doses that were just 0.036% of the clinical loading dose on a mg/m2 basis, there was an increase post implantation loss and a decrease in the number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
# Warnings
### Effect on QT/QTc Interval
- Long-term androgen deprivation therapy prolongs the QT interval. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure and in patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications.
- In the randomized, active-controlled trial comparing Degarelix to leuprolide, periodic electrocardiograms were performed. Seven patients, three ( 500 msec. From baseline to end of study the median change for Degarelix was 12.3 msec and for leuprolide was 16.7 msec.
- Therapy with Degarelix results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after Degarelix may be affected. The therapeutic effect of Degarelix should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.
# 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.
- A total of 1325 patients with prostate cancer received Degarelix either as a monthly treatment (60-160 mg) or as a single dose (up to 320 mg). A total of 1032 patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for one year or more. The most commonly observed adverse reactions during Degarelix therapy included injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reaction incidences of 1% or less.
- Degarelix was studied in an active-controlled trial (N = 610) in which patients with prostate cancer were randomized to receive Degarelix (subcutaneous) or leuprolide (intramuscular) monthly for 12 months. Adverse reactions reported in 5% of patients or more are shown in Table 1.
- The most frequently reported adverse reactions at the injection sites were pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). These adverse reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Grade 3 injection site reactions occurred in 2% or less of patients receiving degarelix.
- Hepatic laboratory abnormalities were primarily Grade 1 or 2 and were generally reversible. Grade 3 hepatic laboratory abnormalities occurred in less than 1% of patients.
- In 1-5% of patients the following adverse reactions, not already listed, were considered related to Degarelix by the investigator:
- Body as a whole: Asthenia, fever, night sweats; Digestive system: Nausea; Nervous system: Dizziness, headache, insomnia.
- The following adverse reactions, not already listed, were reported to be drug-related by the investigator in ≥1% of patients: erectile dysfunction, gynecomastia, hyperhidrosis, testicular atrophy, and diarrhea.
- Changes in bone density:
- Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist. It can be anticipated that long periods of medical castration in men will result in decreased bone density.
- Anti-degarelix antibody development has been observed in 10% of patients after treatment with Degarelix for 1 year. There is no indication that the efficacy or safety of Degarelix treatment is affected by antibody formation.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Degarelix in the drug label.
# Drug Interactions
- No drug-drug interaction studies were conducted.
- Degarelix is not a substrate for the human CYP450 system. Degarelix is not an inducer or inhibitor of the CYP450 system in vitro. Therefore, clinically significant CYP450 pharmacokinetic drug-drug interactions are unlikely.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Women who are or may become pregnant should not take Degarelix . When degarelix was given to rabbits during early organogenesis at doses of 0.002 mg/kg/day (about 0.02% of the clinical loading dose on a mg/m2 basis), there was an increase in early post-implantation loss. Degarelix given to rabbits during mid and late organogenesis at doses of 0.006 mg/kg/day (about 0.05% of the clinical loading dose on a mg/m2 basis) caused embryo/fetal lethality and abortion. When degarelix was given to female rats during early organogenesis, at doses of 0.0045 mg/kg/day (about 0.036% of the clinical loading dose on a mg/m2 basis), there was an increase in early post-implantation loss. When degarelix was given to female rats during mid and late organogenesis, at doses of 0.045 mg/kg/day (about 0.36% of the clinical loading dose on a mg/m2 basis), there was an increase in the number of minor skeletal abnormalities and variants.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Degarelix in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Degarelix during labor and delivery.
### Nursing Mothers
- Degarelix is not indicated for use in women and is contraindicated in women who are or who may become pregnant. 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 degarelix, 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
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Of the total number of subjects in clinical studies of Degarelix , 82% were age 65 and over, while 42% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Degarelix with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Degarelix with respect to specific racial populations.
### Renal Impairment
- No pharmacokinetic studies in renally impaired patients have been conducted. At least 20-30% of a given dose of degarelix is excreted unchanged in the urine.
- A population pharmacokinetic analysis of data from the randomized study demonstrated that there is no significant effect of mild renal impairment creatinine clearance (CrCL) 50-80 mL/min] on either the degarelix concentration or testosterone concentration. Data on patients with moderate or severe renal impairment is limited and therefore degarelix should be used with caution in patients with CrCL < 50 mL/min.
### Hepatic Impairment
- Patients with hepatic impairment were excluded from the randomized trial.
- A single dose of 1 mg degarelix administered as an intravenous infusion over 1 hour was studied in 16 non-prostate cancer patients with either mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Compared to non-prostate cancer patients with normal liver function, the exposure of degarelix decreased by 10% and 18% in patients with mild and moderate hepatic impairment, respectively. Therefore, dose adjustment is not necessary in patients with mild or moderate hepatic impairment. However, since hepatic impairment can lower degarelix exposure, it is recommended that in patients with hepatic impairment testosterone concentrations should be monitored on a monthly basis until medical castration is achieved. Once medical castration is achieved, an every-other-month testosterone monitoring approach could be considered.
- Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Degarelix in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Degarelix in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
- The therapeutic effect of Degarelix should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.
# IV Compatibility
There is limited information regarding IV Compatibility of Degarelix in the drug label.
# Overdosage
- There have been no reports of overdose with Degarelix . In the case of overdose, however, discontinue Degarelix , treat the patient symptomatically, and institute supportive measures.
- As with all prescription drugs, this medicine should be kept out of the reach of children.
# Pharmacology
## Mechanism of Action
- Degarelix is a GnRH receptor antagonist. It binds reversibly to the pituitary GnRH receptors, thereby reducing the release of gonadotropins and consequently testosterone.
## Structure
- Degarelix is a sterile lyophilized powder for injection containing degarelix (as the acetate) and mannitol. Degarelix is a synthetic linear decapeptide amide containing seven unnatural amino acids, five of which are D-amino acids. The acetate salt of degarelix is a white to off-white amorphous powder of low density as obtained after lyophilization.
- The chemical name of degarelix is D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-carbonyl]amino]-L phenylalanyl-4--D-phenylalanyl-L leucyl-N6–(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical formula of C82H103N18O16Cl and a molecular weight of 1632.3 Da.
- Degarelix has the following structural formula:
- Degarelix delivers degarelix acetate, equivalent to 120 mg of degarelix for the starting dose, and 80 mg of degarelix for the maintenance dose. The 80 mg vial contains 200 mg mannitol and the 120 mg vial contains 150 mg mannitol.
## Pharmacodynamics
- A single dose of 240 mg Degarelix causes a decrease in the plasma concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and subsequently testosterone.
- Degarelix is effective in achieving and maintaining testosterone suppression below the castration level of 50 ng/dL.
## Pharmacokinetics
- Degarelix forms a depot upon subcutaneous administration, from which degarelix is released to the circulation. Following administration of Degarelix 240 mg at a product concentration of 40 mg/mL, the mean Cmax was 26.2 ng/mL (coefficient of variation, CV 83%) and the mean AUC was 1054 ngday/mL (CV 35%). Typically Cmax occurred within 2 days after subcutaneous administration. In prostate cancer patients at a product concentration of 40 mg/mL, the pharmacokinetics of degarelix were linear over a dose range of 120 to 240 mg. The pharmacokinetic behavior of the drug is strongly influenced by its concentration in the injection solution.
- The distribution volume of degarelix after intravenous (> 1 L/kg) or subcutaneous administration (> 1000L) indicates that degarelix is distributed throughout total body water. In vitro plasma protein binding of degarelix is estimated to be approximately 90%.
- Degarelix is subject to peptide hydrolysis during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the feces. No quantitatively significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate, inducer or inhibitor of the CYP450 or p-glycoprotein transporter systems.
- Following subcutaneous administration of 240 mg Degarelix at a concentration of 40 mg/mL to prostate cancer patients, degarelix is eliminated in a biphasic fashion, with a median terminal half-life of approximately 53 days. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the Degarelix depot formed at the injection site(s). Approximately 20-30% of a given dose of degarelix was renally excreted, suggesting that approximately 70-80% is excreted via the hepato-biliary system in humans. Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr.
- There was no effect of age, weight, or race on the degarelix pharmacokinetic parameters or testosterone concentration.
## Nonclinical Toxicology
- Degarelix was administered subcutaneously to rats every 2 weeks for 2 years at doses of 2, 10 and 25 mg/kg (about 9, 45 and 120% of the recommended human loading dose on a mg/m2 basis). Long term treatment with degarelix at 25 mg/kg caused an increase in the combined incidence of benign hemangiomas plus malignant hemangiosarcomas in females.
- Degarelix was administered subcutaneously to mice every 2 weeks for 2 years at doses of 2, 10 and 50 mg/kg (about 5, 22 and 120% of the recommended human loading dose on a mg/m2 basis). There was no statistically significant increase in tumor incidence associated with this treatment.
- Degarelix did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration) nor in in vivo rodent bone marrow micronucleus tests.
- Single degarelix doses of ≥ 1 mg/kg (about 5% of the clinical loading dose on a mg/m2 basis) caused reversible infertility in male rats. Single doses of ≥ 0.1 mg/kg (about 0.5% of the clinical loading dose on a mg/m2 basis) caused a infertilitydecrease in fertility in female rats.
# Clinical Studies
- The safety and efficacy of Degarelix were evaluated in an open-label, multi-center, randomized, parallel-group study in patients with prostate cancer. A total of 620 patients were randomized to receive one of two Degarelix dosing regimens or leuprolide for one year:
- Degarelix at a starting dose of 240 mg (40 mg/mL) followed by monthly doses of 160 mg (40 mg/mL) subcutaneously,
- Degarelix at a starting dose of 240 mg (40 mg/mL) followed by monthly doses of 80 mg (20 mg/mL) subcutaneously,
- Leuprolide 7.5 mg intramuscularly monthly.
- Serum levels of testosterone were measured at screening, on Day 0, 1, 3, 7, 14, and 28 in the first month, and then monthly until the end of the study.
- The clinical trial population (n=610) across all treatment arms had an overall median age of approximately 73 (range 50 to 98). The ethnic/racial distribution was 84% white, 6% black, and 10% others. Disease stage was distributed approximately as follows: 20% metastatic, 29% locally advanced (T3/T4 Nx M0 or N1 M0), 31% localized (T1 or T2 N0 M0), and 20% classified as other (including patients whose disease metastatic status could not be determined definitively - or patients with PSA relapse after primary curative therapy). In addition, the median testosterone baseline value across treatment arms was approximately 400 ng/dL.
- The primary objective was to demonstrate that Degarelix is effective with respect to achieving and maintaining testosterone suppression to castration levels (T ≤ 50 ng/dL), during 12 months treatment. The results are shown in Table 2.
- Percentage changes in testosterone from baseline to Day 28 (median with interquartile ranges) are shown in Figure 2 and the percentages of patients who attained the medical castration of testosterone ≤ 50 ng/dL are summarized in Table 3.
- In the clinical trial, PSA levels were monitored as a secondary endpoint. PSA levels were lowered by 64% two weeks after administration of Degarelix , 85% after one month, 95% after three months, and remained suppressed throughout the one year of treatment. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline is related to a clinical benefit.
# How Supplied
- Degarelix is available as:
- NDC 55566-8401-1, Starting dose – One carton contains:Two vials each with 120 mg powder for injection
- NDC 55566-8301-1, Maintenance dose – One carton contains:One vial with 80 mg powder for injection
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
- Caution should be exercised in handling and preparing the solution of Degarelix . Several guidelines on proper handling and disposal of anticancer drugs have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling Degarelix . If Degarelix solution contacts the skin, immediately wash the skin thoroughly with soap and water. If Degarelix contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to read the Patient Labeling carefully.
- Patients should be informed of the possible side effects of androgen deprivation therapy, including hot flashes, flushing of the skin, increased weight, decreased sex drive, and difficulties with erectile function. Possible side effects related to therapy with Degarelix include redness, swelling, and itching at the injection site; these are usually mild, self limiting, and decrease within three days.
# Precautions with Alcohol
- Alcohol-Degarelix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FIRMAGON®
# Look-Alike Drug Names
There is limited information regarding Degarelix Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Degarelix
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
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# Overview
Degarelix is an anti-neoplastic agent that is FDA approved for the treatment of patients with advanced prostate cancer. Common adverse reactions include injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT),asthenia, fever, night sweats, Nausea, Dizziness, headache and insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Degarelix is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer
- Degarelix is for subcutaneous administration only and is not to be administered intravenously.
- Degarelix is administered as a subcutaneous injection in the abdominal region. As with other drugs administered by subcutaneous injection, the injection site should vary periodically. Injections should be given in areas of the abdomen that will not be exposed to pressure, e.g. not close to waistband or belt nor close to the ribs.
- Degarelix is supplied as a powder to be reconstituted with Sterile Water for Injection, USP (WFI). The reconstitution procedure needs to be carefully followed. Administration of other concentrations is not recommended. See Instructions for Proper Use.
- NOTE:
- Gloves should be worn during preparation and administration
- Reconstituted drug must be administered within one hour after addition of Sterile Water for Injection, USP (WFI)
- Keep the vials vertical at all times
- Do not shake the vials
- Follow aseptic technique
- The Treatment Initiation pack contains 2 vials of Degarelix 120 mg that must be prepared for 2 subcutaneous injections. Hence, the instructions here below need to be repeated a second time.
- Prepare Degarelix 120 mg for reconstitution by gathering the following:
- 6 mL of Sterile Water for Injection, USP (WFI); Do not use Bacteriostatic Water for Injection
- 2 reconstitution needles – 21G / 2 inch
- 2 administration needles for subcutaneous injection – 27G / 1-1/4 inch
- 2 injection syringes (5 mL)
- Draw up 3 mL WFI with a reconstitution needle (21G / 2 in).
- Inject the WFI slowly into the Degarelix 120 mg vial. To keep the product and syringe sterile, do not remove the syringe and the needle.
- Keeping the vial in an upright position, swirl it very gently until the liquid looks clear and without undissolved powder or particles. If the powder adheres to the vial over the liquid surface, the vial can be tilted slightly to dissolve powder. Avoid shaking to prevent foam formation. A ring of small air bubbles on the surface of the liquid is acceptable. The reconstitution procedure may take up to 15 minutes.
- Tilt the vial slightly and keep the needle in the lowest part of the vial. Withdraw 3 mL of Degarelix 120 mg without turning the vial upside down.
- Exchange the reconstitution needle with the administration needle for deep subcutaneous injection (27G / 1-1/4 in). Remove any air bubbles.
- Inject 3 mL of Degarelix 120 mg subcutaneously immediately after reconstitution.
- Grasp the skin of the abdomen, elevate the subcutaneous tissue. Insert the needle deeply at an angle of not less than 45 degrees.
- Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, the reconstituted product can no longer be used. Discontinue the procedure and discard the syringe and the needle (reconstitute a new dose for the patient).
- Repeat reconstitution procedure for the second dose. Choose a different injection site and inject 3 mL.
- The Treatment Maintenance pack contains 1 vial of Degarelix 80 mg that must be prepared for subcutaneous injection.
- Prepare Degarelix 80 mg for reconstitution by gathering the following:
- 4.2 mL of Sterile Water for Injection, USP (WFI); Do not use Bacteriostatic Water for Injection
- 1 reconstitution needle – 21G / 2 inch
- 1 administration needle for subcutaneous injection – 27G / 1-1/4 inch
- 1 injection syringe (5 mL)
- Draw up 4.2 mL WFI with the reconstitution needle (21G / 2 in).
- Inject the WFI slowly into the Degarelix 80 mg vial. To keep the product and syringe sterile, do not remove the syringe and the needle.
- Keeping the vial in an upright position, swirl it very gently until the liquid looks clear and without undissolved powder or particles. If the powder adheres to the vial over the liquid surface, the vial can be tilted slightly to dissolve powder. Avoid shaking to prevent foam formation. A ring of small air bubbles on the surface of the liquid is acceptable. The reconstitution procedure may take up to 15 minutes.
- Tilt the vial slightly and keep the needle in the lowest part of the vial. Withdraw 4 mL of Degarelix 80 mg without turning the vial upside down.
- Exchange the reconstitution needle with the administration needle for deep subcutaneous injection (27G / 1-1/4 in). Remove any air bubbles.
- Inject 4 mL of Degarelix 80 mg subcutaneously immediately after reconstitution:
- Grasp the skin of the abdomen, elevate the subcutaneous tissue. Insert the needle deeply at an angle of not less than 45 degrees.
- Gently pull back the plunger to check if blood is aspirated. If blood appears in the syringe, the reconstituted product can no longer be used. Discontinue the procedure and discard the syringe and the needle (reconstitute a new dose for the patient).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Degarelix in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Degarelix in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Safety and effectiveness in pediatric patients have not been established.
### Non–Guideline-Supported Use
Safety and effectiveness in pediatric patients have not been established.
# Contraindications
- Degarelix is contraindicated in patients with known hypersensitivity to degarelix or to any of the product components.
- Degarelix is contraindicated in women who are or may become pregnant. Degarelix can cause fetal harm when administered to a pregnant woman. Degarelix given to rabbits during organogenesis at doses that were 0.02% of the clinical loading dose (240 mg) on a mg/m2 basis caused embryo/fetal lethality and abortion. When degarelix was given to female rats during organogenesis, at doses that were just 0.036% of the clinical loading dose on a mg/m2 basis, there was an increase post implantation loss and a decrease in the number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
# Warnings
### Effect on QT/QTc Interval
- Long-term androgen deprivation therapy prolongs the QT interval. Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure and in patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications.
- In the randomized, active-controlled trial comparing Degarelix to leuprolide, periodic electrocardiograms were performed. Seven patients, three (<1%) in the pooled degarelix group and four (2%) patients in the leuprolide 7.5 mg group, had a QTcF > 500 msec. From baseline to end of study the median change for Degarelix was 12.3 msec and for leuprolide was 16.7 msec.
- Therapy with Degarelix results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after Degarelix may be affected. The therapeutic effect of Degarelix should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.
# 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.
- A total of 1325 patients with prostate cancer received Degarelix either as a monthly treatment (60-160 mg) or as a single dose (up to 320 mg). A total of 1032 patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for one year or more. The most commonly observed adverse reactions during Degarelix therapy included injection site reactions (e.g., pain, erythema, swelling, or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reaction incidences of 1% or less.
- Degarelix was studied in an active-controlled trial (N = 610) in which patients with prostate cancer were randomized to receive Degarelix (subcutaneous) or leuprolide (intramuscular) monthly for 12 months. Adverse reactions reported in 5% of patients or more are shown in Table 1.
- The most frequently reported adverse reactions at the injection sites were pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). These adverse reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Grade 3 injection site reactions occurred in 2% or less of patients receiving degarelix.
- Hepatic laboratory abnormalities were primarily Grade 1 or 2 and were generally reversible. Grade 3 hepatic laboratory abnormalities occurred in less than 1% of patients.
- In 1-5% of patients the following adverse reactions, not already listed, were considered related to Degarelix by the investigator:
- Body as a whole: Asthenia, fever, night sweats; Digestive system: Nausea; Nervous system: Dizziness, headache, insomnia.
- The following adverse reactions, not already listed, were reported to be drug-related by the investigator in ≥1% of patients: erectile dysfunction, gynecomastia, hyperhidrosis, testicular atrophy, and diarrhea.
- Changes in bone density:
- Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist. It can be anticipated that long periods of medical castration in men will result in decreased bone density.
- Anti-degarelix antibody development has been observed in 10% of patients after treatment with Degarelix for 1 year. There is no indication that the efficacy or safety of Degarelix treatment is affected by antibody formation.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Degarelix in the drug label.
# Drug Interactions
- No drug-drug interaction studies were conducted.
- Degarelix is not a substrate for the human CYP450 system. Degarelix is not an inducer or inhibitor of the CYP450 system in vitro. Therefore, clinically significant CYP450 pharmacokinetic drug-drug interactions are unlikely.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Women who are or may become pregnant should not take Degarelix . When degarelix was given to rabbits during early organogenesis at doses of 0.002 mg/kg/day (about 0.02% of the clinical loading dose on a mg/m2 basis), there was an increase in early post-implantation loss. Degarelix given to rabbits during mid and late organogenesis at doses of 0.006 mg/kg/day (about 0.05% of the clinical loading dose on a mg/m2 basis) caused embryo/fetal lethality and abortion. When degarelix was given to female rats during early organogenesis, at doses of 0.0045 mg/kg/day (about 0.036% of the clinical loading dose on a mg/m2 basis), there was an increase in early post-implantation loss. When degarelix was given to female rats during mid and late organogenesis, at doses of 0.045 mg/kg/day (about 0.36% of the clinical loading dose on a mg/m2 basis), there was an increase in the number of minor skeletal abnormalities and variants.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Degarelix in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Degarelix during labor and delivery.
### Nursing Mothers
- Degarelix is not indicated for use in women and is contraindicated in women who are or who may become pregnant. 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 degarelix, 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
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Of the total number of subjects in clinical studies of Degarelix , 82% were age 65 and over, while 42% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Degarelix with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Degarelix with respect to specific racial populations.
### Renal Impairment
- No pharmacokinetic studies in renally impaired patients have been conducted. At least 20-30% of a given dose of degarelix is excreted unchanged in the urine.
- A population pharmacokinetic analysis of data from the randomized study demonstrated that there is no significant effect of mild renal impairment creatinine clearance (CrCL) 50-80 mL/min] on either the degarelix concentration or testosterone concentration. Data on patients with moderate or severe renal impairment is limited and therefore degarelix should be used with caution in patients with CrCL < 50 mL/min.
### Hepatic Impairment
- Patients with hepatic impairment were excluded from the randomized trial.
- A single dose of 1 mg degarelix administered as an intravenous infusion over 1 hour was studied in 16 non-prostate cancer patients with either mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Compared to non-prostate cancer patients with normal liver function, the exposure of degarelix decreased by 10% and 18% in patients with mild and moderate hepatic impairment, respectively. Therefore, dose adjustment is not necessary in patients with mild or moderate hepatic impairment. However, since hepatic impairment can lower degarelix exposure, it is recommended that in patients with hepatic impairment testosterone concentrations should be monitored on a monthly basis until medical castration is achieved. Once medical castration is achieved, an every-other-month testosterone monitoring approach could be considered.
- Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Degarelix in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Degarelix in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
- The therapeutic effect of Degarelix should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.
# IV Compatibility
There is limited information regarding IV Compatibility of Degarelix in the drug label.
# Overdosage
- There have been no reports of overdose with Degarelix . In the case of overdose, however, discontinue Degarelix , treat the patient symptomatically, and institute supportive measures.
- As with all prescription drugs, this medicine should be kept out of the reach of children.
# Pharmacology
## Mechanism of Action
- Degarelix is a GnRH receptor antagonist. It binds reversibly to the pituitary GnRH receptors, thereby reducing the release of gonadotropins and consequently testosterone.
## Structure
- Degarelix is a sterile lyophilized powder for injection containing degarelix (as the acetate) and mannitol. Degarelix is a synthetic linear decapeptide amide containing seven unnatural amino acids, five of which are D-amino acids. The acetate salt of degarelix is a white to off-white amorphous powder of low density as obtained after lyophilization.
- The chemical name of degarelix is D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-L leucyl-N6–(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical formula of C82H103N18O16Cl and a molecular weight of 1632.3 Da.
- Degarelix has the following structural formula:
- Degarelix delivers degarelix acetate, equivalent to 120 mg of degarelix for the starting dose, and 80 mg of degarelix for the maintenance dose. The 80 mg vial contains 200 mg mannitol and the 120 mg vial contains 150 mg mannitol.
## Pharmacodynamics
- A single dose of 240 mg Degarelix causes a decrease in the plasma concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and subsequently testosterone.
- Degarelix is effective in achieving and maintaining testosterone suppression below the castration level of 50 ng/dL.
## Pharmacokinetics
- Degarelix forms a depot upon subcutaneous administration, from which degarelix is released to the circulation. Following administration of Degarelix 240 mg at a product concentration of 40 mg/mL, the mean Cmax was 26.2 ng/mL (coefficient of variation, CV 83%) and the mean AUC was 1054 ng•day/mL (CV 35%). Typically Cmax occurred within 2 days after subcutaneous administration. In prostate cancer patients at a product concentration of 40 mg/mL, the pharmacokinetics of degarelix were linear over a dose range of 120 to 240 mg. The pharmacokinetic behavior of the drug is strongly influenced by its concentration in the injection solution.
- The distribution volume of degarelix after intravenous (> 1 L/kg) or subcutaneous administration (> 1000L) indicates that degarelix is distributed throughout total body water. In vitro plasma protein binding of degarelix is estimated to be approximately 90%.
- Degarelix is subject to peptide hydrolysis during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the feces. No quantitatively significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate, inducer or inhibitor of the CYP450 or p-glycoprotein transporter systems.
- Following subcutaneous administration of 240 mg Degarelix at a concentration of 40 mg/mL to prostate cancer patients, degarelix is eliminated in a biphasic fashion, with a median terminal half-life of approximately 53 days. The long half-life after subcutaneous administration is a consequence of a very slow release of degarelix from the Degarelix depot formed at the injection site(s). Approximately 20-30% of a given dose of degarelix was renally excreted, suggesting that approximately 70-80% is excreted via the hepato-biliary system in humans. Following subcutaneous administration of degarelix to prostate cancer patients the clearance is approximately 9 L/hr.
- There was no effect of age, weight, or race on the degarelix pharmacokinetic parameters or testosterone concentration.
## Nonclinical Toxicology
- Degarelix was administered subcutaneously to rats every 2 weeks for 2 years at doses of 2, 10 and 25 mg/kg (about 9, 45 and 120% of the recommended human loading dose on a mg/m2 basis). Long term treatment with degarelix at 25 mg/kg caused an increase in the combined incidence of benign hemangiomas plus malignant hemangiosarcomas in females.
- Degarelix was administered subcutaneously to mice every 2 weeks for 2 years at doses of 2, 10 and 50 mg/kg (about 5, 22 and 120% of the recommended human loading dose [240 mg] on a mg/m2 basis). There was no statistically significant increase in tumor incidence associated with this treatment.
- Degarelix did not cause genetic damage in standard in vitro assays (bacterial mutation, human lymphocyte chromosome aberration) nor in in vivo rodent bone marrow micronucleus tests.
- Single degarelix doses of ≥ 1 mg/kg (about 5% of the clinical loading dose on a mg/m2 basis) caused reversible infertility in male rats. Single doses of ≥ 0.1 mg/kg (about 0.5% of the clinical loading dose on a mg/m2 basis) caused a infertilitydecrease in fertility in female rats.
# Clinical Studies
- The safety and efficacy of Degarelix were evaluated in an open-label, multi-center, randomized, parallel-group study in patients with prostate cancer. A total of 620 patients were randomized to receive one of two Degarelix dosing regimens or leuprolide for one year:
- Degarelix at a starting dose of 240 mg (40 mg/mL) followed by monthly doses of 160 mg (40 mg/mL) subcutaneously,
- Degarelix at a starting dose of 240 mg (40 mg/mL) followed by monthly doses of 80 mg (20 mg/mL) subcutaneously,
- Leuprolide 7.5 mg intramuscularly monthly.
- Serum levels of testosterone were measured at screening, on Day 0, 1, 3, 7, 14, and 28 in the first month, and then monthly until the end of the study.
- The clinical trial population (n=610) across all treatment arms had an overall median age of approximately 73 (range 50 to 98). The ethnic/racial distribution was 84% white, 6% black, and 10% others. Disease stage was distributed approximately as follows: 20% metastatic, 29% locally advanced (T3/T4 Nx M0 or N1 M0), 31% localized (T1 or T2 N0 M0), and 20% classified as other (including patients whose disease metastatic status could not be determined definitively - or patients with PSA relapse after primary curative therapy). In addition, the median testosterone baseline value across treatment arms was approximately 400 ng/dL.
- The primary objective was to demonstrate that Degarelix is effective with respect to achieving and maintaining testosterone suppression to castration levels (T ≤ 50 ng/dL), during 12 months treatment. The results are shown in Table 2.
- Percentage changes in testosterone from baseline to Day 28 (median with interquartile ranges) are shown in Figure 2 and the percentages of patients who attained the medical castration of testosterone ≤ 50 ng/dL are summarized in Table 3.
- In the clinical trial, PSA levels were monitored as a secondary endpoint. PSA levels were lowered by 64% two weeks after administration of Degarelix , 85% after one month, 95% after three months, and remained suppressed throughout the one year of treatment. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline is related to a clinical benefit.
# How Supplied
- Degarelix is available as:
- NDC 55566-8401-1, Starting dose – One carton contains:Two vials each with 120 mg powder for injection
- NDC 55566-8301-1, Maintenance dose – One carton contains:One vial with 80 mg powder for injection
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
- Caution should be exercised in handling and preparing the solution of Degarelix . Several guidelines on proper handling and disposal of anticancer drugs have been published.1-4 To minimize the risk of dermal exposure, always wear impervious gloves when handling Degarelix . If Degarelix solution contacts the skin, immediately wash the skin thoroughly with soap and water. If Degarelix contacts mucous membranes, the membranes should be flushed immediately and thoroughly with water
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to read the Patient Labeling carefully.
- Patients should be informed of the possible side effects of androgen deprivation therapy, including hot flashes, flushing of the skin, increased weight, decreased sex drive, and difficulties with erectile function. Possible side effects related to therapy with Degarelix include redness, swelling, and itching at the injection site; these are usually mild, self limiting, and decrease within three days.
# Precautions with Alcohol
- Alcohol-Degarelix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- FIRMAGON®
# Look-Alike Drug Names
There is limited information regarding Degarelix Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Degarelix | |
317cedbe7619d545bfc78f7ae62b191df2dc2da3 | wikidoc | Degloving | Degloving
Degloving is a type of injury wherein an extensive section of skin is completely torn off the underlying tissue, severing its blood supply. It is named by analogy to the process of removing a glove.
Typically, degloving injuries affect the extremities and limbs; this is because any injury which would induce degloving of the head or torso is likely to be lethal. However, controlled facial degloving is often featured in plastic surgery.
Alexandros Kyriakidis established that degloved skin is effectively dead, and should be treated as a skin graft.
Many small mammals are able to induce degloving of their tails to escape capture ; this is comparable to tail autotomy in reptiles. | Degloving
Degloving is a type of injury wherein an extensive section of skin is completely torn off the underlying tissue, severing its blood supply. It is named by analogy to the process of removing a glove.
Typically, degloving injuries affect the extremities and limbs; this is because any injury which would induce degloving of the head or torso is likely to be lethal. However, controlled facial degloving is often featured in plastic surgery.
Alexandros Kyriakidis established that degloved skin is effectively dead, and should be treated as a skin graft.
Many small mammals are able to induce degloving of their tails to escape capture [1]; this is comparable to tail autotomy in reptiles.
# External links
- Report on degloving injuries in children
- Guide to treatment of degloving injuries in pet rats
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Degloving | |
258e8fe85e197dfedf4923bd31fb571486d9a9dc | wikidoc | Delamanid | Delamanid
# Overview
Delamanid (USAN, codenamed OPC-67683) is an experimental drug for the treatment of multi-drug-resistant tuberculosis. It works by blocking the synthesis of mycolic acids in Mycobacterium tuberculosis, the organism which causes tuberculosis, thus destabilising its cell wall.
In phase II clinical trials, the drug was used in combination with standard treatments, such as four or five of the drugs ethambutol, isoniazid, pyrazinamide, rifampicin, aminoglycoside antibiotics, and quinolones. Healing rates (measured as sputum culture conversion) were significantly better in patients who additionally took delamanid.
The European Medicines Agency (EMA) recommended conditional marketing authorization for delamanid in adults with multidrug-resistant pulmonary tuberculosis without other treatment options because of resistance or tolerability. The EMA considered the data show that the benefits of delamanid outweigh the risks, but that additional studies were needed on the long-term effectiveness. | Delamanid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Delamanid (USAN, codenamed OPC-67683) is an experimental drug for the treatment of multi-drug-resistant tuberculosis. It works by blocking the synthesis of mycolic acids in Mycobacterium tuberculosis, the organism which causes tuberculosis, thus destabilising its cell wall.
In phase II clinical trials, the drug was used in combination with standard treatments, such as four or five of the drugs ethambutol, isoniazid, pyrazinamide, rifampicin, aminoglycoside antibiotics, and quinolones. Healing rates (measured as sputum culture conversion) were significantly better in patients who additionally took delamanid.
The European Medicines Agency (EMA) recommended conditional marketing authorization for delamanid in adults with multidrug-resistant pulmonary tuberculosis without other treatment options because of resistance or tolerability. The EMA considered the data show that the benefits of delamanid outweigh the risks, but that additional studies were needed on the long-term effectiveness. | https://www.wikidoc.org/index.php/Delamanid | |
3a28e67772e7a6a7f56ad3b8312d8eafb9faad7e | wikidoc | Deliriant | Deliriant
The deliriants (or anticholinergics) are a special class of acetylcholine-inhibitor dissociatives. The name comes from their primary effect of inducing a medical state of frank delirium, characterized by stupor, utter confusion, confabulation, and regression to "phantom" behaviors such as disrobing and plucking. Other commonly reported behaviors include holding full and lifelike conversations with imagined people, finishing a complex, multi-stage action (such as getting dressed) and then suddenly discovering you had not even begun yet, and being unable to recognize one's own reflection in a mirror (and thus becoming angry with the "stranger's" acts of mimicry). The effects have been likened to sleepwalking, a fugue state or a psychotic episode (particularly in that the subject has minimal control over their actions and little to no recall of the experience). This is a notable departure from typical hallucinogens.
Included in this group are such Solanaceae plants as deadly nightshade, mandrake, henbane and datura (containing tropane alkaloids sometimes referred to as the Belladonna alkaloids), as well as a number of pharmaceutical drugs such as the antihistamine diphenhydramine (Benadryl) and the antiemetics dimenhydrinate (Dramamine or Gravol) and scopolamine. The chemical warfare agent BZ (3-Quinuclidinyl benzilate) is a highly-potent anticholinergic military incapacitating agent.
Despite the fully-legal status of several common deliriant plants, deliriants are largely unpopular as recreational drugs due to the severe and unpleasant nature of their disassociative effects. User reports of recreational deleriant usage on Erowid generally indicate a firm unwillingness to repeat the experience. In addition to their potentially-dangerous mental effects, many tropane alkaloids (such as scopolamine and atropine) are highly poisonous and can cause death due to tachycardia-induced heart failure and hyperthermia even in small doses. Other physical effects include intense and painful drying of the eyes and mucous membranes, as well as a pronounced dilation of the pupils which can last for several days resulting in sensitivity to light, blurry vision and inability to read.
Deliriants are common to European mythology, including the plants mandrake, deadly nightshade, and various datura species.
# Pharmacological classes of deliriants, and their general subjective effects
Entries marked with a # are naturally occurring
## Anticholinergics
### Tropanes
- Atropine (racemic Hyoscyamine) #
- Scopolamine #
- Hyoscyamine #
### Disubstituted glycolic acid esters
- 3-quinuclidinyl benzylate
- Ditran
- Benactyzine (Amisyl)
## Antihistaminics
- diphenhydramine (Benadryl or Unisom)
- dimenhydrinate (Dramamine)
- cyclizine (Marezine or Marzine) | Deliriant
The deliriants (or anticholinergics) are a special class of acetylcholine-inhibitor dissociatives. The name comes from their primary effect of inducing a medical state of frank delirium, characterized by stupor, utter confusion, confabulation, and regression to "phantom" behaviors such as disrobing and plucking. Other commonly reported behaviors include holding full and lifelike conversations with imagined people, finishing a complex, multi-stage action (such as getting dressed) and then suddenly discovering you had not even begun yet, and being unable to recognize one's own reflection in a mirror (and thus becoming angry with the "stranger's" acts of mimicry). The effects have been likened to sleepwalking, a fugue state or a psychotic episode (particularly in that the subject has minimal control over their actions and little to no recall of the experience). This is a notable departure from typical hallucinogens.
Included in this group are such Solanaceae plants as deadly nightshade, mandrake, henbane and datura (containing tropane alkaloids sometimes referred to as the Belladonna alkaloids), as well as a number of pharmaceutical drugs such as the antihistamine diphenhydramine (Benadryl) and the antiemetics dimenhydrinate (Dramamine or Gravol) and scopolamine. The chemical warfare agent BZ (3-Quinuclidinyl benzilate) is a highly-potent anticholinergic military incapacitating agent.
Despite the fully-legal status of several common deliriant plants, deliriants are largely unpopular as recreational drugs due to the severe and unpleasant nature of their disassociative effects. User reports of recreational deleriant usage on Erowid generally indicate a firm unwillingness to repeat the experience. In addition to their potentially-dangerous mental effects, many tropane alkaloids (such as scopolamine and atropine) are highly poisonous and can cause death due to tachycardia-induced heart failure and hyperthermia even in small doses. Other physical effects include intense and painful drying of the eyes and mucous membranes, as well as a pronounced dilation of the pupils which can last for several days resulting in sensitivity to light, blurry vision and inability to read.
Deliriants are common to European mythology, including the plants mandrake, deadly nightshade, and various datura species.
# Pharmacological classes of deliriants, and their general subjective effects
Entries marked with a # are naturally occurring
## Anticholinergics
### Tropanes
- Atropine (racemic Hyoscyamine) #
- Scopolamine #
- Hyoscyamine #
### Disubstituted glycolic acid esters
- 3-quinuclidinyl benzylate
- Ditran
- Benactyzine (Amisyl)
## Antihistaminics
- diphenhydramine (Benadryl or Unisom)
- dimenhydrinate (Dramamine)
- cyclizine (Marezine or Marzine) | https://www.wikidoc.org/index.php/Deliriant | |
34d9dd7783912f5b1a47f4b458ca30b559d9c207 | wikidoc | Delta ray | Delta ray
A delta ray is sometimes used to describe any recoil particle that causes secondary ionization. The term was coined by J.J. Thomson. It is entirely unrelated to the family of subatomic particles named delta baryon. The term is rarely used today.
# Characteristics
A delta ray is characterized by very fast electrons produced in quantity by alpha particles or other fast energetic charged particles knocking orbiting electrons out of atoms. Collectively, these electrons are defined as delta radiation when they have sufficient energy to ionize further atoms through subsequent interactions on their own. Delta rays appear as branches in the main track of a cloud chamber. These branches will appear nearer the start of the track of a heavy charged particle, where more energy is imparted to the ionized electrons.
# Delta rays in particle accelerators
Otherwise called a knock-on electron, the term "delta ray" is also used in high energy physics to describe single electrons in particle accelerators that are exhibiting characteristic deceleration. In a bubble chamber, electrons will lose their energy more quickly than other particles through Bremsstrahlung and will create a spiral track due to their small mass and the magnetic field. The Bremsstrahlung rate is proportional to the square of the acceleration of the electron.
# References in popular culture
In science fiction, a "delta ray" is often used to describe an undefined, fictional type of ray or radiation, sometimes as a hazard, sometimes used in energy weapons. | Delta ray
A delta ray is sometimes used to describe any recoil particle that causes secondary ionization. The term was coined by J.J. Thomson. It is entirely unrelated to the family of subatomic particles named delta baryon. The term is rarely used today.
# Characteristics
A delta ray is characterized by very fast electrons produced in quantity by alpha particles or other fast energetic charged particles knocking orbiting electrons out of atoms. Collectively, these electrons are defined as delta radiation when they have sufficient energy to ionize further atoms through subsequent interactions on their own. Delta rays appear as branches in the main track of a cloud chamber. These branches will appear nearer the start of the track of a heavy charged particle, where more energy is imparted to the ionized electrons.
# Delta rays in particle accelerators
Otherwise called a knock-on electron, the term "delta ray" is also used in high energy physics to describe single electrons in particle accelerators that are exhibiting characteristic deceleration. In a bubble chamber, electrons will lose their energy more quickly than other particles through Bremsstrahlung and will create a spiral track due to their small mass and the magnetic field. The Bremsstrahlung rate is proportional to the square of the acceleration of the electron.
# References in popular culture
In science fiction, a "delta ray" is often used to describe an undefined, fictional type of ray or radiation, sometimes as a hazard, sometimes used in energy weapons. | https://www.wikidoc.org/index.php/Delta_ray | |
9df94ed001861ba1411ff2b1dc04f5f5c2fe61f9 | wikidoc | Dendrimer | Dendrimer
# Overview
Dendrimers are repeatedly branched molecules. The huge number of papers on dendritic architectures such as dendrimers, dendronized, hyperbranched and brush-polymers has generated a vast variety of inconsistent terms and definitions making a clear and concise unfolding of this topic highly difficult. The purpose of this section is to provide the vocabulary required for the description of chemical and physical phenomena as well as application aspects associated with the research in the area of dendritic molecules.
Dendritic molecules are repeatedly branched species that are characterized by their structure perfection. The latter is based on the evaluation of both symmetry and polydispersity. The area of dendritic molecules can roughly be divided into the low-molecular weight and the high-molecular weight species. The first category includes dendrimers and dendrons whereas the second encompasses dendronized polymers, hyperbranched polymers, and brush-polymers (also called bottle-brushes).
The name comes from the Greek "δενδρον"/dendron, meaning "tree". Synonymous terms are arborols and cascade-molecules. Dendrimer is an internationally accepted term.
Dendrimers and dendrons are repeatedly branched, monodisperse, and usually highly symmetric compounds. There is no apparent difference in defining dendrimer and dendron. A dendron usually contains a single chemically addressable group that is called focal point.
Because of the lack of the molar mass distribution high-molar-mass dendrimers and dendrons are macromolecules but not polymers.
The first dendrimers were described by Vögtle in 1978, by Denkewalter and coworkers at Allied Corporation as polylysine dendrimers in 1981, by Tomalia at Dow Chemical in 1983 and in 1985, and by Newkome in 1985. In 1990s dendrimers caused an explosion of scientific interest because of their unique molecular architecture (Fig 1). This resulted in over 5,000 scientific papers and patents published by the end of 2005.
# Properties and applications
The properties of dendrimers are dominated by the functional groups on the molecular surface. Dendritic encapsulation of functional molecules allows for the isolation of the active site, a structure that mimics the structure of active sites in biomaterials because dendritic scaffolds separate internal and external functions.. For example, a dendrimer can be water-soluble when its end-group is a hydrophilic group, like a carboxyl group. It is theoretically possible to design a water-soluble dendrimer with internal hydrophobicity, which would allow it to carry a hydrophobic drug in its interior. Recently it has been shown that redox-active nanoparticles can be synthesized, placing the redox molecules between the nanoparticle core and the dendritic wedges; despite their isolation, some of the redox molecules (COOH in this case) remained uncoupled, and thus still reactive.
Another property is that the volume of a dendrimer increases when it has a positive charge. If this property can be applied, dendrimers can be used for drug delivery systems (DDS) that can give medication to the affected part inside a patient's body directly.
## Photonic excited molecules
The inside of a dendrimer has a unique chemical environment because of its high density. From this property, it has been discovered that azobenzene is photoisomerized by very weak infrared rays when covered by a dendrimer . Through the discovery of a function that catches light and conveys this energy using excitation of the molecule, attempts have recently been made to synthesize dendrimers that insert porphyrin, absorb light, and photosynthesize artificially. In addition, the development of organic electroluminescent devices and their applications has been undertaken by researchers all over the world.
# Synthesis
In the synthesis of dendrimers, monomers lead to a monodisperse polymer, tree-like, or generational structure. There are two defined methods of dendrimer synthesis, divergent synthesis and convergent synthesis. Divergent syntheses assemble the molecule from the core, extending radially to the periphery and in contrast convergent methods start at the surface and proceed inwards, before the attachment of pre-synthesised dendrons to the core.
However, because a repeated reaction which consists of many steps is needed to protect the active site, it is difficult to synthesize dendrimers even if both methods are used. This is why there are obstacles to the synthesis of large quantities of dendrimers. Presently, the only kilogram-scale producers of dendrimers is Dendritech
The original Newkome dendrimer or arborol (1985) started by nucleophilic substitution of 1-bromopentane by triethyl sodiomethanetricarboxylate in dimethylformamide and benzene. The ester groups were then reduced by lithium aluminium hydride to a triol in a deprotection step. Activation of the chain ends was achieved by converting the alcohol groups to tosylate groups with tosyl chloride and pyridine. The tosyl group then served as leaving groups in another reaction with the tricarboxylate, forming generation two.
This sequence can be repeated many times. | Dendrimer
# Overview
Dendrimers are repeatedly branched molecules. The huge number of papers on dendritic architectures such as dendrimers, dendronized, hyperbranched and brush-polymers has generated a vast variety of inconsistent terms and definitions making a clear and concise unfolding of this topic highly difficult. The purpose of this section is to provide the vocabulary required for the description of chemical and physical phenomena as well as application aspects associated with the research in the area of dendritic molecules.
Dendritic molecules are repeatedly branched species that are characterized by their structure perfection. The latter is based on the evaluation of both symmetry and polydispersity. The area of dendritic molecules can roughly be divided into the low-molecular weight and the high-molecular weight species. The first category includes dendrimers and dendrons whereas the second encompasses dendronized polymers, hyperbranched polymers, and brush-polymers (also called bottle-brushes).
The name comes from the Greek "δενδρον"/dendron, meaning "tree". Synonymous terms are arborols and cascade-molecules. Dendrimer is an internationally accepted term.
Dendrimers and dendrons are repeatedly branched, monodisperse, and usually highly symmetric compounds. There is no apparent difference in defining dendrimer and dendron. A dendron usually contains a single chemically addressable group that is called focal point.
Because of the lack of the molar mass distribution high-molar-mass dendrimers and dendrons are macromolecules but not polymers.
The first dendrimers were described by Vögtle in 1978[1], by Denkewalter and coworkers at Allied Corporation as polylysine dendrimers in 1981[2], by Tomalia at Dow Chemical in 1983[3] and in 1985[4], and by Newkome in 1985[5]. In 1990s dendrimers caused an explosion of scientific interest because of their unique molecular architecture (Fig 1). This resulted in over 5,000 scientific papers and patents published by the end of 2005.
# Properties and applications
The properties of dendrimers are dominated by the functional groups on the molecular surface. Dendritic encapsulation of functional molecules allows for the isolation of the active site, a structure that mimics the structure of active sites in biomaterials because dendritic scaffolds separate internal and external functions.[6][7][8]. For example, a dendrimer can be water-soluble when its end-group is a hydrophilic group, like a carboxyl group. It is theoretically possible to design a water-soluble dendrimer with internal hydrophobicity, which would allow it to carry a hydrophobic drug in its interior. Recently it has been shown that redox-active nanoparticles can be synthesized, placing the redox molecules between the nanoparticle core and the dendritic wedges; despite their isolation, some of the redox molecules (COOH in this case) remained uncoupled, and thus still reactive.[9]
Another property is that the volume of a dendrimer increases when it has a positive charge. If this property can be applied, dendrimers can be used for drug delivery systems (DDS) that can give medication to the affected part inside a patient's body directly[10].
## Photonic excited molecules
The inside of a dendrimer has a unique chemical environment because of its high density. From this property, it has been discovered that azobenzene is photoisomerized by very weak infrared rays when covered by a dendrimer [11]. Through the discovery of a function that catches light and conveys this energy using excitation of the molecule, attempts have recently been made to synthesize dendrimers that insert porphyrin, absorb light, and photosynthesize artificially. In addition, the development of organic electroluminescent devices and their applications has been undertaken by researchers all over the world.
# Synthesis
In the synthesis of dendrimers, monomers lead to a monodisperse polymer, tree-like, or generational structure. There are two defined methods of dendrimer synthesis, divergent synthesis and convergent synthesis. Divergent syntheses assemble the molecule from the core, extending radially to the periphery and in contrast convergent methods start at the surface and proceed inwards, before the attachment of pre-synthesised dendrons to the core.
However, because a repeated reaction which consists of many steps is needed to protect the active site, it is difficult to synthesize dendrimers even if both methods are used. This is why there are obstacles to the synthesis of large quantities of dendrimers. Presently, the only kilogram-scale producers of dendrimers is Dendritech [12]
The original Newkome dendrimer or arborol (1985) started by nucleophilic substitution of 1-bromopentane by triethyl sodiomethanetricarboxylate in dimethylformamide and benzene. The ester groups were then reduced by lithium aluminium hydride to a triol in a deprotection step. Activation of the chain ends was achieved by converting the alcohol groups to tosylate groups with tosyl chloride and pyridine. The tosyl group then served as leaving groups in another reaction with the tricarboxylate, forming generation two.
This sequence can be repeated many times. | https://www.wikidoc.org/index.php/Dendrimer | |
1799bd5a4ee748f66a1ce3eefa85159b1f81b5a8 | wikidoc | Denosumab | Denosumab
# Disclaimer
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# Overview
Denosumab is a monoclonal antibody that is FDA approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture, increase bone mass in men with osteoporosis, bone loss in men receiving androgen deprivation therapy for prostate cancer, bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer. Common adverse reactions include hypercholesterolemia, diarrhea, nausea, vomiting, arthralgia, backache, pain in limb, asthenia, headache, cystitis, nasopharyngitis, upper respiratory infection, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Recommended Dosage
- Denosumab should be administered by a healthcare professional.
- Recommended dose 60 mg SC injection once every 6 months.
- Administer Denosumab via subcutaneous injection in the upper arm, the upper thigh, or the abdomen.
- All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily
- If a dose of Denosumab is missed, administer the injection as soon as the patient is available. Thereafter, schedule injections every 6 months from the date of the last injection.
### Preparation and Administration
- Visually inspect Denosumab for particulate matter and discoloration prior to administration whenever solution and container permit. Denosumab is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.
- Latex Allergy: People sensitive to latex should not handle the grey needle cap on the single-use prefilled syringe, which contains dry natural rubber (a derivative of latex).
Prior to administration, Denosumab may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Denosumab in any other way.
Instructions for Prefilled Syringe with Needle Safety Guard
IMPORTANT: In order to minimize accidental needlesticks, the Denosumab single-use prefilled syringe will have a green safety guard; manually activate the safety guard after the injection is given.
DO NOT slide the green safety guard forward over the needle before administering the injection; it will lock in place and prevent injection.
Activate the green safety guard (slide over the needle) after the injection.
The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex); people sensitive to latex should not handle the cap.
Step 1: Remove Grey Needle Cap
Step 2: Administer Subcutaneous Injection
DO NOT put grey needle cap back on needle.
Step 3: Immediately Slide Green Safety Guard Over Needle
With the needle pointing away from you…
Hold the prefilled syringe by the clear plastic finger grip with one hand. Then, with the other hand, grasp the green safety guard by its base and gently slide it towards the needle until the green safety guard locks securely in place and/or you hear a “click.” DO NOT grip the green safety guard too firmly – it will move easily if you hold and slide it gently.
Immediately dispose of the syringe and needle cap in the nearest sharps container. DO NOT put the needle cap back on the used syringe.
Instructions for Single-use Vial
For administration of Denosumab from the single-use vial, use a 27-gauge needle to withdraw and inject the 1 mL dose. Do not re-enter the vial. Discard vial and any liquid remaining in the vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Denosumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Denosumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Denosumab is not recommended in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Denosumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Denosumab in pediatric patients.
# Contraindications
### Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with Denosumab.
### Pregnancy
Denosumab may cause fetal harm when administered to a pregnant woman. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Denosumab is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
### Hypersensitivity
Denosumab is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling and urticaria
# Warnings
### Drug Products with Same Active Ingredient
Denosumab contains the same active ingredient (denosumab) found in Xgeva. Patients receiving Denosumab should not receive Xgeva.
### Hypersensitivity
Clinically significant hypersensitivity including anaphylaxis has been reported with Denosumab. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Denosumab.
### Hypocalcemia and Mineral Metabolism
Hypocalcemia may be exacerbated by the use of Denosumab. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Denosumab. In patients predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment (creatinine clearance <30 mL/min or receiving dialysis), clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended.
Hypocalcemia following Denosumab administration is a significant risk in patients with severe renal impairment or receiving dialysis. These patients may also develop marked elevations of serum parathyroid hormone (PTH). Instruct all patients with severe renal impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.
Adequately supplement all patients with calcium and vitamin D.
### Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab. A routine oral exam should be performed by the prescriber prior to initiation of Denosumab treatment. A dental examination with appropriate preventive dentistry should be considered prior to treatment with Denosumab in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Denosumab.
For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment.
Patients who are suspected of having or who develop ONJ while on Denosumab should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Denosumab therapy should be considered based on individual benefit-risk assessment.
### Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical low-energy or low trauma fractures of the shaft have been reported in patients receiving Denosumab. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents.
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.During Denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Denosumab therapy should be considered, pending a risk/benefit assessment, on an individual basis.
### Serious Infections
In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Denosumab group than in the placebo group. Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more frequent in patients treated with Denosumab. Endocarditis was also reported more frequently in Denosumab-treated patients. The incidence of opportunistic infections was similar between placebo and Denosumab groups, and the overall incidence of infections was similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.
Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. Consider the benefit-risk profile in such patients before treating with Denosumab. In patients who develop serious infections while on Denosumab, prescribers should assess the need for continued Denosumab therapy.
### Dermatologic Adverse Reactions
In a large clinical trial of over 7800 women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate in the Denosumab group compared to the placebo group. Most of these events were not specific to the injection site . Consider discontinuing Denosumab if severe symptoms develop.
### Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Denosumab. The time to onset of symptoms varied from one day to several months after starting Denosumab. Consider discontinuing use if severe symptoms develop .
### Suppression of Bone Turnover
In clinical trials in women with postmenopausal osteoporosis, treatment with Denosumab resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment with Denosumab are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with Denosumab may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. Monitor patients for these consequences.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are discussed below and also elsewhere in the labeling:
- Hypocalcemia
- Serious Infections
- Dermatologic adverse reactions
- Osteonecrosis of the Jaw
- Atypical subtrochanteric and diaphyseal femoral fractures
The most common adverse reactions reported with Denosumab in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.
The most common adverse reactions reported with Denosumab in men with osteoporosis are back pain, arthralgia, and nasopharyngitis.
The most common (per patient incidence ≥ 10%) adverse reactions reported with Denosumab in patients with bone loss receiving androgen deprivation therapy for prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials.
The most common adverse reactions leading to discontinuation of Denosumab in patients with postmenopausal osteoporosis are back pain and constipation.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
The safety of Denosumab in the treatment of postmenopausal osteoporosis was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 7808 postmenopausal women aged 60 to 91 years. A total of 3876 women were exposed to placebo and 3886 women were exposed to Denosumab administered subcutaneously once every 6 months as a single 60 mg dose. All women were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.
The incidence of all-cause mortality was 2.3% (n = 90) in the placebo group and 1.8% (n = 70) in the Denosumab group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the Denosumab group. The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and Denosumab groups, respectively.
Adverse reactions reported in ≥ 2% of postmenopausal women with osteoporosis and more frequently in the Denosumab-treated women than in the placebo-treated women are shown in the table below.
Hypocalcemia
Decreases in serum calcium levels to less than 8.5 mg/dL at any visit were reported in 0.4% women in the placebo group and 1.7% women in the Denosumab group. The nadir in serum calcium level occurs at approximately day 10 after Denosumab dosing in subjects with normal renal function.
In clinical studies, subjects with impaired renal function were more likely to have greater reductions in serum calcium levels compared to subjects with normal renal function. In a study of 55 subjects with varying degrees of renal function, serum calcium levels < 7.5 mg/dL or symptomatic hypocalcemia were observed in 5 subjects. These included no subjects in the normal renal function group, 10% of subjects in the creatinine clearance 50 to 80 mL/min group, 29% of subjects in the creatinine clearance < 30 mL/min group, and 29% of subjects in the hemodialysis group. These subjects did not receive calcium and vitamin D supplementation. In a study of 4550 postmenopausal women with osteoporosis, the mean change from baseline in serum calcium level 10 days after Denosumab dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance ≥ 30 mL/min.
Serious Infections
Receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed on activated T and B lymphocytes and in lymph nodes. Therefore, a RANKL inhibitor such as Denosumab may increase the risk of infection.
In the clinical study of 7808 postmenopausal women with osteoporosis, the incidence of infections resulting in death was 0.2% in both placebo and Denosumab treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the Denosumab groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% Denosumab), urinary tract (0.5% placebo vs. 0.7% Denosumab), and ear (0.0% placebo vs. 0.1% Denosumab) were reported. Endocarditis was reported in no placebo patients and 3 patients receiving Denosumab.
Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with Denosumab (< 0.1% placebo vs. 0.4% Denosumab).
The incidence of opportunistic infections was similar to that reported with placebo.
Dermatologic Reactions
A significantly higher number of patients treated with Denosumab developed epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 10.8% of the Denosumab groups (p < 0.0001). Most of these events were not specific to the injection site.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw has been reported in the osteoporosis clinical trial program in patients treated with Denosumab.
Atypical Subtrochanteric and Diaphyseal Fractures
In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with Denosumab. The duration of Denosumab exposure to time of atypical femoral fracture diagnosis was as early as 2½ years.
Pancreatitis
Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Denosumab groups. Of these reports, 1 patient in the placebo group and all 8 patients in the Denosumab group had serious events, including one death in the Denosumab group. Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable.
New Malignancies
The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Denosumab groups. New malignancies related to the breast (0.7% placebo vs. 0.9% Denosumab), reproductive system (0.2% placebo vs. 0.5% Denosumab), and gastrointestinal system (0.6% placebo vs. 0.9% Denosumab) were reported. A causal relationship to drug exposure has not been established.
The safety of Denosumab in the treatment of men with osteoporosis was assessed in a 1-year randomized, double-blind, placebo-controlled study. A total of 120 men were exposed to placebo and 120 men were exposed to Denosumab administered subcutaneously once every 6 months as a single 60 mg dose. All men were instructed to take at least 1000 mg of calcium and 800 IU of vitamin D supplementation per day.
The incidence of all-cause mortality was 0.8% (n = 1) in the placebo group and 0.8% (n = 1) in the Denosumab group. The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the Denosumab group. The percentage of patients who withdrew from the study due to adverse events was 0% and 2.5% for the placebo and Denosumab groups, respectively.
Adverse reactions reported in ≥ 5% of men with osteoporosis and more frequently with Denosumab than in the placebo-treated patients were: back pain (6.7% placebo vs. 8.3% Denosumab), arthralgia (5.8% placebo vs. 6.7% Denosumab), and nasopharyngitis (5.8% placebo vs. 6.7% Denosumab).
Serious Infections
Serious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the Denosumab group.
Dermatologic Reactions
Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 4 patients (3.3%) in the placebo group and 5 patients (4.2%) in the Denosumab group.
Osteonecrosis of the Jaw
No cases of ONJ were reported.
Pancreatitis
Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the Denosumab group.
New Malignancies
New malignancies were reported in no patients in the placebo group and 4 (3.3%) patients (3 prostate cancers, 1 basal cell carcinoma) in the Denosumab group.
The safety of Denosumab in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) was assessed in a 3‑year, randomized, double-blind, placebo-controlled, multinational study of 1468 men aged 48 to 97 years. A total of 725 men were exposed to placebo and 731 men were exposed to Denosumab administered once every 6 months as a single 60 mg subcutaneous dose. All men were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.
The incidence of serious adverse events was 30.6% in the placebo group and 34.6% in the Denosumab group. The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the placebo and Denosumab groups, respectively.
The safety of Denosumab in the treatment of bone loss in women with nonmetastatic breast cancer receiving aromatase inhibitor.
## Postmarketing Experience
Because postmarketing 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.
The following adverse reactions have been identified during post approval use of Denosumab:
- Drug-related hypersensitivity reactions: anaphylaxis, rash, urticaria, facial swelling, and erythema
- Hypocalcemia: severe symptomatic hypocalcemia
- Musculoskeletal pain, including severe cases
- Parathyroid Hormone (PTH): Marked elevation in serum PTH in patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis.
# Drug Interactions
In subjects with postmenopausal osteoporosis, Denosumab (60 mg subcutaneous injection) did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4), indicating that it should not affect the pharmacokinetics of drugs metabolized by this enzyme in this population.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Risk Summary
Denosumab may cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Denosumab is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Women who become pregnant during Denosumab 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.
Clinical Considerations
The effects of Denosumab on the fetus are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies, such as denosumab, are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Denosumab therapy, treatment should be discontinued and the patient should consult their physician.
Animal Data
The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to 1 month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels).
Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated.
In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Denosumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Denosumab during labor and delivery.
### Nursing Mothers
It is not known whether Denosumab is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Denosumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Maternal exposure to Denosumab during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated
### Pediatric Use
Denosumab is not recommended in pediatric patients. The safety and effectiveness of Denosumab in pediatric patients have not been established.
Treatment with Denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Denosumab therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 10 and 50 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered every 6 months, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab.
Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes, reduced hematopoiesis, tooth malalignment, and decreased neonatal growth. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth.
### Geriatic Use
Of the total number of patients in clinical studies of Denosumab, 9943 patients (76%) were ≥ 65 years old, while 3576 (27%) were ≥ 75 years old. Of the patients in the osteoporosis study in men, 133 patients (55%) were ≥ 65 years old, while 39 patients (16%) were ≥ 75 years old. No overall differences in safety or efficacy 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.
### Gender
Denosumab may cause fetal harm.
The extent to which denosumab is present in seminal fluid is unknown. There is a potential for fetal exposure to denosumab when a man treated with Denosumab has unprotected sexual intercourse with a pregnant partner. The risk of fetal harm is likely to be low. Advise men being treated with Denosumab who have a pregnant partner of this potential risk.
### Race
There is no FDA guidance on the use of Denosumab with respect to specific racial populations.
### Renal Impairment
No dose adjustment is necessary in patients with renal impairment.
In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcemia. Consider the benefit-risk profile when administering Denosumab to patients with severe renal impairment or receiving dialysis. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.
### Hepatic Impairment
No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Denosumab.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Denosumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Denosumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Subcutaneous injection
### Monitoring
There is limited information about the drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
There is no experience with overdosage with Denosumab.
# Pharmacology
## Mechanism of Action
Denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.
## Structure
Denosumab (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
Denosumab is a sterile, preservative-free, clear, colorless to pale yellow solution.
Each 1 mL single-use prefilled syringe of Denosumab contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.
Each 1 mL single-use vial of Denosumab contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.
## Pharmacodynamics
In clinical studies, treatment with 60 mg of Denosumab resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of Denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of Denosumab on bone remodeling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by Denosumab was similar to that observed in patients initiating Denosumab treatment.
Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e. osteocalcin and procollagen type 1 N-terminal peptide ) were observed starting 1 month after the first dose of Denosumab. After discontinuation of Denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months.
## Pharmacokinetics
In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered Denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (Cmax) was 6.75 mcg/mL (standard deviation = 1.89 mcg/mL). The median time to maximum denosumab concentration (Tmax) was 10 days (range: 3 to 21 days). After Cmax, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg×day/mL (SD = 101 mcg×day/mL).
No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months.
Denosumab pharmacokinetics were not affected by the formation of binding antibodies.
A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg).
Drug Interactions
In a study of 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered two weeks after a single dose of denosumab (60 mg subcutaneous injection), which approximates the Tmax of denosumab. Denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the pharmacokinetics of drugs metabolized by CYP3A4 in postmenopausal women with osteoporosis.
Specific Populations
Gender:Mean serum denosumab concentration-time profiles observed in a study conducted in healthy men ≥ 50 years were similar to those observed in a study conducted in postmenopausal women using the same dose regimen.
Age: The pharmacokinetics of denosumab were not affected by age across all populations studied whose ages ranged from 28 to 87 years.
Race: The pharmacokinetics of denosumab were not affected by race.
Renal Impairment: In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary.
Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.
Mutagenicity
The genotoxic potential of denosumab has not been evaluated.
Impairment of Fertility
Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg).
### Animal Toxicology and/or Pharmacology
Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.
In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and increased bone mineral density (BMD) and strength of cancellous and cortical bone at doses 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg). Bone tissue was normal with no evidence of mineralization defects, accumulation of osteoid, or woven bone.
Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (“knockout”) mice or use of other biological inhibitors of the RANK/RANKL pathway, namely OPG-Fc, provided additional information on the pharmacodynamic properties of denosumab. RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy). Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued.
# Clinical Studies
### Postmenopausal Women with Osteoporosis
The efficacy and safety of Denosumab in the treatment of postmenopausal osteoporosis was demonstrated in a 3-year, randomized, double-blind, placebo-controlled trial. Enrolled women had a baseline BMD T‑score between -2.5 and -4.0 at either the lumbar spine or total hip. Women with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget’s disease) or on therapies that affect bone were excluded from this study. The 7808 enrolled women were aged 60 to 91 years with a mean age of 72 years. Overall, the mean baseline lumbar spine BMD T-score was -2.8, and 23% of women had a vertebral fracture at baseline. Women were randomized to receive subcutaneous injections of either placebo (N = 3906) or Denosumab 60 mg (N = 3902) once every 6 months. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4-L4) using a semiquantitative scoring method. Secondary efficacy variables included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years.
Effect on Vertebral Fractures
Denosumab significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years (p < 0.0001), as shown in Table 2. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the Denosumab-treated women. The absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3.
Denosumab was effective in reducing the risk for new morphometric vertebral fractures regardless of age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for osteoporosis.
Effect on Hip Fractures
The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Denosumab-treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a relative risk reduction of 40% at 3 years (p = 0.04) (Figure 1).
Effect on Nonvertebral Fractures
Treatment with Denosumab resulted in a significant reduction in the incidence of nonvertebral fractures (Table 3)
Effect on Bone Mineral Density (BMD)
Treatment with Denosumab significantly increased BMD at all anatomic sites measured at 3 years. The treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% at the femoral neck. Consistent effects on BMD were observed at the lumbar spine, regardless of baseline age, race, weight/body mass index (BMI), baseline BMD, and level of bone turnover.
After Denosumab discontinuation, BMD returned to approximately baseline levels within 12 months.
Bone Histology and Histomorphometry
A total of 115 transiliac crest bone biopsy specimens were obtained from 92 postmenopausal women with osteoporosis at either month 24 and/or month 36 (53 specimens in Denosumab group, 62 specimens in placebo group). Of the biopsies obtained, 115 (100%) were adequate for qualitative histology and 7 (6%) were adequate for full quantitative histomorphometry assessment.
Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Denosumab.
The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In patients treated with Denosumab, 35% had no tetracycline label present at the month 24 biopsy and 38% had no tetracycline label present at the month 36 biopsy, while 100% of placebo-treated patients had double label present at both time points. When compared to placebo, treatment with Denosumab resulted in virtually absent activation frequency and markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.
### Treatment to Increase Bone Mass in Men with Osteoporosis
The efficacy and safety of Denosumab in the treatment to increase bone mass in men with osteoporosis was demonstrated in a 1-year, randomized, double-blind, placebo-controlled trial. Enrolled men had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck were also enrolled if there was a history of prior fragility fracture. Men with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget’s disease) or on therapies that may affect bone were excluded from this study. The 242 men enrolled in the study ranged in age from 31 to 84 years with a mean age of 65 years. Men were randomized to receive SC injections of either placebo (n = 121) or Denosumab 60 mg (n = 121) once every 6 months. All men received at least 1000 mg calcium and at least 800 IU vitamin D supplementation daily.
Effect on Bone Mineral Density (BMD)
The primary efficacy variable was percent change in lumbar spine BMD from baseline to 1 year. Secondary efficacy variables included percent change in total hip, and femoral neck BMD from baseline to 1 year.
Treatment with Denosumab significantly increased BMD at 1 year. The treatment differences in BMD at 1 year were 4.8% (+0.9% placebo, +5.7% Denosumab; (95% CI: 4.0, 5.6); p < 0.0001) at the lumbar spine, 2.0% (+0.3% placebo, +2.4% Denosumab) at the total hip, and 2.2% (0.0% placebo, +2.1% Denosumab) at femoral neck. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, BMD, testosterone concentrations and level of bone turnover.
Bone Histology and Histomorphometry
A total of 29 transiliac crest bone biopsy specimens were obtained from men with osteoporosis at 12 months (17 specimens in Denosumab group, 12 specimens in placebo group). Of the biopsies obtained, 29 (100%) were adequate for qualitative histology and, in Denosumab patients, 6 (35%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Denosumab. The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In patients treated with Denosumab, 6% had no tetracycline label present at the month 12 biopsy, while 100% of placebo-treated patients had double label present. When compared to placebo, treatment with Denosumab resulted in markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.
### Treatment of Bone Loss in Men with Prostate Cancer
The efficacy and safety of Denosumab in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) were demonstrated in a 3‑year, randomized (1:1), double-blind, placebo-controlled, multinational study. Men less than 70 years of age had either a BMD T‑score at the lumbar spine, total hip, or femoral neck between ‑1.0 and -4.0, or a history of an osteoporotic fracture. The mean baseline lumbar spine BMD T-score was -0.4, and 22% of men had a vertebral fracture at baseline. The 1468 men enrolled ranged in age from 48 to 97 years (median 76 years). Men were randomized to receive subcutaneous injections of either placebo (n = 734) or Denosumab 60 mg (n = 734) once every 6 months for a total of 6 doses. Randomization was stratified by age ( 6 months). Seventy-nine percent of patients received ADT for more than 6 months at study entry. All men received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
Effect on Bone Mineral Density (BMD)
The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 24. An additional key secondary efficacy variable was the incidence of new vertebral fracture through month 36 diagnosed based on x-ray evaluation by two independent radiologists. Lumbar spine BMD was higher at 2 years in Denosumab-treated patients as compared to placebo-treated patients .
With approximately 62% of patients followed for 3 years, treatment differences in BMD at 3 years were 7.9% (-1.2% placebo, +6.8% Denosumab) at the lumbar spine, 5.7% (-2.6% placebo, +3.2% Denosumab) at the total hip, and 4.9% (-1.8% placebo, +3.0% Denosumab) at the femoral neck. Consistent effects on BMD were observed at the lumbar spine in relevant subgroups defined by baseline age, BMD, and baseline history of vertebral fracture.
Effect on Vertebral Fractures
Denosumab significantly reduced the incidence of new vertebral fractures at 3 years (p = 0.0125), as shown in Table 4.
### Treatment of Bone Loss in Women with Breast Cancer
The efficacy and safety of Denosumab in the treatment of bone loss in women receiving adjuvant aromatase inhibitor (AI) therapy for breast cancer was assessed in a 2‑year, randomized (1:1), double-blind, placebo-controlled, multinational study. Women had baseline BMD T-scores between ‑1.0 to ‑2.5 at the lumbar spine, total hip, or femoral neck, and had not experienced fracture after age 25. The mean baseline lumbar spine BMD T-score was -1.1, and 2.0% of women had a vertebral fracture at baseline. The 252 women enrolled ranged in age from 35 to 84 years (median 59 years). Women were randomized to receive subcutaneous injections of either placebo (n = 125) or Denosumab 60 mg (n = 127) once every 6 months for a total of 4 doses. Randomization was stratified by duration of adjuvant AI therapy at trial entry (≤ 6 months vs. > 6 months). Sixty-two percent of patients received adjuvant AI therapy for more than 6 months at study entry. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
Effect on Bone Mineral Density (BMD)
The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 12. Lumbar spine BMD was higher at 12 months in Denosumab-treated patients as compared to placebo-treated patients .
With approximately 81% of patients followed for 2 years, treatment differences in BMD at 2 years were 7.6% (-1.4% placebo, +6.2% Denosumab) at the lumbar spine, 4.7 % (-1.0% placebo, +3.8% Denosumab) at the total hip, and 3.6% (-0.8% placebo, +2.8% Denosumab) at the femoral neck.
# How Supplied
Denosumab is supplied in a single-use prefilled syringe with a safety guard or in a single-use vial. The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex).
## Storage
Store Denosumab in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Prior to administration, Denosumab may be allowed to reach room temperature (up to 25°C/77°F) in the original container. Once removed from the refrigerator, Denosumab must not be exposed to temperatures above 25°C/77°F and must be used within 14 days. If not used within the 14 days, Denosumab should be discarded. Do not use Denosumab after the expiry date printed on the label.
Protect Denosumab from direct light and heat.
Avoid vigorous shaking of Denosumab.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
### Drug Products with Same Active Ingredient
Advise patients that denosumab is also marketed as Xgeva, and if taking Denosumab, they should not receive Xgeva .
### Hypersensitivity
Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions that they should not receive denosumab (Denosumab or Xgeva) .
### Hypocalcemia
Adequately supplement patients with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving Denosumab . Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcemia.
### Osteonecrosis of the Jaw
Advise patients to maintain good oral hygiene during treatment with Denosumab and to inform their dentist prior to dental procedures that they are receiving Denosumab. Patients should inform their physician or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery .
### Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Advise patients to report new or unusual thigh, hip, or groin pain .
### Serious Infections
Advise patients to seek prompt medical attention if they develop signs or symptoms of infections, including cellulitis .
### Dermatologic Reactions
Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatological reactions (dermatitis, rashes, and eczema) .
### Musculoskeletal Pain
Inform patients that severe bone, joint, and/or muscle pain have been reported in patients taking Denosumab. Patients should report severe symptoms if they develop .
### Embryo-Fetal Toxicity
Pregnancy
Advise patients that Denosumab is contraindicated in women who are pregnant and may cause fetal harm .
Males
Advise patients of a potential for fetal exposure to denosumab when a man treated with Denosumab has unprotected sexual intercourse with a pregnant partner
### Nursing Mothers
Advise patients that because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Denosumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother .
### Schedule of Administration
If a dose of Denosumab is missed, administer the injection as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection.
# Precautions with Alcohol
Alcohol-Denosumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Prolia
- Xgeva
# Look-Alike Drug Names
There is limited information about the look-alike names.
# Drug Shortage Status
# Price | Denosumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Sree Teja Yelamanchili, MBBS [3]
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# Overview
Denosumab is a monoclonal antibody that is FDA approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture, increase bone mass in men with osteoporosis, bone loss in men receiving androgen deprivation therapy for prostate cancer, bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer. Common adverse reactions include hypercholesterolemia, diarrhea, nausea, vomiting, arthralgia, backache, pain in limb, asthenia, headache, cystitis, nasopharyngitis, upper respiratory infection, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Recommended Dosage
- Denosumab should be administered by a healthcare professional.
- Recommended dose 60 mg SC injection once every 6 months.
- Administer Denosumab via subcutaneous injection in the upper arm, the upper thigh, or the abdomen.
- All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily
- If a dose of Denosumab is missed, administer the injection as soon as the patient is available. Thereafter, schedule injections every 6 months from the date of the last injection.
### Preparation and Administration
- Visually inspect Denosumab for particulate matter and discoloration prior to administration whenever solution and container permit. Denosumab is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.
- Latex Allergy: People sensitive to latex should not handle the grey needle cap on the single-use prefilled syringe, which contains dry natural rubber (a derivative of latex).
Prior to administration, Denosumab may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Denosumab in any other way.
Instructions for Prefilled Syringe with Needle Safety Guard
IMPORTANT: In order to minimize accidental needlesticks, the Denosumab single-use prefilled syringe will have a green safety guard; manually activate the safety guard after the injection is given.
DO NOT slide the green safety guard forward over the needle before administering the injection; it will lock in place and prevent injection.
Activate the green safety guard (slide over the needle) after the injection.
The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex); people sensitive to latex should not handle the cap.
Step 1: Remove Grey Needle Cap
Step 2: Administer Subcutaneous Injection
DO NOT put grey needle cap back on needle.
Step 3: Immediately Slide Green Safety Guard Over Needle
With the needle pointing away from you…
Hold the prefilled syringe by the clear plastic finger grip with one hand. Then, with the other hand, grasp the green safety guard by its base and gently slide it towards the needle until the green safety guard locks securely in place and/or you hear a “click.” DO NOT grip the green safety guard too firmly – it will move easily if you hold and slide it gently.
Immediately dispose of the syringe and needle cap in the nearest sharps container. DO NOT put the needle cap back on the used syringe.
Instructions for Single-use Vial
For administration of Denosumab from the single-use vial, use a 27-gauge needle to withdraw and inject the 1 mL dose. Do not re-enter the vial. Discard vial and any liquid remaining in the vial.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Denosumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Denosumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Denosumab is not recommended in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Denosumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Denosumab in pediatric patients.
# Contraindications
### Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with Denosumab.
### Pregnancy
Denosumab may cause fetal harm when administered to a pregnant woman. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Denosumab is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
### Hypersensitivity
Denosumab is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling and urticaria
# Warnings
### Drug Products with Same Active Ingredient
Denosumab contains the same active ingredient (denosumab) found in Xgeva. Patients receiving Denosumab should not receive Xgeva.
### Hypersensitivity
Clinically significant hypersensitivity including anaphylaxis has been reported with Denosumab. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Denosumab.
### Hypocalcemia and Mineral Metabolism
Hypocalcemia may be exacerbated by the use of Denosumab. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Denosumab. In patients predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment (creatinine clearance <30 mL/min or receiving dialysis), clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended.
Hypocalcemia following Denosumab administration is a significant risk in patients with severe renal impairment [creatinine clearance <30 mL/min] or receiving dialysis. These patients may also develop marked elevations of serum parathyroid hormone (PTH). Instruct all patients with severe renal impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.
Adequately supplement all patients with calcium and vitamin D.
### Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab. A routine oral exam should be performed by the prescriber prior to initiation of Denosumab treatment. A dental examination with appropriate preventive dentistry should be considered prior to treatment with Denosumab in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Denosumab.
For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment.
Patients who are suspected of having or who develop ONJ while on Denosumab should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Denosumab therapy should be considered based on individual benefit-risk assessment.
### Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical low-energy or low trauma fractures of the shaft have been reported in patients receiving Denosumab. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents.
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.During Denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Denosumab therapy should be considered, pending a risk/benefit assessment, on an individual basis.
### Serious Infections
In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Denosumab group than in the placebo group. Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more frequent in patients treated with Denosumab. Endocarditis was also reported more frequently in Denosumab-treated patients. The incidence of opportunistic infections was similar between placebo and Denosumab groups, and the overall incidence of infections was similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.
Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. Consider the benefit-risk profile in such patients before treating with Denosumab. In patients who develop serious infections while on Denosumab, prescribers should assess the need for continued Denosumab therapy.
### Dermatologic Adverse Reactions
In a large clinical trial of over 7800 women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate in the Denosumab group compared to the placebo group. Most of these events were not specific to the injection site . Consider discontinuing Denosumab if severe symptoms develop.
### Musculoskeletal Pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Denosumab. The time to onset of symptoms varied from one day to several months after starting Denosumab. Consider discontinuing use if severe symptoms develop .
### Suppression of Bone Turnover
In clinical trials in women with postmenopausal osteoporosis, treatment with Denosumab resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment with Denosumab are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with Denosumab may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. Monitor patients for these consequences.
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are discussed below and also elsewhere in the labeling:
- Hypocalcemia
- Serious Infections
- Dermatologic adverse reactions
- Osteonecrosis of the Jaw
- Atypical subtrochanteric and diaphyseal femoral fractures
The most common adverse reactions reported with Denosumab in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.
The most common adverse reactions reported with Denosumab in men with osteoporosis are back pain, arthralgia, and nasopharyngitis.
The most common (per patient incidence ≥ 10%) adverse reactions reported with Denosumab in patients with bone loss receiving androgen deprivation therapy for prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials.
The most common adverse reactions leading to discontinuation of Denosumab in patients with postmenopausal osteoporosis are back pain and constipation.
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
The safety of Denosumab in the treatment of postmenopausal osteoporosis was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 7808 postmenopausal women aged 60 to 91 years. A total of 3876 women were exposed to placebo and 3886 women were exposed to Denosumab administered subcutaneously once every 6 months as a single 60 mg dose. All women were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.
The incidence of all-cause mortality was 2.3% (n = 90) in the placebo group and 1.8% (n = 70) in the Denosumab group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the Denosumab group. The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and Denosumab groups, respectively.
Adverse reactions reported in ≥ 2% of postmenopausal women with osteoporosis and more frequently in the Denosumab-treated women than in the placebo-treated women are shown in the table below.
Hypocalcemia
Decreases in serum calcium levels to less than 8.5 mg/dL at any visit were reported in 0.4% women in the placebo group and 1.7% women in the Denosumab group. The nadir in serum calcium level occurs at approximately day 10 after Denosumab dosing in subjects with normal renal function.
In clinical studies, subjects with impaired renal function were more likely to have greater reductions in serum calcium levels compared to subjects with normal renal function. In a study of 55 subjects with varying degrees of renal function, serum calcium levels < 7.5 mg/dL or symptomatic hypocalcemia were observed in 5 subjects. These included no subjects in the normal renal function group, 10% of subjects in the creatinine clearance 50 to 80 mL/min group, 29% of subjects in the creatinine clearance < 30 mL/min group, and 29% of subjects in the hemodialysis group. These subjects did not receive calcium and vitamin D supplementation. In a study of 4550 postmenopausal women with osteoporosis, the mean change from baseline in serum calcium level 10 days after Denosumab dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance ≥ 30 mL/min.
Serious Infections
Receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed on activated T and B lymphocytes and in lymph nodes. Therefore, a RANKL inhibitor such as Denosumab may increase the risk of infection.
In the clinical study of 7808 postmenopausal women with osteoporosis, the incidence of infections resulting in death was 0.2% in both placebo and Denosumab treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the Denosumab groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% Denosumab), urinary tract (0.5% placebo vs. 0.7% Denosumab), and ear (0.0% placebo vs. 0.1% Denosumab) were reported. Endocarditis was reported in no placebo patients and 3 patients receiving Denosumab.
Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with Denosumab (< 0.1% placebo vs. 0.4% Denosumab).
The incidence of opportunistic infections was similar to that reported with placebo.
Dermatologic Reactions
A significantly higher number of patients treated with Denosumab developed epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 10.8% of the Denosumab groups (p < 0.0001). Most of these events were not specific to the injection site.
Osteonecrosis of the Jaw
Osteonecrosis of the jaw has been reported in the osteoporosis clinical trial program in patients treated with Denosumab.
Atypical Subtrochanteric and Diaphyseal Fractures
In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with Denosumab. The duration of Denosumab exposure to time of atypical femoral fracture diagnosis was as early as 2½ years.
Pancreatitis
Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Denosumab groups. Of these reports, 1 patient in the placebo group and all 8 patients in the Denosumab group had serious events, including one death in the Denosumab group. Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable.
New Malignancies
The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Denosumab groups. New malignancies related to the breast (0.7% placebo vs. 0.9% Denosumab), reproductive system (0.2% placebo vs. 0.5% Denosumab), and gastrointestinal system (0.6% placebo vs. 0.9% Denosumab) were reported. A causal relationship to drug exposure has not been established.
The safety of Denosumab in the treatment of men with osteoporosis was assessed in a 1-year randomized, double-blind, placebo-controlled study. A total of 120 men were exposed to placebo and 120 men were exposed to Denosumab administered subcutaneously once every 6 months as a single 60 mg dose. All men were instructed to take at least 1000 mg of calcium and 800 IU of vitamin D supplementation per day.
The incidence of all-cause mortality was 0.8% (n = 1) in the placebo group and 0.8% (n = 1) in the Denosumab group. The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the Denosumab group. The percentage of patients who withdrew from the study due to adverse events was 0% and 2.5% for the placebo and Denosumab groups, respectively.
Adverse reactions reported in ≥ 5% of men with osteoporosis and more frequently with Denosumab than in the placebo-treated patients were: back pain (6.7% placebo vs. 8.3% Denosumab), arthralgia (5.8% placebo vs. 6.7% Denosumab), and nasopharyngitis (5.8% placebo vs. 6.7% Denosumab).
Serious Infections
Serious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the Denosumab group.
Dermatologic Reactions
Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 4 patients (3.3%) in the placebo group and 5 patients (4.2%) in the Denosumab group.
Osteonecrosis of the Jaw
No cases of ONJ were reported.
Pancreatitis
Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the Denosumab group.
New Malignancies
New malignancies were reported in no patients in the placebo group and 4 (3.3%) patients (3 prostate cancers, 1 basal cell carcinoma) in the Denosumab group.
The safety of Denosumab in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) was assessed in a 3‑year, randomized, double-blind, placebo-controlled, multinational study of 1468 men aged 48 to 97 years. A total of 725 men were exposed to placebo and 731 men were exposed to Denosumab administered once every 6 months as a single 60 mg subcutaneous dose. All men were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.
The incidence of serious adverse events was 30.6% in the placebo group and 34.6% in the Denosumab group. The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the placebo and Denosumab groups, respectively.
The safety of Denosumab in the treatment of bone loss in women with nonmetastatic breast cancer receiving aromatase inhibitor.
## Postmarketing Experience
Because postmarketing 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.
The following adverse reactions have been identified during post approval use of Denosumab:
- Drug-related hypersensitivity reactions: anaphylaxis, rash, urticaria, facial swelling, and erythema
- Hypocalcemia: severe symptomatic hypocalcemia
- Musculoskeletal pain, including severe cases
- Parathyroid Hormone (PTH): Marked elevation in serum PTH in patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis.
# Drug Interactions
In subjects with postmenopausal osteoporosis, Denosumab (60 mg subcutaneous injection) did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4), indicating that it should not affect the pharmacokinetics of drugs metabolized by this enzyme in this population.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
Risk Summary
Denosumab may cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Denosumab is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Women who become pregnant during Denosumab 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.
Clinical Considerations
The effects of Denosumab on the fetus are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies, such as denosumab, are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Denosumab therapy, treatment should be discontinued and the patient should consult their physician.
Animal Data
The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to 1 month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels).
Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated.
In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Denosumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Denosumab during labor and delivery.
### Nursing Mothers
It is not known whether Denosumab is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Denosumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Maternal exposure to Denosumab during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated
### Pediatric Use
Denosumab is not recommended in pediatric patients. The safety and effectiveness of Denosumab in pediatric patients have not been established.
Treatment with Denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Denosumab therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 10 and 50 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered every 6 months, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab.
Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes, reduced hematopoiesis, tooth malalignment, and decreased neonatal growth. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth.
### Geriatic Use
Of the total number of patients in clinical studies of Denosumab, 9943 patients (76%) were ≥ 65 years old, while 3576 (27%) were ≥ 75 years old. Of the patients in the osteoporosis study in men, 133 patients (55%) were ≥ 65 years old, while 39 patients (16%) were ≥ 75 years old. No overall differences in safety or efficacy 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.
### Gender
Denosumab may cause fetal harm.
The extent to which denosumab is present in seminal fluid is unknown. There is a potential for fetal exposure to denosumab when a man treated with Denosumab has unprotected sexual intercourse with a pregnant partner. The risk of fetal harm is likely to be low. Advise men being treated with Denosumab who have a pregnant partner of this potential risk.
### Race
There is no FDA guidance on the use of Denosumab with respect to specific racial populations.
### Renal Impairment
No dose adjustment is necessary in patients with renal impairment.
In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcemia. Consider the benefit-risk profile when administering Denosumab to patients with severe renal impairment or receiving dialysis. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.
### Hepatic Impairment
No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Denosumab.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Denosumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Denosumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Subcutaneous injection
### Monitoring
There is limited information about the drug monitoring.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
There is no experience with overdosage with Denosumab.
# Pharmacology
## Mechanism of Action
Denosumab binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.
## Structure
Denosumab (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
Denosumab is a sterile, preservative-free, clear, colorless to pale yellow solution.
Each 1 mL single-use prefilled syringe of Denosumab contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.
Each 1 mL single-use vial of Denosumab contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.
## Pharmacodynamics
In clinical studies, treatment with 60 mg of Denosumab resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of Denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of Denosumab on bone remodeling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by Denosumab was similar to that observed in patients initiating Denosumab treatment.
Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e. osteocalcin and procollagen type 1 N-terminal peptide [PlNP]) were observed starting 1 month after the first dose of Denosumab. After discontinuation of Denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months.
## Pharmacokinetics
In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered Denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (Cmax) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (Tmax) was 10 days (range: 3 to 21 days). After Cmax, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg×day/mL (SD = 101 mcg×day/mL).
No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months.
Denosumab pharmacokinetics were not affected by the formation of binding antibodies.
A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg).
Drug Interactions
In a study of 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered two weeks after a single dose of denosumab (60 mg subcutaneous injection), which approximates the Tmax of denosumab. Denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the pharmacokinetics of drugs metabolized by CYP3A4 in postmenopausal women with osteoporosis.
Specific Populations
Gender:Mean serum denosumab concentration-time profiles observed in a study conducted in healthy men ≥ 50 years were similar to those observed in a study conducted in postmenopausal women using the same dose regimen.
Age: The pharmacokinetics of denosumab were not affected by age across all populations studied whose ages ranged from 28 to 87 years.
Race: The pharmacokinetics of denosumab were not affected by race.
Renal Impairment: In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary.
Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity
The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.
Mutagenicity
The genotoxic potential of denosumab has not been evaluated.
Impairment of Fertility
Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg).
### Animal Toxicology and/or Pharmacology
Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.
In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and increased bone mineral density (BMD) and strength of cancellous and cortical bone at doses 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg). Bone tissue was normal with no evidence of mineralization defects, accumulation of osteoid, or woven bone.
Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (“knockout”) mice or use of other biological inhibitors of the RANK/RANKL pathway, namely OPG-Fc, provided additional information on the pharmacodynamic properties of denosumab. RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy). Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued.
# Clinical Studies
### Postmenopausal Women with Osteoporosis
The efficacy and safety of Denosumab in the treatment of postmenopausal osteoporosis was demonstrated in a 3-year, randomized, double-blind, placebo-controlled trial. Enrolled women had a baseline BMD T‑score between -2.5 and -4.0 at either the lumbar spine or total hip. Women with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget’s disease) or on therapies that affect bone were excluded from this study. The 7808 enrolled women were aged 60 to 91 years with a mean age of 72 years. Overall, the mean baseline lumbar spine BMD T-score was -2.8, and 23% of women had a vertebral fracture at baseline. Women were randomized to receive subcutaneous injections of either placebo (N = 3906) or Denosumab 60 mg (N = 3902) once every 6 months. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4-L4) using a semiquantitative scoring method. Secondary efficacy variables included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years.
Effect on Vertebral Fractures
Denosumab significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years (p < 0.0001), as shown in Table 2. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the Denosumab-treated women. The absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3.
Denosumab was effective in reducing the risk for new morphometric vertebral fractures regardless of age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for osteoporosis.
Effect on Hip Fractures
The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Denosumab-treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a relative risk reduction of 40% at 3 years (p = 0.04) (Figure 1).
Effect on Nonvertebral Fractures
Treatment with Denosumab resulted in a significant reduction in the incidence of nonvertebral fractures (Table 3)
Effect on Bone Mineral Density (BMD)
Treatment with Denosumab significantly increased BMD at all anatomic sites measured at 3 years. The treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% at the femoral neck. Consistent effects on BMD were observed at the lumbar spine, regardless of baseline age, race, weight/body mass index (BMI), baseline BMD, and level of bone turnover.
After Denosumab discontinuation, BMD returned to approximately baseline levels within 12 months.
Bone Histology and Histomorphometry
A total of 115 transiliac crest bone biopsy specimens were obtained from 92 postmenopausal women with osteoporosis at either month 24 and/or month 36 (53 specimens in Denosumab group, 62 specimens in placebo group). Of the biopsies obtained, 115 (100%) were adequate for qualitative histology and 7 (6%) were adequate for full quantitative histomorphometry assessment.
Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Denosumab.
The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In patients treated with Denosumab, 35% had no tetracycline label present at the month 24 biopsy and 38% had no tetracycline label present at the month 36 biopsy, while 100% of placebo-treated patients had double label present at both time points. When compared to placebo, treatment with Denosumab resulted in virtually absent activation frequency and markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.
### Treatment to Increase Bone Mass in Men with Osteoporosis
The efficacy and safety of Denosumab in the treatment to increase bone mass in men with osteoporosis was demonstrated in a 1-year, randomized, double-blind, placebo-controlled trial. Enrolled men had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck were also enrolled if there was a history of prior fragility fracture. Men with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget’s disease) or on therapies that may affect bone were excluded from this study. The 242 men enrolled in the study ranged in age from 31 to 84 years with a mean age of 65 years. Men were randomized to receive SC injections of either placebo (n = 121) or Denosumab 60 mg (n = 121) once every 6 months. All men received at least 1000 mg calcium and at least 800 IU vitamin D supplementation daily.
Effect on Bone Mineral Density (BMD)
The primary efficacy variable was percent change in lumbar spine BMD from baseline to 1 year. Secondary efficacy variables included percent change in total hip, and femoral neck BMD from baseline to 1 year.
Treatment with Denosumab significantly increased BMD at 1 year. The treatment differences in BMD at 1 year were 4.8% (+0.9% placebo, +5.7% Denosumab; (95% CI: 4.0, 5.6); p < 0.0001) at the lumbar spine, 2.0% (+0.3% placebo, +2.4% Denosumab) at the total hip, and 2.2% (0.0% placebo, +2.1% Denosumab) at femoral neck. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, BMD, testosterone concentrations and level of bone turnover.
Bone Histology and Histomorphometry
A total of 29 transiliac crest bone biopsy specimens were obtained from men with osteoporosis at 12 months (17 specimens in Denosumab group, 12 specimens in placebo group). Of the biopsies obtained, 29 (100%) were adequate for qualitative histology and, in Denosumab patients, 6 (35%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Denosumab. The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In patients treated with Denosumab, 6% had no tetracycline label present at the month 12 biopsy, while 100% of placebo-treated patients had double label present. When compared to placebo, treatment with Denosumab resulted in markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.
### Treatment of Bone Loss in Men with Prostate Cancer
The efficacy and safety of Denosumab in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) were demonstrated in a 3‑year, randomized (1:1), double-blind, placebo-controlled, multinational study. Men less than 70 years of age had either a BMD T‑score at the lumbar spine, total hip, or femoral neck between ‑1.0 and -4.0, or a history of an osteoporotic fracture. The mean baseline lumbar spine BMD T-score was -0.4, and 22% of men had a vertebral fracture at baseline. The 1468 men enrolled ranged in age from 48 to 97 years (median 76 years). Men were randomized to receive subcutaneous injections of either placebo (n = 734) or Denosumab 60 mg (n = 734) once every 6 months for a total of 6 doses. Randomization was stratified by age (< 70 years vs. ≥ 70 years) and duration of ADT at trial entry (≤ 6 months vs. > 6 months). Seventy-nine percent of patients received ADT for more than 6 months at study entry. All men received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
Effect on Bone Mineral Density (BMD)
The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 24. An additional key secondary efficacy variable was the incidence of new vertebral fracture through month 36 diagnosed based on x-ray evaluation by two independent radiologists. Lumbar spine BMD was higher at 2 years in Denosumab-treated patients as compared to placebo-treated patients [-1.0% placebo, +5.6% Denosumab; treatment difference 6.7% (95% CI: 6.2, 7.1); p < 0.0001].
With approximately 62% of patients followed for 3 years, treatment differences in BMD at 3 years were 7.9% (-1.2% placebo, +6.8% Denosumab) at the lumbar spine, 5.7% (-2.6% placebo, +3.2% Denosumab) at the total hip, and 4.9% (-1.8% placebo, +3.0% Denosumab) at the femoral neck. Consistent effects on BMD were observed at the lumbar spine in relevant subgroups defined by baseline age, BMD, and baseline history of vertebral fracture.
Effect on Vertebral Fractures
Denosumab significantly reduced the incidence of new vertebral fractures at 3 years (p = 0.0125), as shown in Table 4.
### Treatment of Bone Loss in Women with Breast Cancer
The efficacy and safety of Denosumab in the treatment of bone loss in women receiving adjuvant aromatase inhibitor (AI) therapy for breast cancer was assessed in a 2‑year, randomized (1:1), double-blind, placebo-controlled, multinational study. Women had baseline BMD T-scores between ‑1.0 to ‑2.5 at the lumbar spine, total hip, or femoral neck, and had not experienced fracture after age 25. The mean baseline lumbar spine BMD T-score was -1.1, and 2.0% of women had a vertebral fracture at baseline. The 252 women enrolled ranged in age from 35 to 84 years (median 59 years). Women were randomized to receive subcutaneous injections of either placebo (n = 125) or Denosumab 60 mg (n = 127) once every 6 months for a total of 4 doses. Randomization was stratified by duration of adjuvant AI therapy at trial entry (≤ 6 months vs. > 6 months). Sixty-two percent of patients received adjuvant AI therapy for more than 6 months at study entry. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
Effect on Bone Mineral Density (BMD)
The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 12. Lumbar spine BMD was higher at 12 months in Denosumab-treated patients as compared to placebo-treated patients [-0.7% placebo, +4.8% Denosumab; treatment difference 5.5% (95% CI: 4.8, 6.3); p < 0.0001].
With approximately 81% of patients followed for 2 years, treatment differences in BMD at 2 years were 7.6% (-1.4% placebo, +6.2% Denosumab) at the lumbar spine, 4.7 % (-1.0% placebo, +3.8% Denosumab) at the total hip, and 3.6% (-0.8% placebo, +2.8% Denosumab) at the femoral neck.
# How Supplied
Denosumab is supplied in a single-use prefilled syringe with a safety guard or in a single-use vial. The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex).
## Storage
Store Denosumab in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Prior to administration, Denosumab may be allowed to reach room temperature (up to 25°C/77°F) in the original container. Once removed from the refrigerator, Denosumab must not be exposed to temperatures above 25°C/77°F and must be used within 14 days. If not used within the 14 days, Denosumab should be discarded. Do not use Denosumab after the expiry date printed on the label.
Protect Denosumab from direct light and heat.
Avoid vigorous shaking of Denosumab.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
### Drug Products with Same Active Ingredient
Advise patients that denosumab is also marketed as Xgeva, and if taking Denosumab, they should not receive Xgeva [see Warnings and Precautions (5.1)].
### Hypersensitivity
Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions that they should not receive denosumab (Denosumab or Xgeva) [see Warnings & Precautions (5.2), Contraindications (4.3)].
### Hypocalcemia
Adequately supplement patients with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving Denosumab [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcemia.
### Osteonecrosis of the Jaw
Advise patients to maintain good oral hygiene during treatment with Denosumab and to inform their dentist prior to dental procedures that they are receiving Denosumab. Patients should inform their physician or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery [see Warnings and Precautions (5.4)].
### Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Advise patients to report new or unusual thigh, hip, or groin pain [see Warnings and Precautions (5.5)].
### Serious Infections
Advise patients to seek prompt medical attention if they develop signs or symptoms of infections, including cellulitis [see Warnings and Precautions (5.6)].
### Dermatologic Reactions
Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatological reactions (dermatitis, rashes, and eczema) [see Warnings and Precautions (5.7)].
### Musculoskeletal Pain
Inform patients that severe bone, joint, and/or muscle pain have been reported in patients taking Denosumab. Patients should report severe symptoms if they develop [see Warnings and Precautions (5.8)].
### Embryo-Fetal Toxicity
Pregnancy
Advise patients that Denosumab is contraindicated in women who are pregnant and may cause fetal harm [see Contraindications (4.2), Use in Specific Populations (8.1)].
Males
Advise patients of a potential for fetal exposure to denosumab when a man treated with Denosumab has unprotected sexual intercourse with a pregnant partner [see Use in Specific Populations (8.8)]
### Nursing Mothers
Advise patients that because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Denosumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother [see Use in Specific Populations (8.3)].
### Schedule of Administration
If a dose of Denosumab is missed, administer the injection as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection.
# Precautions with Alcohol
Alcohol-Denosumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Prolia
- Xgeva
# Look-Alike Drug Names
There is limited information about the look-alike names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Denosumab | |
f803457150d6ce3bdbc272fae2181dba16b1b1c1 | wikidoc | Dentition | Dentition
# Overview
Dentition is the development of teeth and their arrangement in the mouth.
All mammals except the monotremes, the edentates, the pangolins, and the cetaceans have up to four distinct types of teeth, with a maximum number for each. These are the incisor (cutting), the canine, the premolar, and the molar (grinding). Mammals that have distinct types of teeth are heterodont; others are homodont.
The number of teeth of each type is written as a dental formula for one side of the mouth, with the upper and lower teeth shown on separate rows. The number of teeth in a mouth is twice that listed as there are two sides. In each set, incisors are indicated first, canines second, premolars third, and finally molars. For example, the formula 2.1.2.3 for upper teeth indicates 2 incisors, 1 canine, 2 premolars, and 3 molars on one side of the upper mouth.
The human dental formula is:
Of cats it is:
The last upper premolar and first lower molar of the cat, since it is a carnivore, are called carnassials and are used to slice meat and skin. The armadillo, being homodont, has a dental formula that is simply 7/7.
The maximum dental formula for placental mammals is:
Non-placental mammals such as marsupials can have more teeth than placentals. The opossum's dental formula is:
In many mammals the children have a set of teeth that fall out and are replaced by adult teeth. These are called deciduous teeth, baby teeth or milk teeth. Animals that have two sets of teeth, one followed by the other, are said to be diphyodont. Normally the formula for milk teeth is the same as for adult teeth except that the premolars are missing.
The milk tooth formula for humans is:
The kitten has 26 teeth.
Teeth are numbered starting at 1 in each group, except the premolars which end at 4. This means that the carnassials are always the fourth upper premolar and the first lower molar. Thus the human teeth are I1, I2, C1, P3, P4, M1, M2, and M3.
# Other uses: Dentition in archaeology
Dentition, or the study of teeth, is an important area of study for archaeologists, especially those specializing in the study of older remains. Dentition affords many advantages over studying the rest of the skeleton itself (osteometry). The structure and arrangement of teeth is constant and, although it is inherited, does not undergo extensive change during environmental change, dietary specializations, or alterations in use patterns. The rest of the skeleton is much more likely to exhibit change because of adaptation. Teeth also preserve better than bone, and so the sample of teeth available to archaeologists is much more extensive and therefore more representative.
Dentition is particularly useful in tracking ancient populations' movements, because, although all humans have the same basic 32 teeth, there are subtle differences in the shapes of incisors, the number of grooves on molars, and extra cusps on particular teeth. These differences can not only be associated with different populations across space, but also change over time so that the study of the characteristics of teeth could say which population one is dealing with, and at what point in that population's history they are. | Dentition
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dentition is the development of teeth and their arrangement in the mouth.
All mammals except the monotremes, the edentates, the pangolins, and the cetaceans have up to four distinct types of teeth, with a maximum number for each. These are the incisor (cutting), the canine, the premolar, and the molar (grinding). Mammals that have distinct types of teeth are heterodont; others are homodont.
The number of teeth of each type is written as a dental formula for one side of the mouth, with the upper and lower teeth shown on separate rows. The number of teeth in a mouth is twice that listed as there are two sides. In each set, incisors are indicated first, canines second, premolars third, and finally molars. For example, the formula 2.1.2.3 for upper teeth indicates 2 incisors, 1 canine, 2 premolars, and 3 molars on one side of the upper mouth.
The human dental formula is:
Template:Dentition2
Of cats it is:
Template:Dentition2
The last upper premolar and first lower molar of the cat, since it is a carnivore, are called carnassials and are used to slice meat and skin. The armadillo, being homodont, has a dental formula that is simply 7/7.
The maximum dental formula for placental mammals is:
Template:Dentition2
Non-placental mammals such as marsupials can have more teeth than placentals. The opossum's dental formula is:
Template:Dentition2
In many mammals the children have a set of teeth that fall out and are replaced by adult teeth. These are called deciduous teeth, baby teeth or milk teeth. Animals that have two sets of teeth, one followed by the other, are said to be diphyodont. Normally the formula for milk teeth is the same as for adult teeth except that the premolars are missing.
The milk tooth formula for humans is:
Template:Dentition2
The kitten has 26 teeth.
Teeth are numbered starting at 1 in each group, except the premolars which end at 4. This means that the carnassials are always the fourth upper premolar and the first lower molar. Thus the human teeth are I1, I2, C1, P3, P4, M1, M2, and M3.
# Other uses: Dentition in archaeology
Dentition, or the study of teeth, is an important area of study for archaeologists, especially those specializing in the study of older remains. Dentition affords many advantages over studying the rest of the skeleton itself (osteometry). The structure and arrangement of teeth is constant and, although it is inherited, does not undergo extensive change during environmental change, dietary specializations, or alterations in use patterns. The rest of the skeleton is much more likely to exhibit change because of adaptation. Teeth also preserve better than bone, and so the sample of teeth available to archaeologists is much more extensive and therefore more representative.
Dentition is particularly useful in tracking ancient populations' movements, because, although all humans have the same basic 32 teeth, there are subtle differences in the shapes of incisors, the number of grooves on molars, and extra cusps on particular teeth. These differences can not only be associated with different populations across space, but also change over time so that the study of the characteristics of teeth could say which population one is dealing with, and at what point in that population's history they are. | https://www.wikidoc.org/index.php/Dental_formula | |
669db27183723e51829103688af61734c5c72766 | wikidoc | Dentistry | Dentistry
# Overview
Dentistry is the "evaluation, diagnosis, prevention and/or treatment (nonsurgical, surgical or related procedures) of diseases, disorders and/or conditions of the oral cavity, maxillofacial area and/or the adjacent and associated structures and their impact on the human body". Those in the practice of dentistry are known as dentists. Other people aiding in oral health service include dental assistants, dental hygienists, dental technicians, and dental therapists.
A dentist is a healthcare professional qualified to practice dentistry after graduating with a degree of either Doctor of Dental Surgery (DDS), Doctor of Dental Medicine (DMD), Bachelor of Dentistry (BDent), Bachelor of Dental Science (BDSc), or Bachelor of Dental Surgery/Chirurgiae (BDS) or (BChD) or equivalent. In most western countries, to become a qualified dentist one must usually complete at least 4 years of postgraduate study. Generally, 2 years of clinical experience working with patients in an educational setting are required. While in most countries, dentists neither earn a Doctorate degree, or medical degree, they are afforded the honorary title "Doctor".
# History
Evidence of dentistry has been found in teeth dating from around 5500 BC to 7000 BC. The teeth, showing evidence of holes from dental drills, were found in people of the Indus Valley Civilization. A Sumerian text from 5000 BC describes a "tooth worm" as the cause of dental caries. Evidence of this belief has also been found in India, Egypt, Japan, and China.
The Edwin Smith Papyrus, written in the 17th century BC but which may reflect previous manuscripts from as early as 3000 BC, includes the treatment of several dental ailments. In the 18th century BC, the Code of Hammurabi referenced dental extraction twice as it related to punishment. Examination of the remains of some ancient Egyptians and Greco-Romans reveals early attempts at dental prosthetics and surgery.
Historically, dental extractions have been used to treat a variety of illnesses. During the Middle Ages and throughout the 19th century, dentistry was not a profession in itself, and often dental procedures were performed by barbers or general physicians. Barbers usually limited their practice to extracting teeth, which not only resulted in the alleviation of pain, but often cured a variety of ailments linked to chronic tooth infection. Instruments used for dental extractions date back several centuries. In the 14th century, Guy de Chauliac invented the dental pelican (resembling a pelican's beak) which was used up until the late 18th century. The pelican was replaced by the dental key which, in turn, was replaced by modern forceps in the 20th century.
The first book focused solely on dentistry was the "Artzney Buchlein" in 1530, and the first dental textbook written in English was called "Operator for the Teeth" by Charles Allen in 1685. It is said that the 17th century French physician Pierre Fauchard started dentistry science as we know it today, and he has been named "the father of modern dentistry". Among many of his developments were the extensive use of dental prosthesis, the introduction of dental fillings as a treatment for dental caries and the statement that sugar derivate acids such as tartaric acid are responsible for dental decay.
The Baltimore College of Dental Surgery, the first dental school in the world, opened in Baltimore, Maryland in 1840, and in 1867 Harvard Dental School became the first dental school affiliated with a university. In England, the 1878 British Dentists Act and 1879 Dentists Register limited the title of "dentist" and "dental surgeon" to qualified and registered practitioners. The practice of dentistry in the United Kingdom became fully regulated with the 1921 Dentists Act, which required the registration of anyone practicing dentistry. The British Dental Association, formed in 1880 with Sir John Tomes as president, played a major role in prosecuting dentists practicing illegally.
- Medieval dentist extracting a tooth. London; c. 1360-75.
- Farmer at the dentist, Johann Liss, c. 1616-17.
- A Dentist and Dental Assistant perform surgery on a patient.
# General dentistry
General practitioners of dentistry prevent, evaluate, diagnose, and treat diseases of the oral cavity and associated structures (e.g. the temporomandibular joint), as well as maintain the functionality and esthetics of the teeth and associated tissues and structures. They can prescribe drugs, x-rays, and devices for home or in-office use. Many oral diseases (such as bilateral odontogenic keratocysts) and abnormalities (such as several unerupted teeth) can indicate systemic, neural, or other diseases. A general practitioner may refer patients to their physician or a specialist for further evaluation, or vice versa for treatment.
Contrary to popular belief, most dentists do not regularly clean teeth, and instead delegate this task to other oral health providers (e.g. dental hygienists). Most general practitioners of dentistry perform restorative, prosthetic, routine endodontic therapy, routine periodontal therapy, and simple exodontia, as well as performing examinations. General practitioners can choose which cases to treat, and which will be referred to a specialist for further care. Many general practitioners are comfortable treating more complex cases, as well as placing implants and surgically extracting third molars(wisdom teeth). All dentists must achieve a certain degree of skill in various disciplines in order to graduate from dental school and earn licensure. Many complex procedures are frequently referred to specialists.
# Effectiveness
A 2008 review in the Journal of Dentistry concluded "While laboratory studies suggest a promising potential of ozone in dentistry, this has not been fully realised in clinical studies to date. More well designed and conducted double-blind randomised clinical trials with adequate sample size, limited or no loss to follow up, and carefully standardised methods of measurement and analyses are needed to evaluate the possible use of ozone as a treatment modality in dentistry."
# Specialities
In addition to general dentistry, there are 9 recognized dental specialties in the US, Canada, and Australia. To become a specialist requires one to train in a residency or advanced graduate training program. Once residency is completed, the doctor is granted a certificate of specialty training. Many specialty programs have optional or required advanced degrees such as (MD/MBBS specific to Maxillofacial Surgery), MS, or PhD.
- Dental public health (study of dental epidemiology and social health policies),
- Endodontics (root canal therapy and study of diseases of the dental pulp),
- Oral and Maxillofacial Pathology (study, diagnosis, and sometimes the treatment of oral and maxillofacial related diseases),
- Oral and Maxillofacial Radiology (study and radiologic interpretation of oral and maxillofacial diseases),
- Oral and Maxillofacial Surgery (extractions, facial surgery and implants),
- Orthodontics and Dentofacial Orthopaedics (straightening of teeth and modification of midface and mandibular growth),
- Anesthesiology study how to relieve pain through advanced use of local and general anesthesia techniques
- Periodontics (study and treatment of diseases of the periodontium (non-surgical and surgical), and placement and maintenance of dental implants),
- Pediatric Dentistry (i.e. dentistry for children, formerly known as "pedodontics"),
- Prosthodontics (dentures, bridges and the restoration of implants. Some prosthodontists further their training in "oral and maxillofacial prosthodontics--a discipline concerned with the replacement of missing facial structures--such as ears, eyes, nose, etc.)
Specialists in these fields are designated registrable (U.S. "Board Eligible") and warrant exclusive titles such as orthodontist, oral and maxillofacial surgeon, endodontist, pediatric dentist, periodontist, or prosthodontist upon satisfying certain local (U.S. "Board Certified"), (Australia/NZ: "FRACDS"), or (Canada: "FRCD(C)") registry requirements.
Two other post-graduate formal advanced education programs: General Practice Residency (advanced clinical and didactic training with intense hospital experience) and Advanced Education in General Dentistry (advanced training in clinical dentistry) recognized by the ADA do not lead to specialization.
Special category:
Oral Biology - Research in Dental and Craniofacial Biology
Other dental education exists where no post-graduate formal university training is required: cosmetic dentistry, dental implant, temporo-mandibular joint therapy. These usually require the attendance of one or more continuing education courses that typically last for one to several days. There are restrictions on allowing these dentists to call themselves specialists in these fields. The specialist titles are registrable titles and controlled by the local dental licensing bodies.
Forensic odontology consists of the gathering and use of dental evidence in law. This may be performed by any dentist with experience or training in this field. The function of the forensic dentist is primarily documentation and verification of identity.
Geriatric dentistry or geriodontics is the delivery of dental care to older adults involving the diagnosis, prevention, and treatment of problems associated with normal ageing and age-related diseases as part of an interdisciplinary team with other health care professionals.
Veterinary dentistry, a speciality of veterinary medicine, is the field of dentistry applied to the care of animals .
# Dentistry throughout the world
# Organizations | Dentistry
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dentistry is the "evaluation, diagnosis, prevention and/or treatment (nonsurgical, surgical or related procedures) of diseases, disorders and/or conditions of the oral cavity, maxillofacial area and/or the adjacent and associated structures and their impact on the human body".[1] Those in the practice of dentistry are known as dentists. Other people aiding in oral health service include dental assistants, dental hygienists, dental technicians, and dental therapists.
A dentist is a healthcare professional qualified to practice dentistry after graduating with a degree of either Doctor of Dental Surgery (DDS), Doctor of Dental Medicine (DMD), Bachelor of Dentistry (BDent), Bachelor of Dental Science (BDSc), or Bachelor of Dental Surgery/Chirurgiae (BDS) or (BChD) or equivalent. In most western countries, to become a qualified dentist one must usually complete at least 4 years of postgraduate study. Generally, 2 years of clinical experience working with patients in an educational setting are required. While in most countries, dentists neither earn a Doctorate degree, or medical degree, they are afforded the honorary title "Doctor".[2]
# History
Evidence of dentistry has been found in teeth dating from around 5500 BC to 7000 BC.[3][4] The teeth, showing evidence of holes from dental drills, were found in people of the Indus Valley Civilization.[5] A Sumerian text from 5000 BC describes a "tooth worm" as the cause of dental caries.[6] Evidence of this belief has also been found in India, Egypt, Japan, and China.[7]
The Edwin Smith Papyrus, written in the 17th century BC but which may reflect previous manuscripts from as early as 3000 BC, includes the treatment of several dental ailments.[8][9] In the 18th century BC, the Code of Hammurabi referenced dental extraction twice as it related to punishment.[10] Examination of the remains of some ancient Egyptians and Greco-Romans reveals early attempts at dental prosthetics and surgery.[2]
Historically, dental extractions have been used to treat a variety of illnesses. During the Middle Ages and throughout the 19th century, dentistry was not a profession in itself, and often dental procedures were performed by barbers or general physicians. Barbers usually limited their practice to extracting teeth, which not only resulted in the alleviation of pain, but often cured a variety of ailments linked to chronic tooth infection. Instruments used for dental extractions date back several centuries. In the 14th century, Guy de Chauliac invented the dental pelican[3] (resembling a pelican's beak) which was used up until the late 18th century. The pelican was replaced by the dental key[4] which, in turn, was replaced by modern forceps in the 20th century.
The first book focused solely on dentistry was the "Artzney Buchlein" in 1530, and the first dental textbook written in English was called "Operator for the Teeth" by Charles Allen in 1685.[11] It is said that the 17th century French physician Pierre Fauchard started dentistry science as we know it today, and he has been named "the father of modern dentistry". Among many of his developments were the extensive use of dental prosthesis, the introduction of dental fillings as a treatment for dental caries and the statement that sugar derivate acids such as tartaric acid are responsible for dental decay.
The Baltimore College of Dental Surgery, the first dental school in the world, opened in Baltimore, Maryland in 1840, and in 1867 Harvard Dental School became the first dental school affiliated with a university. In England, the 1878 British Dentists Act and 1879 Dentists Register limited the title of "dentist" and "dental surgeon" to qualified and registered practitioners.[12][11] The practice of dentistry in the United Kingdom became fully regulated with the 1921 Dentists Act, which required the registration of anyone practicing dentistry.[13] The British Dental Association, formed in 1880 with Sir John Tomes as president, played a major role in prosecuting dentists practicing illegally.[12]
- Medieval dentist extracting a tooth. London; c. 1360-75.
- Farmer at the dentist, Johann Liss, c. 1616-17.
- A Dentist and Dental Assistant perform surgery on a patient.
# General dentistry
General practitioners of dentistry prevent, evaluate, diagnose, and treat diseases of the oral cavity and associated structures (e.g. the temporomandibular joint), as well as maintain the functionality and esthetics of the teeth and associated tissues and structures. They can prescribe drugs, x-rays, and devices for home or in-office use. Many oral diseases (such as bilateral odontogenic keratocysts) and abnormalities (such as several unerupted teeth) can indicate systemic, neural, or other diseases. A general practitioner may refer patients to their physician or a specialist for further evaluation, or vice versa for treatment.
Contrary to popular belief, most dentists do not regularly clean teeth, and instead delegate this task to other oral health providers (e.g. dental hygienists). Most general practitioners of dentistry perform restorative, prosthetic, routine endodontic therapy, routine periodontal therapy, and simple exodontia, as well as performing examinations. General practitioners can choose which cases to treat, and which will be referred to a specialist for further care. Many general practitioners are comfortable treating more complex cases, as well as placing implants and surgically extracting third molars(wisdom teeth). All dentists must achieve a certain degree of skill in various disciplines in order to graduate from dental school and earn licensure. Many complex procedures are frequently referred to specialists.
# Effectiveness
A 2008 review in the Journal of Dentistry concluded "While laboratory studies suggest a promising potential of ozone in dentistry, this has not been fully realised in clinical studies to date. More well designed and conducted double-blind randomised clinical trials with adequate sample size, limited or no loss to follow up, and carefully standardised methods of measurement and analyses are needed to evaluate the possible use of ozone as a treatment modality in dentistry."[14]
# Specialities
In addition to general dentistry, there are 9 recognized dental specialties in the US, Canada, and Australia. To become a specialist requires one to train in a residency or advanced graduate training program. Once residency is completed, the doctor is granted a certificate of specialty training. Many specialty programs have optional or required advanced degrees such as (MD/MBBS specific to Maxillofacial Surgery), MS, or PhD.
- Dental public health (study of dental epidemiology and social health policies),
- Endodontics (root canal therapy and study of diseases of the dental pulp),
- Oral and Maxillofacial Pathology (study, diagnosis, and sometimes the treatment of oral and maxillofacial related diseases),
- Oral and Maxillofacial Radiology (study and radiologic interpretation of oral and maxillofacial diseases),
- Oral and Maxillofacial Surgery (extractions, facial surgery and implants),
- Orthodontics and Dentofacial Orthopaedics (straightening of teeth and modification of midface and mandibular growth),
- Anesthesiology study how to relieve pain through advanced use of local and general anesthesia techniques
- Periodontics (study and treatment of diseases of the periodontium (non-surgical and surgical), and placement and maintenance of dental implants),
- Pediatric Dentistry (i.e. dentistry for children, formerly known as "pedodontics"),
- Prosthodontics (dentures, bridges and the restoration of implants. Some prosthodontists further their training in "oral and maxillofacial prosthodontics--a discipline concerned with the replacement of missing facial structures--such as ears, eyes, nose, etc.)
Specialists in these fields are designated registrable (U.S. "Board Eligible") and warrant exclusive titles such as orthodontist, oral and maxillofacial surgeon, endodontist, pediatric dentist, periodontist, or prosthodontist upon satisfying certain local (U.S. "Board Certified"), (Australia/NZ: "FRACDS"), or (Canada: "FRCD(C)") registry requirements.
Two other post-graduate formal advanced education programs: General Practice Residency (advanced clinical and didactic training with intense hospital experience) and Advanced Education in General Dentistry (advanced training in clinical dentistry) recognized by the ADA do not lead to specialization.
Special category:
Oral Biology - Research in Dental and Craniofacial Biology
Other dental education exists where no post-graduate formal university training is required: cosmetic dentistry, dental implant, temporo-mandibular joint therapy. These usually require the attendance of one or more continuing education courses that typically last for one to several days. There are restrictions on allowing these dentists to call themselves specialists in these fields. The specialist titles are registrable titles and controlled by the local dental licensing bodies.
Forensic odontology consists of the gathering and use of dental evidence in law. This may be performed by any dentist with experience or training in this field. The function of the forensic dentist is primarily documentation and verification of identity.
Geriatric dentistry or geriodontics is the delivery of dental care to older adults involving the diagnosis, prevention, and treatment of problems associated with normal ageing and age-related diseases as part of an interdisciplinary team with other health care professionals.
Veterinary dentistry, a speciality of veterinary medicine, is the field of dentistry applied to the care of animals [5][6].
# Dentistry throughout the world
# Organizations | https://www.wikidoc.org/index.php/Dental_specialties | |
be3abc104dd605dcbf3043727be3d57213f9721c | wikidoc | Denturist | Denturist
# Overview
A Dental prosthetist or Denturist is a form of dental technician who constructs removable oral prosthesis (dentures) direct to the patient.
They are also known as registered clinical dental technicians in some countries. The major difference from a dental technician is that dental prosthetists do not typically work under the instruction of a dentist. Their duties are typically restricted to making just removable prosthesis, and referral to a dentist for other forms of dental work may be required.
They should not be confused with prosthodontists, who are qualified specialist dentists for making fixed or removable appliances for patients.
# Traditional duties
According to the National Denturist Association website , Denturists can perform the follow functions:
1. Perform a complete visual/digital oral examination and evaluation of the patient. This includes obtaining a complete medical and dental history of the patient.
2. Makes impressions, makes necessary jaw relation records, selects the artificial teeth, designs the dentures.
3. Fabricate and insert the dentures in the mouths of patients.
4. Performs any adjunctive services such as Repair or Relines or Adjustments of removable dentures.
5. Supervises auxiliary personnel in the performance of their delegated duties.
# Training
In order to become licensed as a Denturist an individual must graduate from an accredited course, usually two to three years in length, in addition to having at least four years experience and background in dental technology in most states and some provinces.
# Denturism
Denturism is defined as the practice by Denturists of making artificial dentures and fitting them to patients.
Denturism is a recognized profession throughout the world, in which a specialized dental practitioner, a Denturist, provides dentures and dental appliances directly to the public without the supervision of a Dentist.
The International Federation of Denturistsconsists of national organizations of Denturism
from around the world who are interested in furthering the profession, and providing the world's edentulous population with affordable, professional denture care.
Denturism is legislated and practiced in six U.S. states, Maine, Arizona, Washington, Oregon, Montana, and Colorado. It is illegal in other states, including Florida.
According to the College of Denturists of Ontario,Denturism has been a regulated profession in the Canadian province since 1973.
Currently eight of the ten Canadian provinces recognize the profession.
More recently the United Kingdom has legislated the profession. In the U.K.
Denturists are termed “Clinical Dental Technicians”. According to the Clinical Dental Technician’s Association,” Professional Clinical Dental Technicians are members of the Dental Health Care Team specifically trained and educated in the skills and knowledge necessary to provide a removable appliance service directly to the community.
Equipped with solid technical training as a Dental Technician and post-technician training in sciences, clinical skills, and interpersonal skills, the Clinical Dental Technician can design, create, construct and modify (repair and rebase) a removable appliance to insure optimal fit, maximum comfort and general well-being of patients. These skills enable the Clinical Dental Technician, whilst remaining a member of the Dental Health Care Team to work independently of other Dental Health Care providers.”
Australia is another country where the profession of Denturism is accepted and regulated.
In Australia a Denturist is referred to as a Dental Prosthetist.The Australian Dental Prosthetists Associationis the national organization in Australia.
# Distinguishing from dental technicians
A licensed Denturist is not only a Dental technician, although most Denturists were previously Dental technicians who sought the necessary further education in Denturism. This previous training and experience gives Denturists a unique advantage in that they become extremely familiar with cases of edentulism,oral anatomy and landmarks since that is their sole work as
Dental Technologists.
# Distinguishing from other dental professionals
According to the International Federation of Denturists,"University-trained dentists perform the full range of services related to the patient dental health care and well being (assessment, diagnosis, treatment etc.). The scope of practice for Denturists includes clinical work, but clearly delineates and draws distinctions between adjustment and/or alteration to natural teeth/tissues of the mouth, and appliances. Denturists work with constructed or prosthetic (artificial replacement) devices only. Dental technicians, by contrast, work in laboratories and are trained to make appliances for dentists. They have neither the technical training nor the legislated mandate to work directly with patients." | Denturist
# Overview
A Dental prosthetist or Denturist is a form of dental technician who constructs removable oral prosthesis (dentures) direct to the patient.[1]
They are also known as registered clinical dental technicians in some countries. The major difference from a dental technician is that dental prosthetists do not typically work under the instruction of a dentist. Their duties are typically restricted to making just removable prosthesis, and referral to a dentist for other forms of dental work may be required.
They should not be confused with prosthodontists, who are qualified specialist dentists for making fixed or removable appliances for patients.
# Traditional duties
According to the National Denturist Association website , Denturists can perform the follow functions:
1. Perform a complete visual/digital oral examination and evaluation of the patient. This includes obtaining a complete medical and dental history of the patient.
2. Makes impressions, makes necessary jaw relation records, selects the artificial teeth, designs the dentures.
3. Fabricate and insert the dentures in the mouths of patients.
4. Performs any adjunctive services such as Repair or Relines or Adjustments of removable dentures.
5. Supervises auxiliary personnel in the performance of their delegated duties.
# Training
In order to become licensed as a Denturist an individual must graduate from an accredited course, usually two to three years in length, in addition to having at least four years experience and background in dental technology in most states and some provinces.
# Denturism
Denturism is defined as the practice by Denturists of making artificial dentures and fitting them to patients.[2]
Denturism is a recognized profession throughout the world, in which a specialized dental practitioner, a Denturist, provides dentures and dental appliances directly to the public without the supervision of a Dentist.
The International Federation of Denturistsconsists of national organizations of Denturism
from around the world who are interested in furthering the profession, and providing the world's edentulous population with affordable, professional denture care.
Denturism is legislated and practiced in six U.S. states, Maine, Arizona, Washington, Oregon, Montana, and Colorado. It is illegal in other states, including Florida.[3]
According to the College of Denturists of Ontario,Denturism has been a regulated profession in the Canadian province since 1973.
Currently eight of the ten Canadian provinces recognize the profession.
More recently the United Kingdom has legislated the profession. In the U.K.
Denturists are termed “Clinical Dental Technicians”. According to the Clinical Dental Technician’s Association,” Professional Clinical Dental Technicians are members of the Dental Health Care Team specifically trained and educated in the skills and knowledge necessary to provide a removable appliance service directly to the community.
Equipped with solid technical training as a Dental Technician and post-technician training in sciences, clinical skills, and interpersonal skills, the Clinical Dental Technician can design, create, construct and modify (repair and rebase) a removable appliance to insure optimal fit, maximum comfort and general well-being of patients. These skills enable the Clinical Dental Technician, whilst remaining a member of the Dental Health Care Team to work independently of other Dental Health Care providers.”
Australia is another country where the profession of Denturism is accepted and regulated.
In Australia a Denturist is referred to as a Dental Prosthetist.The Australian Dental Prosthetists Associationis the national organization in Australia.
# Distinguishing from dental technicians
A licensed Denturist is not only a Dental technician, although most Denturists were previously Dental technicians who sought the necessary further education in Denturism. This previous training and experience gives Denturists a unique advantage in that they become extremely familiar with cases of edentulism,oral anatomy and landmarks since that is their sole work as
Dental Technologists.
# Distinguishing from other dental professionals
According to the International Federation of Denturists,"University-trained dentists perform the full range of services related to the patient dental health care and well being (assessment, diagnosis, treatment etc.). The scope of practice for Denturists includes clinical work, but clearly delineates and draws distinctions between adjustment and/or alteration to natural teeth/tissues of the mouth, and appliances. Denturists work with constructed or prosthetic (artificial replacement) devices only. Dental technicians, by contrast, work in laboratories and are trained to make appliances for dentists. They have neither the technical training nor the legislated mandate to work directly with patients." | https://www.wikidoc.org/index.php/Denturist | |
ff60e82a4444ef161ecabafacaddd889034ed20d | wikidoc | Vomitoxin | Vomitoxin
Vomitoxin, also known as deoxynivalenol (DON), is a type B trichothecene, an epoxy-sesquiterpeneoid. This mycotoxin occurs predominantly in grains such as wheat, barley, oats, rye, and maize, and less often in rice, sorghum, and triticale. The occurrence of deoxynivalenol is associated primarily with Fusarium graminearum (Gibberella zeae) and F. culmorum, both of which are important plant pathogens which cause Fusarium head blight in wheat and Gibberella ear rot in maize. A direct relationship between the incidence of Fusarium head blight and contamination of wheat with deoxynivalenol has been established. The incidence of Fusarium head blight is strongly associated with moisture at the time of flowering (anthesis), and the timing of rainfall, rather than the amount, is the most critical factor.
F. graminearum grows optimally at a temperature of 25 °C and at a water activity above 0.88. F. culmorum grows optimally at 21 °C and at a water activity above 0.87. The geographical distribution of the two species appears to be related to temperature, F. graminearum being the commoner species and occurring in warmer climates. Deoxynivalenol has been implicated in incidents of mycotoxicoses in both humans and farm animals.
Vomitoxin is rather a mild toxin compared to other toxins which can form in grains and forages. Reduced feed intake, and the accompanying decrease in performance, are the only symptoms of vomitoxin toxicity livestock producers will likely encounter. This response to vomitoxin appears to occur through the central nervous system. Vomitoxin belongs to a class of mycotoxins (tricothecenes) which are strong protein inhibitors. Inhibition of protein synthesis following exposure to vomitoxin causes the brain to increase its uptake of the amino acid tryptophan and, in turn, its synthesis of serotonin. Increased levels of serotonin are believed to be responsible for the anorexic effects of DON and other tricothecenes. Irritation of the gastrointestinal tract may also play a role in reducing feed intake... This fact may also partially explain the high incidence of pars esaughageal stomach ulcers observed in sows off feed during feed refusal.
- Human foods: Vomitoxin is not a known carcinogen as with aflatoxin. Large amounts of grain with vomitoxin would have to be consumed to pose a health risk to humans. The FDA has established a level of 1 ppm (parts per million) restriction of vomitoxin.
- Companion animals: Dogs and cats are restricted to 5 ppm and of grains and grain byproducts and that the grains not exceed 40% percent of the diet.
- Livestock and farm animals: In animals and livestock, vomitoxin causes a refusal to feed and lack of weight gain when fed above advised levels. Restrictions are set at 10 ppm for poultry and ruminating beef and feedlot cattle older than 4 months. Ingredients may not exceed 50% of the animal's diet. Dairy cow limits are set at 2 ppm. | Vomitoxin
Template:Chembox new
Vomitoxin, also known as deoxynivalenol (DON), is a type B trichothecene, an epoxy-sesquiterpeneoid. This mycotoxin occurs predominantly in grains such as wheat, barley, oats, rye, and maize, and less often in rice, sorghum, and triticale. The occurrence of deoxynivalenol is associated primarily with Fusarium graminearum (Gibberella zeae) and F. culmorum, both of which are important plant pathogens which cause Fusarium head blight in wheat and Gibberella ear rot in maize. A direct relationship between the incidence of Fusarium head blight and contamination of wheat with deoxynivalenol has been established. The incidence of Fusarium head blight is strongly associated with moisture at the time of flowering (anthesis), and the timing of rainfall, rather than the amount, is the most critical factor.
F. graminearum grows optimally at a temperature of 25 °C and at a water activity above 0.88. F. culmorum grows optimally at 21 °C and at a water activity above 0.87. The geographical distribution of the two species appears to be related to temperature, F. graminearum being the commoner species and occurring in warmer climates. Deoxynivalenol has been implicated in incidents of mycotoxicoses in both humans and farm animals.
Vomitoxin is rather a mild toxin compared to other toxins which can form in grains and forages. Reduced feed intake, and the accompanying decrease in performance, are the only symptoms of vomitoxin toxicity livestock producers will likely encounter. This response to vomitoxin appears to occur through the central nervous system. Vomitoxin belongs to a class of mycotoxins (tricothecenes) which are strong protein inhibitors. Inhibition of protein synthesis following exposure to vomitoxin causes the brain to increase its uptake of the amino acid tryptophan and, in turn, its synthesis of serotonin. Increased levels of serotonin are believed to be responsible for the anorexic effects of DON and other tricothecenes. Irritation of the gastrointestinal tract may also play a role in reducing feed intake... This fact may also partially explain the high incidence of pars esaughageal stomach ulcers observed in sows off feed during feed refusal.
- Human foods: Vomitoxin is not a known carcinogen as with aflatoxin. Large amounts of grain with vomitoxin would have to be consumed to pose a health risk to humans. The FDA has established a level of 1 ppm (parts per million) restriction of vomitoxin.
- Companion animals: Dogs and cats are restricted to 5 ppm and of grains and grain byproducts and that the grains not exceed 40% percent of the diet.
- Livestock and farm animals: In animals and livestock, vomitoxin causes a refusal to feed and lack of weight gain when fed above advised levels. Restrictions are set at 10 ppm for poultry and ruminating beef and feedlot cattle older than 4 months. Ingredients may not exceed 50% of the animal's diet. Dairy cow limits are set at 2 ppm. | https://www.wikidoc.org/index.php/Deoxynivalenol | |
5f1793086c713de16ee07f9129beabd5138f7ec6 | wikidoc | Deracoxib | Deracoxib
Deracoxib is a non-steroidal, anti-inflammatory drug of the coxib class.
# Indications and use
Deracoxib is commonly indicated for the control of pain and inflammation associated with osteoarthritis in dogs. It is not approved or recommended for use of pain control in cats.
# Dosage
Postoperative Pain Relief:
3 to 4 mg/kg/day as needed, not to exceed 7 days.
Osteroarthitis Pain Relief:
1 to 2 mg/kg/day adjusted to minimum effective dose that has good clinical results
This could mean anywhere from 1/4 of a pill every other day to 1 pill every day.
High doses can cause Cox-1 inhibition even though this drug is selective to Cox-2, which in turn can cause the side effects associated with NSAIDs.
# Contraindications
Use of deracoxib should be avoided in dogs who are hypersensitive to deracoxib or other NSAID; it should only be used in such dogs with extreme caution.
It also shouldn't be administered to dogs with gastro-intestinal ulcers, renal disease, hepatic disorders, hypoproteinemia, dehydration, or cardiac disease without extreme caution.
Dogs with renal disease may need dose adjustment (if the benefits of the medience outweigh the risks) while those on concurrent diuretic therapy are at increased risk for NSAID toxicity and should not be given this medication.
Concurrent use with steriods or other NSAIDs should be avoided.
Safety has not been established in pregnant or nursing dogs, so deracoxib should not be administered to such dogs.
Safetly also hasn't been established in dogs younger than 4 months of age, but young dogs may be given this drug so long as they are monitored closely for side effects.
Dogs weighing less than 6.3 kg (under 4 lbs) should not be given this medience for osteoarthitis pain and inflammation, and those weighing less than 3.1 kg should not be given this medience for post-operative pain relief.
Deracoxib is not approved for use in cats, so it shouldn't be given to them for pain relief.
# Side Effects
As with all NSAIDs, this medication may cause gastric ulercations, evidenced by diarrhea, vomiting, and other GI problems, particularly during long-term use or in sensitive individuals. The medication should be discontinued immediately if such side effects occur and owners should contact their veterinain. Such side effects are more likely to occur if this drug is used in combination with other NSAIDs or with steroids; therefore is not recommended to give it with other NSAIDs or steriods.
Other side effects include depression, lethargy, increase in drinking or urination, jaundice, vomiting, bloody or black stools, pale gums, hot spots, lethargy, increased respiration (fast or heavy breathing), incoordination, and behavior changes.
Because the medication is a Cox-2 inhibitor and less likely to inhibit protective mechanisms of prostaglandins, side effects are not as common as in other NSAIDs such as aspirin. Hence it is considered relatively safe in dogs.
# Brand names
- Novartis: Deramaxx
# External references
- American Clinical insert, Deramaxx
- Canadian Clinical insert, Deramaxx
- Novartis Deramaxx site | Deracoxib
Deracoxib is a non-steroidal, anti-inflammatory drug of the coxib class.
# Indications and use
Deracoxib is commonly indicated for the control of pain and inflammation associated with osteoarthritis in dogs. It is not approved or recommended for use of pain control in cats.
# Dosage
Postoperative Pain Relief:
3 to 4 mg/kg/day as needed, not to exceed 7 days.
Osteroarthitis Pain Relief:
1 to 2 mg/kg/day adjusted to minimum effective dose that has good clinical results
This could mean anywhere from 1/4 of a pill every other day to 1 pill every day.
High doses can cause Cox-1 inhibition even though this drug is selective to Cox-2, which in turn can cause the side effects associated with NSAIDs.
# Contraindications
Use of deracoxib should be avoided in dogs who are hypersensitive to deracoxib or other NSAID; it should only be used in such dogs with extreme caution.
It also shouldn't be administered to dogs with gastro-intestinal ulcers, renal disease, hepatic disorders, hypoproteinemia, dehydration, or cardiac disease without extreme caution.
Dogs with renal disease may need dose adjustment (if the benefits of the medience outweigh the risks) while those on concurrent diuretic therapy are at increased risk for NSAID toxicity and should not be given this medication.
Concurrent use with steriods or other NSAIDs should be avoided.
Safety has not been established in pregnant or nursing dogs, so deracoxib should not be administered to such dogs.
Safetly also hasn't been established in dogs younger than 4 months of age, but young dogs may be given this drug so long as they are monitored closely for side effects.
Dogs weighing less than 6.3 kg (under 4 lbs) should not be given this medience for osteoarthitis pain and inflammation, and those weighing less than 3.1 kg should not be given this medience for post-operative pain relief.
Deracoxib is not approved for use in cats, so it shouldn't be given to them for pain relief.
# Side Effects
As with all NSAIDs, this medication may cause gastric ulercations, evidenced by diarrhea, vomiting, and other GI problems, particularly during long-term use or in sensitive individuals. The medication should be discontinued immediately if such side effects occur and owners should contact their veterinain. Such side effects are more likely to occur if this drug is used in combination with other NSAIDs or with steroids; therefore is not recommended to give it with other NSAIDs or steriods.
Other side effects include depression, lethargy, increase in drinking or urination, jaundice, vomiting, bloody or black stools, pale gums, hot spots, lethargy, increased respiration (fast or heavy breathing), incoordination, and behavior changes.
Because the medication is a Cox-2 inhibitor and less likely to inhibit protective mechanisms of prostaglandins, side effects are not as common as in other NSAIDs such as aspirin. Hence it is considered relatively safe in dogs.
# Brand names
- Novartis: Deramaxx
# External references
- American Clinical insert, Deramaxx
- Canadian Clinical insert, Deramaxx
- Novartis Deramaxx site
Template:Pharma-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Deracoxib | |
1121a2c8c49ae91c732f8da9a56b7c5fa531edaf | wikidoc | DermAtlas | DermAtlas
DermAtlas is an open access web site devoted to dermatology that is hosted by Johns Hopkins University. Its goal is to build a large high quality dermatologic atlas, a database of images of skin conditions, and it encourages its users to submit their dermatology images and links for inclusion.
It is edited in a collaborative fashion by physicians around the globe and includes an online Dermatology Quiz, that allows any one to test their dermatology knowledge.
The database currently includes over 9500 images and consists of both clinical images and histological images. | DermAtlas
DermAtlas is an open access web site devoted to dermatology that is hosted by Johns Hopkins University. Its goal is to build a large high quality dermatologic atlas, a database of images of skin conditions, and it encourages its users to submit their dermatology images and links for inclusion.
It is edited in a collaborative fashion by physicians around the globe and includes an online Dermatology Quiz,[1] that allows any one to test their dermatology knowledge.
The database currently includes over 9500 images and consists of both clinical images and histological images. | https://www.wikidoc.org/index.php/DermAtlas | |
db7f59b3cefd640a2eee9d942bc456954796d85a | wikidoc | Dermcidin | Dermcidin
Dermicidin, also known as proteolysis-inducing factor (PIF), is a protein that in humans is encoded by the DCD gene. It is an anti-microbial peptide secreted by human eccrine sweat glands onto the skin as a part of the innate host defense of the immune system. It is also involved in proteolysis.
# Function
Dermicidin is a secreted protein that is subsequently processed into mature peptides of distinct biological activities. The C-terminal peptide is constitutively expressed in sweat and has antibacterial and antifungal activities. The N-terminal peptide, also known as diffusible survival evasion peptide, promotes neural cell survival under conditions of severe oxidative stress. A glycosylated form of the N-terminal peptide may be associated with cachexia (muscle wasting) in cancer patients.
The C-termial precursor DCD-1L is a 48 residue peptide that shows partial helicity in solution, as evidenced by the determination of its solution structure by NMR and CD-spectroscopy. The full length precursor is processed by undetermined proteases present in human sweat, to form several shorter peptides that show variable antimicrobial activity, named according to their C-terminal triplet of amino acids and their residue length. One such active peptide is SSL25, which shows a 2-fold increase in activity against E.coli compared to DCD-1L.
# Mechanism
The crystal structure of dermicidin has been solved in solution to reveal a hexameric helix-bundle, mediated by Zn ion binding. This is observed to form a tilted channel in membranes under computational examination by molecular dynamics simulations, and one suggested mechanism of antimicrobial action inferred from this observation is by ion gradient decoupling across biological membranes. This is supported by concurrent observations in experimental studies of a voltage dependent depolarization of lipid bilayers. | Dermcidin
Dermicidin, also known as proteolysis-inducing factor (PIF), is a protein that in humans is encoded by the DCD gene.[1][2] It is an anti-microbial peptide[2] secreted by human eccrine sweat glands onto the skin as a part of the innate host defense of the immune system. It is also involved in proteolysis.[2]
# Function
Dermicidin is a secreted protein that is subsequently processed into mature peptides of distinct biological activities. The C-terminal peptide is constitutively expressed in sweat and has antibacterial and antifungal activities. The N-terminal peptide, also known as diffusible survival evasion peptide, promotes neural cell survival under conditions of severe oxidative stress. A glycosylated form of the N-terminal peptide may be associated with cachexia (muscle wasting) in cancer patients.[2]
The C-termial precursor DCD-1L is a 48 residue peptide that shows partial helicity in solution, as evidenced by the determination of its solution structure by NMR and CD-spectroscopy. The full length precursor is processed by undetermined proteases present in human sweat, to form several shorter peptides that show variable antimicrobial activity, named according to their C-terminal triplet of amino acids and their residue length. One such active peptide is SSL25, which shows a 2-fold increase in activity against E.coli compared to DCD-1L.[3]
# Mechanism
The crystal structure of dermicidin has been solved in solution to reveal a hexameric helix-bundle, mediated by Zn ion binding.[4] This is observed to form a tilted channel in membranes under computational examination by molecular dynamics simulations, and one suggested mechanism of antimicrobial action inferred from this observation is by ion gradient decoupling across biological membranes. This is supported by concurrent observations in experimental studies of a voltage dependent depolarization of lipid bilayers. | https://www.wikidoc.org/index.php/Dermcidin | |
9d275b59502d2a79e811d629ea9bfb711058e1ce | wikidoc | Desiccant | Desiccant
A desiccant is a hygroscopic substance that induces or sustains a state of dryness (desiccation) in its local vicinity in a moderately-well sealed container.
Commonly encountered pre-packaged desiccants are solids, and work through absorption or adsorption of water, or a combination of the two. Desiccants for specialised purposes may be in forms other than solid, and may work through other principles, such as chemical bonding of water molecules.
Pre-packaged desiccant is most commonly used to remove excessive humidity that would normally degrade or even destroy products sensitive to moisture. Silica gel, calcium sulfate, calcium chloride, montmorillonite clay, and molecular sieves are commonly used as desiccants.
Rice is a common "low-tech" alternative, frequently used for example in salt-shakers to maintain granularity of table-salt for effective pouring or shaking. Rice, however, is not a good general purpose desiccant since, unless immersed in an organism-hostile environment like pure salt, over time may be eaten by creatures that might in turn pollute the product that is being preserved. Salt itself is another effective desiccant, used for millennia in preparation of dried foodstuffs.
# Toxicity
A desiccant may be chosen for a particular task based not only on its effectiveness at drying, but also perhaps for any natural antibiotic/fungicidal/pesticidal effect, or for a lack of harmful effect on humans -- for instance salt has a natural antibiotic and anti-fungal effect and is not harmful to humans when consumed in moderate quantities, hence its popular use as drying agent in preparation of dried foods.
# Chemical reactivity
Because of their common use in preservation, usually it is desirable for a desiccant to be substantially chemically stable or chemically inert, and a number of useful desiccants with this property have been identified and are in common use, such as silica gel, chalk- and clay-based desiccants.
# Performance efficiency
One measure of desiccant efficiency is the ratio (or percentage) of water storeable in the desiccant, relative to the mass of desiccant (ie weight).
Another measure is the residual relative humidity of the air or other fluid being dried.
The performance of any desiccant varies with temperature and both relative humidity and absolute humidity. To some extent, desiccant performance can be precisely described, but most commonly, the final choice of which desiccant best suits a given situation, how much of it to use, and in what form, is made based on testing and practical experience.
# Coloured saturation indicators
Often some sort of humidity indicator is included in the desiccant to show, by color changes, the degree of water-saturation of the desiccant. One commonly used indicator is cobalt chloride (CoCl2). Anhydrous cobalt chloride is blue. When it bonds with two water molecules, (CoCl22H2O), it turns purple. Further hydration results in the pink hexaaquacobalt(II) chloride complex Cl2.
# Desiccant regeneration
Most useful desiccants can be recycled by thermally-induced drying, for example, in a conventional kitchen oven, or with solar energy. A cost-effective, low-energy, continuous-cycle desiccant dehumidifier or desiccant regeneration system can be easily designed from off-the-shelf component parts.
# Drying of solvents
Desiccants are also used to dry solvents, typically used for moisture free reactions (e.g. the Grignard reaction). While various desiccants are used in a variety of ways, the method generally involves stirring the desired solvent with the drying agent.
Often, the drying agent will react with moisture to form an insoluble solid in the solvent being dehydrated, thus the precipitate can be removed by filtration. For more demanding applications, requiring very pure, anhydrous solvents a distillation rig is used to remove moisture and other impurities simultaneously. | Desiccant
A desiccant is a hygroscopic substance that induces or sustains a state of dryness (desiccation) in its local vicinity in a moderately-well sealed container.
Commonly encountered pre-packaged desiccants are solids, and work through absorption or adsorption of water, or a combination of the two. Desiccants for specialised purposes may be in forms other than solid, and may work through other principles, such as chemical bonding of water molecules.
Pre-packaged desiccant is most commonly used to remove excessive humidity that would normally degrade or even destroy products sensitive to moisture. Silica gel, calcium sulfate, calcium chloride, montmorillonite clay, and molecular sieves are commonly used as desiccants.
Rice is a common "low-tech" alternative, frequently used for example in salt-shakers to maintain granularity of table-salt for effective pouring or shaking. Rice, however, is not a good general purpose desiccant since, unless immersed in an organism-hostile environment like pure salt, over time may be eaten by creatures that might in turn pollute the product that is being preserved. Salt itself is another effective desiccant, used for millennia in preparation of dried foodstuffs.
# Toxicity
A desiccant may be chosen for a particular task based not only on its effectiveness at drying, but also perhaps for any natural antibiotic/fungicidal/pesticidal effect, or for a lack of harmful effect on humans -- for instance salt has a natural antibiotic and anti-fungal effect and is not harmful to humans when consumed in moderate quantities, hence its popular use as drying agent in preparation of dried foods.
# Chemical reactivity
Because of their common use in preservation, usually it is desirable for a desiccant to be substantially chemically stable or chemically inert, and a number of useful desiccants with this property have been identified and are in common use, such as silica gel, chalk- and clay-based desiccants.
# Performance efficiency
One measure of desiccant efficiency is the ratio (or percentage) of water storeable in the desiccant, relative to the mass of desiccant (ie weight).
Another measure is the residual relative humidity of the air or other fluid being dried.
The performance of any desiccant varies with temperature and both relative humidity and absolute humidity. To some extent, desiccant performance can be precisely described, but most commonly, the final choice of which desiccant best suits a given situation, how much of it to use, and in what form, is made based on testing and practical experience.
# Coloured saturation indicators
Often some sort of humidity indicator is included in the desiccant to show, by color changes, the degree of water-saturation of the desiccant. One commonly used indicator is cobalt chloride (CoCl2). Anhydrous cobalt chloride is blue. When it bonds with two water molecules, (CoCl2•2H2O), it turns purple. Further hydration results in the pink hexaaquacobalt(II) chloride complex [Co(H2O)6]Cl2.
# Desiccant regeneration
Most useful desiccants can be recycled by thermally-induced drying, for example, in a conventional kitchen oven, or with solar energy. A cost-effective, low-energy, continuous-cycle desiccant dehumidifier or desiccant regeneration system can be easily designed from off-the-shelf component parts.
# Drying of solvents
Desiccants are also used to dry solvents, typically used for moisture free reactions (e.g. the Grignard reaction). While various desiccants are used in a variety of ways, the method generally involves stirring the desired solvent with the drying agent.
Often, the drying agent will react with moisture to form an insoluble solid in the solvent being dehydrated, thus the precipitate can be removed by filtration. For more demanding applications, requiring very pure, anhydrous solvents a distillation rig is used to remove moisture and other impurities simultaneously. | https://www.wikidoc.org/index.php/Desiccant | |
24436314000a7117ca1c4e1052ae151311779045 | wikidoc | Desirudin | Desirudin
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# Black Box Warning
# Overview
Desirudin is a direct thrombin inhibitor that is FDA approved for the {{{indicationType}}} of deep vein thrombosis in patients undergoing elective hip replacement surgery. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hemorrhage, injection site mass, wound secretion, anemia, deep thrombophlebitis, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- All patients should be evaluated for bleeding disorder risk before prophylactic administration of Iprivask.
- Initial Dosage
- In patients undergoing hip replacement surgery, the recommended dose of Iprivask is 15 mg every 12 hours administered by subcutaneous injection with the initial dose given up to 5 to 15 minutes prior to surgery, but after induction of regional block anesthesia, if used. Up to 12 days administration (average duration 9 to 12 days) of Iprivask has been well tolerated in controlled clinical trials.
- Dose in Renal Impairment
- Dose in Hepatic Impairment
- In the absence of clinical studies in this population, dosing recommendations cannot be made at this time.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Desirudin in adult patients.
### Non–Guideline-Supported Use
- Equivalent or slightly better efficacy compared to heparin for thrombolysis in patients with acute coronary syndrome; desirudin administration is also associated with a lower early reinfarction rate.
- Intravenous desirudin (20 mgbolus followed by an infusion of 0.16 mg/kg/hr for 24 hours) is associated with a reduced early cardiac events in patients undergoing percutaneous transluminal coronary angioplasty.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness 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 Desirudin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Desirudin in pediatric patients.
# Contraindications
- Iprivask is contraindicated in patients with known hypersensitivity to natural or recombinant hirudins, and in patients with active bleeding and/or irreversible coagulation disorders.
# Warnings
- Spinal/Epidural Anesthesia
- As with other anticoagulants, there is a risk of neuraxial hematoma formation with the concurrent use of desirudin and spinal/epidural anesthesia, which has the potential to result in long term or permanent paralysis. The risk may be greater with the use of post-operative indwelling catheters or the concomitant use of additional drugs affecting hemostasis such as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), platelet inhibitors or other anticoagulants. The risk may also be increased by traumatic or repeated neuraxial puncture.
- To reduce the potential risk of bleeding associated with the concurrent use of desirudin and epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug should be considered when scheduling or using epidural or spinal anesthesia in proximity to desirudin administration. The physician should consider placement of the catheter prior to initiating desirudin and removal of the catheter when the anticoagulant effect of desirudin is low.
- Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
- The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
- Iprivask cannot be used interchangeably with other hirudins as they differ in manufacturing process and specific biological activity (ATUs). Each of these medicines has its own instructions for use.
- Renal Impairment
- Iprivask must be used with caution in patients with renal impairment, particularly in those with moderate and severe renal impairment (creatinine clearance ≤60 mL/min/1.73 m2 body surface area). Dose reductions by factors of three and nine are recommended for patients with moderate and severe renal impairment respectively. In addition, daily aPTT and serum creatinine monitoring are recommended for patients with moderate or severe renal impairment.
- Hemorrhagic Events
- Iprivask is not intended for intramuscular injection as local hematoma formation may result.
- Iprivask, like other anticoagulants, should be used with caution in patients with increased risks of hemorrhage such as those with recent major surgery, organ biopsy or puncture of a non-compressible vessel within the last month; a history of hemorrhagic stroke, intracranial or intraocular bleeding including diabetic retinopathy; recent ischemic stroke, severe uncontrolled hypertension, bacterial endocarditis, a known hemostatic disorder (congenital or acquired, e.g. hemophilia, liver disease) or a history of gastrointestinal or pulmonary bleeding within the past 3 months.
- Bleeding can occur at any site during therapy with Iprivask. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.
- Antibodies/Re-exposure
- Antibodies have been reported in patients treated with hirudins. Potential for cross-sensitivity to hirudin products cannot be excluded. Irritative skin reactions were observed in 9/322 volunteers exposed to Iprivask by subcutaneous injection or IV bolus or infusion in single or multiple administrations of the drug. Allergic events were reported in <2% of patients who were administered desirudin in Phase III clinical trials. Allergic events were reported in 1% of patients receiving unfractionated heparin and 1% of patients receiving enoxaparin. Hirudin-specific IgE evaluations may not be indicative of sensitivity to Iprivask as this test was not always positive in the presence of symptoms. Very rarely, anti-hirudin antibodies have been detected upon re-exposure to desirudin. Fatal anaphylactoid reactions have been reported during hirudin therapy.
- Hepatic Impairment/Liver Injury
- No information is available about the use of desirudin in patients with hepatic impairment/liver injury. Although Iprivask is not significantly metabolized by the liver, hepatic impairment or serious liver injury (e.g., liver cirrhosis) may alter the anticoagulant effect of Iprivask due to coagulation defects secondary to reduced generation of vitamin K-dependent coagulation factors. Iprivask should be used with caution in these patients.
- Laboratory Tests
- Activated partial thromboplastin time (aPTT) should be monitored daily in patients with increased risk of bleeding and/or renal impairment. Serum creatinine should be monitored daily in patients with renal impairment. Peak aPTT should not exceed two times control. Should peak aPTT exceed this level, dose reduction is advised based on the degree of aPTT abnormality. If necessary, therapy with desirudin should be interrupted until aPTT falls to less than two times control, at which time treatment with desirudin can be resumed at a reduced dose. Thrombin time (TT) is not a suitable test for routine monitoring of Iprivask therapy. Dose adjustments based on serum creatinine may be necessary.
# Adverse Reactions
## Clinical Trials Experience
- In the Phase II and III clinical studies, desirudin was administered to 2159 patients undergoing elective hip replacement surgery to determine the safety and efficacy of Iprivask in preventing VTE in this population. Below is the safety profile of the Iprivask 15 mg (q12h) regimen from these 5 multicenter clinical trials.
- Hemorrhagic Events: The following rates of hemorrhagic events have been reported during clinical trials.
- a – Includes hematomas which occurred at an incidence of 6% in the Iprivask and enoxaparin treatment groups and 5% in the heparin treatment group.
- b – Bleeding complications were considered serious if preoperative transfusion requirements exceeded 5 units of whole blood or packed red cells, or if total transfusion requirements up to postoperative Day 6 inclusive exceeded 7 units of whole blood or packed red cells, or total blood loss up to postoperative Day 6 inclusive exceeded 3500 mL.
- c – Bleeding complications were considered major if the hemorrhage was: (1) overt and it produced a fall in hemoglobin of ≥2g/dL or if it lead to a transfusion of 2 or more units of whole or packed cells outside the perioperative period (the time from start of surgery until up to 12 hours after); (2) Retroperitoneal, intracranial, intraocular, intraspinal, or occurred in a major prosthetic joint.
- Non-hemorrhagic Events
- Non-hemorrhagic adverse events occurring at ≥2% incidence in patients treated with Iprivask 15 mg (q 12h) during elective hip replacement surgery and considered to be remotely, possibly, or probably related to desirudin are provided below.
- a – Represents events reported while on treatment, excluding unrelated adverse events
- b – All hemorrhages that occurred are included in Hemorrhagic Events.
- Related Adverse Events with a Frequency of 0.2% (in decreasing order of frequency): thrombosis, hypotension, leg edema, fever, decreased hemoglobin, hematuria, dizziness, epistaxis, vomiting, impaired healing, cerebrovascular disorder, leg pain, hematemesis.
- Allergic Reactions
- In clinical studies, allergic events were reported <2% overall and in 2% of patients who were administered 15 mg desirudin.
## Postmarketing Experience
- In addition to adverse events reported from clinical trials the following adverse events have been identified during post approval use of Iprivask. These events were reported voluntarily from a population of unknown size and the frequency of occurrence cannot be determined precisely: rare reports of major hemorrhages, some of which were fatal, and anaphylactic/anaphylactoid reactions.
# Drug Interactions
- Any agent which may enhance the risk of hemorrhage should be discontinued prior to initiation of desirudin therapy. These agents include medications such as Dextran 40, systemic glucocorticoids, thrombolytics, and anticoagulants. If co-administration cannot be avoided, close clinical and laboratory monitoring should be conducted. During prophylaxis of venous thromboembolism, concomitant treatment with heparins (unfractionated and low-molecular weight heparins) or dextrans is not recommended. The effects of desirudin and unfractionated heparins on prolongation of aPTT are additive.
- As with other anticoagulants, desirudin should be used with caution in conjunction with drugs which affect platelet function. These medications include systemic salicylates, NSAIDs including ketorolac, acetylsalicylic acid, ticlopidine, dipyridamole, sulfinpyrazone, clopidogrel, abciximab and other glycoprotein IIb/IIIa antagonists.
- Use in patients switching from oral anticoagulants to Iprivask or from Iprivask to oral anticoagulants. The concomitant administration of warfarin did not significantly affect the pharmacokinetic effects of desirudin. When warfarin and desirudin were co-administered, greater inhibition of hemostasis measured by activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) was observed. If a patient is switched from oral anticoagulants to Iprivask therapy or from Iprivask to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods. That activity should be taken into account in the evaluation of the overall coagulation status of the patient during the switch.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well controlled studies in pregnant women. Iprivask should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Animal Data
- Teratology studies have been performed in rats at subcutaneous doses in a range of 1 to 15 mg/kg/day (about 0.3 to 4 times the recommended human dose based on body surface area) and in rabbits at IV doses in a range of 0.6 to 6 mg/kg/day (about 0.3 to 3 times the recommended human dose based on body surface area) and have revealed desirudin to be teratogenic. Observed teratogenic findings were: omphalocele, asymmetric and fused sternebrae, edema, shortened hind limbs, etc. in rats; and spina bifida, malrotated hind limb, hydrocephaly, gastroschisis, etc. in rabbits.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Desirudin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Desirudin during labor and delivery.
### Nursing Mothers
- It is not known whether desirudin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when desirudin is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- In three clinical studies of Iprivask, the percentage of patients greater than 65 years of age treated with 15 mg of Iprivask subcutaneously every 12 hours was 58.5%, while 20.8% were 75 years of age or older. Elderly patients treated with Iprivask had a reduction in the incidence of VTE similar to that observed in the younger patients, and a slightly lower incidence of VTE compared to those patients treated with heparin or enoxaparin.
- Regarding safety, in the clinical studies the incidence of hemorrhage (major or otherwise) in patients 65 years of age or older was similar to that in patients less than 65 years of age. In addition, the elderly had a similar incidence of total, treatment-related, or serious adverse events compared to those patients less than 65 years of age. Serious adverse events occurred more frequently in patients 75 years of age or older as compared to those less than 65 years of age. In general, 15 mg desirudin every 12 hours can be used safely in the geriatric population as in the population of patients less than 65 years of age so long as renal function is adequate.
### Gender
There is no FDA guidance on the use of Desirudin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Desirudin with respect to specific racial populations.
### Renal Impairment
- Iprivask must be used with caution in patients with renal impairment, particularly in those with moderate and severe renal impairment (creatinine clearance ≤60 mL/min/1.73 m2 body surface area). Dose reductions by factors of three and nine are recommended for patients with moderate and severe renal impairment respectively. In addition, daily aPTT and serum creatinine monitoring are recommended for patients with moderate or severe renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Desirudin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Desirudin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Desirudin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
- Daily aPTT and serum creatinine monitoring are recommended for patients with moderate or severe renal impairment.
- Activated partial thromboplastin time (aPTT) should be monitored daily in patients with increased risk of bleeding.
- Peak aPTT should not exceed two times control.
- Should peak aPTT exceed this level, dose reduction is advised based on the degree of aPTT abnormality. If necessary, therapy with desirudin should be interrupted until aPTT falls to less than two times control, at which time treatment with desirudin can be resumed at a reduced dose.
- Thrombin time (TT) is not a suitable test for routine monitoring of Iprivask therapy.
- Dose adjustments based on serum creatinine may be necessary.
- Any agent which may enhance the risk of hemorrhage should be discontinued prior to initiation of desirudin therapy.
- These agents include medications such as Dextran 40, systemic glucocorticoids, thrombolytics, and anticoagulants.
- If co-administration cannot be avoided, close clinical and laboratory monitoring should be conducted.
- The concomitant administration of warfarin did not significantly affect the pharmacokinetic effects of desirudin.
- When warfarin and desirudin were co-administered, greater inhibition of hemostasis measured by activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) was observed. If a patient is switched from oral anticoagulants to Iprivask therapy or from Iprivask to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods.
# IV Compatibility
There is limited information regarding IV Compatibility of Desirudin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In an open, pilot, dose-ascending study to assess safety, the highest dose of desirudin (40 mg q12h) caused excessive hemorrhage.
- In case of overdose, most likely reflected in hemorrhagic complications or suggested by excessively high aPTT values, Iprivask therapy should be discontinued.
- Emergency procedures should be instituted as appropriate (for example, determination of aPTT and other coagulation levels, hemoglobin, the use of blood transfusion or plasma expanders).
### Management
- No specific antidote for Iprivask is available; however, the anticoagulant effect of desirudin is partially reversible using thrombin-rich plasma concentrates while aPTT levels can be reduced by the IV administration of 0.3 µg/kg DDAVP (desmopressin). The clinical effectiveness of DDAVP in treating bleeding due to desirudin overdose has not been studied.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Desirudin in the drug label.
# Pharmacology
There is limited information regarding Desirudin Pharmacology in the drug label.
## Mechanism of Action
- Desirudin is a selective inhibitor of free circulating and clot-bound thrombin. The anticoagulant properties of desirudin are demonstrated by its ability to prolong the clotting time of human plasma. One molecule of desirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected. Activated partial thromboplastin time (aPTT) is a measure of the anticoagulant activity of desirudin and increases in a dose-dependent fashion.
## Structure
- Iprivask® (desirudin for injection) is a specific inhibitor of human thrombin. It has a protein structure that is similar to that of hirudin, the naturally occurring anticoagulant present in the peripharyngeal glands in the medicinal leech,Hirudo medicinalis. Hirudin is a single polypeptide chain of 65 amino acids residues and contains three disulfide bridges. Desirudin has a chemical formula of C287H440N80O110S6 with a molecular weight of 6963.52. Desirudin, which is expressed in yeast (Saccharomyces cerevisiae, strain TR 1456) by recombinant DNA technology differs from the natural hirudin by lack of a sulfate group on Tyr-63. The biological activity of desirudin is determined through a chromogenic assay which measures the ability of desirudin to inhibit the hydrolysis of a chromogenic peptidic substrate by thrombin in comparison to a desirudin standard. One vial of desirudin contains 15.75 mg desirudin corresponding to approximately 315,000 antithrombin units (ATU) or 20,000 ATU per milligram of desirudin with reference to the WHO International Standard (prepared 1991) for alphathrombin.
## Pharmacodynamics
- The pharmacodynamic effect of desirudin on proteolytic activity of thrombin was assessed as an increase in aPTT. A mean peak aPTT prolongation of about 1.38 times baseline value (range 0.58 to 3.41) was observed following subcutaneous b.i.d. injections of 15 mg desirudin. Thrombin time (TT) frequently exceeds 200 seconds even at low plasma concentrations of desirudin, which renders this test unsuitable for routine monitoring of Iprivask therapy. At therapeutic serum concentrations, desirudin has no effect on other enzymes of the hemostatic system such as factors IXa, Xa, kallikrein, plasmin, tissue plasminogen activator, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin, chymotrypsin, or on complement activation by the classical or alternative pathways.
## Pharmacokinetics
- Pharmacokinetic parameters were calculated based on plasma concentration data obtained by a non-specific ELISA method that does not discriminate between native desirudin and its metabolites. It is not known if the metabolites are pharmacologically active.
- The absorption of desirudin is complete when subcutaneously administered at doses of 0.3 mg/kg or 0.5 mg/kg. Following subcutaneous administration of single doses of 0.1 to 0.75 mg/kg, plasma concentrations of desirudin increased to a maximum level (Cmax) between 1 and 3 hours. Both Cmax and area-under-the-curve (AUC) values are dose proportional.
- The pharmacokinetic properties of desirudin following intravenous (IV) administration are well described by a two- or three- compartment disposition model. Desirudin is distributed in the extracellular space with a volume of distribution at steady state of 0.25 L/kg, independent of the dose. Desirudin binds specifically and directly to thrombin, forming an extremely tight, non-covalent complex with an inhibition constant of approximately 2.6 x 10-13 M. Thus, free or protein bound desirudin immediately binds circulating thrombin. The pharmacological effect of desirudin is not modified when co-administered with highly protein bound drugs (>99%).
- Human and animal data suggest that desirudin is primarily eliminated and metabolized by the kidney. The total urinary excretion of unchanged desirudin amounts to 40 to 50% of the administered dose. Metabolites lacking one or two C-terminal amino acids constitute a minor proportion of the material recovered from urine (< 7%). There is no evidence for the presence of other metabolites. This indicates that desirudin is metabolized by stepwise degradation from the C-terminus probably catalyzed by carboxypeptidase(s) such as carboxypeptidase A, originating from the pancreas. Total clearance of desirudin is approximately 1.5 to 2.7 mL/min/kg following either subcutaneous or IV administration and is independent of dose. This clearance value is close to the glomerular filtration rate.
- The elimination of desirudin from plasma is rapid after IV administration, with approximately 90% of the dose disappearing from the plasma within 2 hours of the injection. Plasma concentrations of desirudin then decline with a mean terminal elimination half-life of 2 to 3 hours. After subcutaneous administration, the mean terminal elimination half-life is also approximately 2 hours.
- In a pharmacokinetic study of renally impaired subjects, subjects with mild creatinine clearance between 61 and 90 mL/min/1.73 m2 body surface area, moderate (creatinine clearance between 31 and 60 mL/min/1.73 m2 body surface area), and severe (creatinine clearance below 31 mL/min/1.73 m2 body surface area) renal impairment, were administered a single IV dose of 0.5, 0.25, or 0.125 mg/kg desirudin, respectively. This resulted in mean dose-normalized AUCeffect (AUC0-60th for aPTT prolongation) increases of approximately 3-, and 9-fold for the moderate and severe renally impaired subjects, respectively, compared with healthy individuals. In subjects with mild renal impairment, there was no increase in AUCeffect compared with healthy individuals. In subjects with severe renal impairment, terminal elimination half-lives were prolonged up to 12 hours compared with 2 to 4 hours in normal volunteers or subjects with mild to moderate renal impairment. Dose adjustments are recommended in certain circumstances in relation to the degree of impairment or degree of aPTT abnormality.
- No pharmacokinetic studies have been conducted to investigate the effects of Iprivask in hepatic impairment.
- The mean plasma clearance of desirudin in patients ≥65 years of age (n=12; 110 mL/min) is approximately 28% lower than in patients <65 years of age (n=8; 153 mL/min). Population pharmacokinetics conducted in 301 patients undergoing elective total hip replacement indicate that age or gender do not affect the systemic clearance of desirudin when renal creatinine clearance is considered. This drug is substantially excreted by the kidney, and the risk of adverse events due to it 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. Dosage adjustment in the case of moderate and severe renal impairment is necessary.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term studies in animals have been performed to evaluate the carcinogenic potential of desirudin.
- Desirudin was not genotoxic in the Ames test, the Chinese hamster lung cell (V79/HGPRT) forward mutation test or the rat micronucleus test. It was, however, equivocal in its genotoxic effect in Chinese hamster ovarian cell (CCL 61) chromosome aberration tests.
- Desirudin at subcutaneous doses up to 10mg/kg/day (about 2.7 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.
- Animal Toxicology and/or Pharmacology
- Desirudin produced bleeding, local inflammation, and granulation at injection sites in rat and dog toxicity studies. In a 28-day study in Rhesus monkeys, there was also evidence of subcutaneous bleeding and local inflammation at the injection sites. In addition, desirudin was immunogenic in dogs and formed antibody complexes resulting in prolonged half-life and accumulation. Desirudin showed sensitization potential in guinea pig immediate and delayed hypersensitivity models.
# Clinical Studies
- Iprivask was evaluated in two controlled, randomized, multicenter, clinical efficacy trials and a controlled, double-blind, dose-finding study. In the efficacy studies, Iprivask was compared to subcutaneously administered unfractionated heparin or enoxaparin sodium for the reduction of the risk of venous thromboembolic events (VTE) in patients undergoing total hip replacement surgery. In all studies Iprivask was initiated prior to surgery and continued for 8 to 12 days postoperatively (median duration 10 days). Patients who received Iprivask had a lower incidence of VTE. The efficacy studies are described below.
- In the first study, Iprivask 15 mg subcutaneously administered every 12 hours was compared to unfractionated heparin 5000 IU subcutaneously administered every 8 hours. A total of 445 patients were randomized in the study, 436 patients were treated, and 85 of the treated patients were excluded from efficacy analysis, mainly because of no phlebography or inadequate reading of phlebography. Patients ranged in age from 34 to 89 years (mean age 68.4 years) with 41.8% men and 58.2% women. All enrolled patients were Caucasian. Iprivask significantly reduced the number of total VTE compared to unfractionated heparin: Evaluable population: Iprivask, 13/174 (7.5%) vs. heparin, 41/177 (23.2%); p value <0.001; Intent-to-Treat population: Iprivask 13/225 (5.8%) vs. heparin 42/220 (19.1%); p value <0.0001.]. Significantly fewer patients in the group treated with Iprivask experienced proximal DVT than those patients treated with heparin: Evaluable population: Iprivask 6/174 (3.4%) vs. heparin 29/177 (16.4%); p value <0.001: Intent-to-Treat population: Iprivask 6/225 (2.7%) vs. heparin 30/220 (13.6%); p value <0.0001.
- In a second study, Iprivask 15 mg subcutaneously administered every 12 hours was compared to enoxaparin sodium 40 mg subcutaneously administered every 24 hours. A total of 2079 patients were randomized in the study, 2049 patients were treated, and 508 of the treated patients were excluded from efficacy analysis mainly because of no phlebography or inadequate reading of phlebography. Patients ranged in age from 18 to 90 years (mean age 68.5 years) with 41.7% men and 58.5% women. All enrolled patients were Caucasian. In both the evaluable patient population and the intent-to-treat population, patients who received Iprivask had a lower incidence of major VTE, total VTE, and proximal DVT than did patients who received enoxaparin (see table below).
- In a multicenter, double-blind, dose-finding study, Iprivask 10 mg, 15 mg, and 20 mg subcutaneously administered every 12 hours was compared to unfractionated heparin 5,000 IU administered every 8 hours SC in patients undergoing hip replacement surgery. A dose response was seen with regard to both effectiveness and bleeding complications. The 15-mg and 20-mg doses were superior to heparin and the 10-mg dose. In a smaller, open-labeled, dose-finding study of Iprivask 10 mg, 15 mg, 20 mg, and 40 mg subcutaneously administered every 12 hours in patients undergoing hip replacement surgery, the 40-mg dose was associated with unacceptable major bleeding.
# How Supplied
- Iprivask (desirudin for injection) is supplied as a single dose (15.75 mg) lyophilized powder with an accompanying sterile, non-pyrogenic diluent .
- Each Iprivask Vial contains 15.75 mg desirudin and the following inactive ingredients: 1.31 mg anhydrous magnesium chloride USP, sodium hydroxide for injection USP.
- Each carton (NDC 42998-715-10) of Iprivask (desirudin for injection) contains 10 individual doses of Iprivask, each in a separate tray.
- Each tray of Iprivask (desirudin for injection) contains:
- One (1) x 15.75 mg Single Dose Vial
- One (1) x 0.6 mL Prefilled syringe of Diluent
- One (1) Eclipse™ needle
- One (1) Vial Adapter
- Each prefilled syringe of diluent contains 0.6 mL Mannitol USP (3% w/v) in Water for Injection provided for reconstitution of the desirudin lyophilized powder.
- Storage: Protect from light.
- Unopened vials or prefilled syringes: Store at 25°C (77°F); excursions permitted to 15–30°C (59-86°F).
- Keep this and all medicines out of the reach of children.
## Storage
There is limited information regarding Desirudin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to watch carefully for any signs of bleeding or bruising and to report these to their health care provider when they occur.
- Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter medications or herbal products, prior to Iprivask use. Examples of other medications that should not be taken with Iprivask are aspirin, non-steroidal anti-inflammatory drugs including ketorolac, acetylsalicylic acid ticlopidine, dipyridamole, sulfinpyrazone, clopidogrel, abciximab and other glycoprotein IIb/IIIa antagonists.
- Advise patients to read the FDA-approved patient labeling (Product Assembly Instructions for Use).
# Precautions with Alcohol
- Alcohol-Desirudin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Iprivask®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Desirudin
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
Desirudin is a direct thrombin inhibitor that is FDA approved for the {{{indicationType}}} of deep vein thrombosis in patients undergoing elective hip replacement surgery. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hemorrhage, injection site mass, wound secretion, anemia, deep thrombophlebitis, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- All patients should be evaluated for bleeding disorder risk before prophylactic administration of Iprivask.
- Initial Dosage
- In patients undergoing hip replacement surgery, the recommended dose of Iprivask is 15 mg every 12 hours administered by subcutaneous injection with the initial dose given up to 5 to 15 minutes prior to surgery, but after induction of regional block anesthesia, if used. Up to 12 days administration (average duration 9 to 12 days) of Iprivask has been well tolerated in controlled clinical trials.
- Dose in Renal Impairment
- Dose in Hepatic Impairment
- In the absence of clinical studies in this population, dosing recommendations cannot be made at this time.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Desirudin in adult patients.
### Non–Guideline-Supported Use
- Equivalent or slightly better efficacy compared to heparin for thrombolysis in patients with acute coronary syndrome; desirudin administration is also associated with a lower early reinfarction rate.[1][2][3][4]
- Intravenous desirudin (20 mgbolus followed by an infusion of 0.16 mg/kg/hr for 24 hours) is associated with a reduced early cardiac events in patients undergoing percutaneous transluminal coronary angioplasty.[5][6]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and effectiveness 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 Desirudin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Desirudin in pediatric patients.
# Contraindications
- Iprivask is contraindicated in patients with known hypersensitivity to natural or recombinant hirudins, and in patients with active bleeding and/or irreversible coagulation disorders.
# Warnings
- Spinal/Epidural Anesthesia
- As with other anticoagulants, there is a risk of neuraxial hematoma formation with the concurrent use of desirudin and spinal/epidural anesthesia, which has the potential to result in long term or permanent paralysis. The risk may be greater with the use of post-operative indwelling catheters or the concomitant use of additional drugs affecting hemostasis such as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), platelet inhibitors or other anticoagulants. The risk may also be increased by traumatic or repeated neuraxial puncture.
- To reduce the potential risk of bleeding associated with the concurrent use of desirudin and epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug should be considered when scheduling or using epidural or spinal anesthesia in proximity to desirudin administration. The physician should consider placement of the catheter prior to initiating desirudin and removal of the catheter when the anticoagulant effect of desirudin is low.
- Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
- The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
- Iprivask cannot be used interchangeably with other hirudins as they differ in manufacturing process and specific biological activity (ATUs). Each of these medicines has its own instructions for use.
- Renal Impairment
- Iprivask must be used with caution in patients with renal impairment, particularly in those with moderate and severe renal impairment (creatinine clearance ≤60 mL/min/1.73 m2 body surface area). Dose reductions by factors of three and nine are recommended for patients with moderate and severe renal impairment respectively. In addition, daily aPTT and serum creatinine monitoring are recommended for patients with moderate or severe renal impairment.
- Hemorrhagic Events
- Iprivask is not intended for intramuscular injection as local hematoma formation may result.
- Iprivask, like other anticoagulants, should be used with caution in patients with increased risks of hemorrhage such as those with recent major surgery, organ biopsy or puncture of a non-compressible vessel within the last month; a history of hemorrhagic stroke, intracranial or intraocular bleeding including diabetic retinopathy; recent ischemic stroke, severe uncontrolled hypertension, bacterial endocarditis, a known hemostatic disorder (congenital or acquired, e.g. hemophilia, liver disease) or a history of gastrointestinal or pulmonary bleeding within the past 3 months.
- Bleeding can occur at any site during therapy with Iprivask. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site.
- Antibodies/Re-exposure
- Antibodies have been reported in patients treated with hirudins. Potential for cross-sensitivity to hirudin products cannot be excluded. Irritative skin reactions were observed in 9/322 volunteers exposed to Iprivask by subcutaneous injection or IV bolus or infusion in single or multiple administrations of the drug. Allergic events were reported in <2% of patients who were administered desirudin in Phase III clinical trials. Allergic events were reported in 1% of patients receiving unfractionated heparin and 1% of patients receiving enoxaparin. Hirudin-specific IgE evaluations may not be indicative of sensitivity to Iprivask as this test was not always positive in the presence of symptoms. Very rarely, anti-hirudin antibodies have been detected upon re-exposure to desirudin. Fatal anaphylactoid reactions have been reported during hirudin therapy.
- Hepatic Impairment/Liver Injury
- No information is available about the use of desirudin in patients with hepatic impairment/liver injury. Although Iprivask is not significantly metabolized by the liver, hepatic impairment or serious liver injury (e.g., liver cirrhosis) may alter the anticoagulant effect of Iprivask due to coagulation defects secondary to reduced generation of vitamin K-dependent coagulation factors. Iprivask should be used with caution in these patients.
- Laboratory Tests
- Activated partial thromboplastin time (aPTT) should be monitored daily in patients with increased risk of bleeding and/or renal impairment. Serum creatinine should be monitored daily in patients with renal impairment. Peak aPTT should not exceed two times control. Should peak aPTT exceed this level, dose reduction is advised based on the degree of aPTT abnormality. If necessary, therapy with desirudin should be interrupted until aPTT falls to less than two times control, at which time treatment with desirudin can be resumed at a reduced dose. Thrombin time (TT) is not a suitable test for routine monitoring of Iprivask therapy. Dose adjustments based on serum creatinine may be necessary.
# Adverse Reactions
## Clinical Trials Experience
- In the Phase II and III clinical studies, desirudin was administered to 2159 patients undergoing elective hip replacement surgery to determine the safety and efficacy of Iprivask in preventing VTE in this population. Below is the safety profile of the Iprivask 15 mg (q12h) regimen from these 5 multicenter clinical trials.
- Hemorrhagic Events: The following rates of hemorrhagic events have been reported during clinical trials.
- a – Includes hematomas which occurred at an incidence of 6% in the Iprivask and enoxaparin treatment groups and 5% in the heparin treatment group.
- b – Bleeding complications were considered serious if preoperative transfusion requirements exceeded 5 units of whole blood or packed red cells, or if total transfusion requirements up to postoperative Day 6 inclusive exceeded 7 units of whole blood or packed red cells, or total blood loss up to postoperative Day 6 inclusive exceeded 3500 mL.
- c – Bleeding complications were considered major if the hemorrhage was: (1) overt and it produced a fall in hemoglobin of ≥2g/dL or if it lead to a transfusion of 2 or more units of whole or packed cells outside the perioperative period (the time from start of surgery until up to 12 hours after); (2) Retroperitoneal, intracranial, intraocular, intraspinal, or occurred in a major prosthetic joint.
- Non-hemorrhagic Events
- Non-hemorrhagic adverse events occurring at ≥2% incidence in patients treated with Iprivask 15 mg (q 12h) during elective hip replacement surgery and considered to be remotely, possibly, or probably related to desirudin are provided below.
- a – Represents events reported while on treatment, excluding unrelated adverse events
- b – All hemorrhages that occurred are included in Hemorrhagic Events.
- Related Adverse Events with a Frequency of <2% and >0.2% (in decreasing order of frequency): thrombosis, hypotension, leg edema, fever, decreased hemoglobin, hematuria, dizziness, epistaxis, vomiting, impaired healing, cerebrovascular disorder, leg pain, hematemesis.
- Allergic Reactions
- In clinical studies, allergic events were reported <2% overall and in 2% of patients who were administered 15 mg desirudin.
## Postmarketing Experience
- In addition to adverse events reported from clinical trials the following adverse events have been identified during post approval use of Iprivask. These events were reported voluntarily from a population of unknown size and the frequency of occurrence cannot be determined precisely: rare reports of major hemorrhages, some of which were fatal, and anaphylactic/anaphylactoid reactions.
# Drug Interactions
- Any agent which may enhance the risk of hemorrhage should be discontinued prior to initiation of desirudin therapy. These agents include medications such as Dextran 40, systemic glucocorticoids, thrombolytics, and anticoagulants. If co-administration cannot be avoided, close clinical and laboratory monitoring should be conducted. During prophylaxis of venous thromboembolism, concomitant treatment with heparins (unfractionated and low-molecular weight heparins) or dextrans is not recommended. The effects of desirudin and unfractionated heparins on prolongation of aPTT are additive.
- As with other anticoagulants, desirudin should be used with caution in conjunction with drugs which affect platelet function. These medications include systemic salicylates, NSAIDs including ketorolac, acetylsalicylic acid, ticlopidine, dipyridamole, sulfinpyrazone, clopidogrel, abciximab and other glycoprotein IIb/IIIa antagonists.
- Use in patients switching from oral anticoagulants to Iprivask or from Iprivask to oral anticoagulants. The concomitant administration of warfarin did not significantly affect the pharmacokinetic effects of desirudin. When warfarin and desirudin were co-administered, greater inhibition of hemostasis measured by activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) was observed. If a patient is switched from oral anticoagulants to Iprivask therapy or from Iprivask to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods. That activity should be taken into account in the evaluation of the overall coagulation status of the patient during the switch.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well controlled studies in pregnant women. Iprivask should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Animal Data
- Teratology studies have been performed in rats at subcutaneous doses in a range of 1 to 15 mg/kg/day (about 0.3 to 4 times the recommended human dose based on body surface area) and in rabbits at IV doses in a range of 0.6 to 6 mg/kg/day (about 0.3 to 3 times the recommended human dose based on body surface area) and have revealed desirudin to be teratogenic. Observed teratogenic findings were: omphalocele, asymmetric and fused sternebrae, edema, shortened hind limbs, etc. in rats; and spina bifida, malrotated hind limb, hydrocephaly, gastroschisis, etc. in rabbits.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Desirudin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Desirudin during labor and delivery.
### Nursing Mothers
- It is not known whether desirudin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when desirudin is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- In three clinical studies of Iprivask, the percentage of patients greater than 65 years of age treated with 15 mg of Iprivask subcutaneously every 12 hours was 58.5%, while 20.8% were 75 years of age or older. Elderly patients treated with Iprivask had a reduction in the incidence of VTE similar to that observed in the younger patients, and a slightly lower incidence of VTE compared to those patients treated with heparin or enoxaparin.
- Regarding safety, in the clinical studies the incidence of hemorrhage (major or otherwise) in patients 65 years of age or older was similar to that in patients less than 65 years of age. In addition, the elderly had a similar incidence of total, treatment-related, or serious adverse events compared to those patients less than 65 years of age. Serious adverse events occurred more frequently in patients 75 years of age or older as compared to those less than 65 years of age. In general, 15 mg desirudin every 12 hours can be used safely in the geriatric population as in the population of patients less than 65 years of age so long as renal function is adequate.
### Gender
There is no FDA guidance on the use of Desirudin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Desirudin with respect to specific racial populations.
### Renal Impairment
- Iprivask must be used with caution in patients with renal impairment, particularly in those with moderate and severe renal impairment (creatinine clearance ≤60 mL/min/1.73 m2 body surface area). Dose reductions by factors of three and nine are recommended for patients with moderate and severe renal impairment respectively. In addition, daily aPTT and serum creatinine monitoring are recommended for patients with moderate or severe renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Desirudin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Desirudin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Desirudin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.
- Daily aPTT and serum creatinine monitoring are recommended for patients with moderate or severe renal impairment.
- Activated partial thromboplastin time (aPTT) should be monitored daily in patients with increased risk of bleeding.
- Peak aPTT should not exceed two times control.
- Should peak aPTT exceed this level, dose reduction is advised based on the degree of aPTT abnormality. If necessary, therapy with desirudin should be interrupted until aPTT falls to less than two times control, at which time treatment with desirudin can be resumed at a reduced dose.
- Thrombin time (TT) is not a suitable test for routine monitoring of Iprivask therapy.
- Dose adjustments based on serum creatinine may be necessary.
- Any agent which may enhance the risk of hemorrhage should be discontinued prior to initiation of desirudin therapy.
- These agents include medications such as Dextran 40, systemic glucocorticoids, thrombolytics, and anticoagulants.
- If co-administration cannot be avoided, close clinical and laboratory monitoring should be conducted.
- The concomitant administration of warfarin did not significantly affect the pharmacokinetic effects of desirudin.
- When warfarin and desirudin were co-administered, greater inhibition of hemostasis measured by activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) was observed. If a patient is switched from oral anticoagulants to Iprivask therapy or from Iprivask to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods.
# IV Compatibility
There is limited information regarding IV Compatibility of Desirudin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In an open, pilot, dose-ascending study to assess safety, the highest dose of desirudin (40 mg q12h) caused excessive hemorrhage.
- In case of overdose, most likely reflected in hemorrhagic complications or suggested by excessively high aPTT values, Iprivask therapy should be discontinued.
- Emergency procedures should be instituted as appropriate (for example, determination of aPTT and other coagulation levels, hemoglobin, the use of blood transfusion or plasma expanders).
### Management
- No specific antidote for Iprivask is available; however, the anticoagulant effect of desirudin is partially reversible using thrombin-rich plasma concentrates while aPTT levels can be reduced by the IV administration of 0.3 µg/kg DDAVP (desmopressin). The clinical effectiveness of DDAVP in treating bleeding due to desirudin overdose has not been studied.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Desirudin in the drug label.
# Pharmacology
There is limited information regarding Desirudin Pharmacology in the drug label.
## Mechanism of Action
- Desirudin is a selective inhibitor of free circulating and clot-bound thrombin. The anticoagulant properties of desirudin are demonstrated by its ability to prolong the clotting time of human plasma. One molecule of desirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected. Activated partial thromboplastin time (aPTT) is a measure of the anticoagulant activity of desirudin and increases in a dose-dependent fashion.
## Structure
- Iprivask® (desirudin for injection) is a specific inhibitor of human thrombin. It has a protein structure that is similar to that of hirudin, the naturally occurring anticoagulant present in the peripharyngeal glands in the medicinal leech,Hirudo medicinalis. Hirudin is a single polypeptide chain of 65 amino acids residues and contains three disulfide bridges. Desirudin has a chemical formula of C287H440N80O110S6 with a molecular weight of 6963.52. Desirudin, which is expressed in yeast (Saccharomyces cerevisiae, strain TR 1456) by recombinant DNA technology differs from the natural hirudin by lack of a sulfate group on Tyr-63. The biological activity of desirudin is determined through a chromogenic assay which measures the ability of desirudin to inhibit the hydrolysis of a chromogenic peptidic substrate by thrombin in comparison to a desirudin standard. One vial of desirudin contains 15.75 mg desirudin corresponding to approximately 315,000 antithrombin units (ATU) or 20,000 ATU per milligram of desirudin with reference to the WHO International Standard (prepared 1991) for alphathrombin.
## Pharmacodynamics
- The pharmacodynamic effect of desirudin on proteolytic activity of thrombin was assessed as an increase in aPTT. A mean peak aPTT prolongation of about 1.38 times baseline value (range 0.58 to 3.41) was observed following subcutaneous b.i.d. injections of 15 mg desirudin. Thrombin time (TT) frequently exceeds 200 seconds even at low plasma concentrations of desirudin, which renders this test unsuitable for routine monitoring of Iprivask therapy. At therapeutic serum concentrations, desirudin has no effect on other enzymes of the hemostatic system such as factors IXa, Xa, kallikrein, plasmin, tissue plasminogen activator, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin, chymotrypsin, or on complement activation by the classical or alternative pathways.
## Pharmacokinetics
- Pharmacokinetic parameters were calculated based on plasma concentration data obtained by a non-specific ELISA method that does not discriminate between native desirudin and its metabolites. It is not known if the metabolites are pharmacologically active.
- The absorption of desirudin is complete when subcutaneously administered at doses of 0.3 mg/kg or 0.5 mg/kg. Following subcutaneous administration of single doses of 0.1 to 0.75 mg/kg, plasma concentrations of desirudin increased to a maximum level (Cmax) between 1 and 3 hours. Both Cmax and area-under-the-curve (AUC) values are dose proportional.
- The pharmacokinetic properties of desirudin following intravenous (IV) administration are well described by a two- or three- compartment disposition model. Desirudin is distributed in the extracellular space with a volume of distribution at steady state of 0.25 L/kg, independent of the dose. Desirudin binds specifically and directly to thrombin, forming an extremely tight, non-covalent complex with an inhibition constant of approximately 2.6 x 10-13 M. Thus, free or protein bound desirudin immediately binds circulating thrombin. The pharmacological effect of desirudin is not modified when co-administered with highly protein bound drugs (>99%).
- Human and animal data suggest that desirudin is primarily eliminated and metabolized by the kidney. The total urinary excretion of unchanged desirudin amounts to 40 to 50% of the administered dose. Metabolites lacking one or two C-terminal amino acids constitute a minor proportion of the material recovered from urine (< 7%). There is no evidence for the presence of other metabolites. This indicates that desirudin is metabolized by stepwise degradation from the C-terminus probably catalyzed by carboxypeptidase(s) such as carboxypeptidase A, originating from the pancreas. Total clearance of desirudin is approximately 1.5 to 2.7 mL/min/kg following either subcutaneous or IV administration and is independent of dose. This clearance value is close to the glomerular filtration rate.
- The elimination of desirudin from plasma is rapid after IV administration, with approximately 90% of the dose disappearing from the plasma within 2 hours of the injection. Plasma concentrations of desirudin then decline with a mean terminal elimination half-life of 2 to 3 hours. After subcutaneous administration, the mean terminal elimination half-life is also approximately 2 hours.
- In a pharmacokinetic study of renally impaired subjects, subjects with mild creatinine clearance between 61 and 90 mL/min/1.73 m2 body surface area, moderate (creatinine clearance between 31 and 60 mL/min/1.73 m2 body surface area), and severe (creatinine clearance below 31 mL/min/1.73 m2 body surface area) renal impairment, were administered a single IV dose of 0.5, 0.25, or 0.125 mg/kg desirudin, respectively. This resulted in mean dose-normalized AUCeffect (AUC0-60th for aPTT prolongation) increases of approximately 3-, and 9-fold for the moderate and severe renally impaired subjects, respectively, compared with healthy individuals. In subjects with mild renal impairment, there was no increase in AUCeffect compared with healthy individuals. In subjects with severe renal impairment, terminal elimination half-lives were prolonged up to 12 hours compared with 2 to 4 hours in normal volunteers or subjects with mild to moderate renal impairment. Dose adjustments are recommended in certain circumstances in relation to the degree of impairment or degree of aPTT abnormality.
- No pharmacokinetic studies have been conducted to investigate the effects of Iprivask in hepatic impairment.
- The mean plasma clearance of desirudin in patients ≥65 years of age (n=12; 110 mL/min) is approximately 28% lower than in patients <65 years of age (n=8; 153 mL/min). Population pharmacokinetics conducted in 301 patients undergoing elective total hip replacement indicate that age or gender do not affect the systemic clearance of desirudin when renal creatinine clearance is considered. This drug is substantially excreted by the kidney, and the risk of adverse events due to it 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. Dosage adjustment in the case of moderate and severe renal impairment is necessary.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- No long-term studies in animals have been performed to evaluate the carcinogenic potential of desirudin.
- Desirudin was not genotoxic in the Ames test, the Chinese hamster lung cell (V79/HGPRT) forward mutation test or the rat micronucleus test. It was, however, equivocal in its genotoxic effect in Chinese hamster ovarian cell (CCL 61) chromosome aberration tests.
- Desirudin at subcutaneous doses up to 10mg/kg/day (about 2.7 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.
- Animal Toxicology and/or Pharmacology
- Desirudin produced bleeding, local inflammation, and granulation at injection sites in rat and dog toxicity studies. In a 28-day study in Rhesus monkeys, there was also evidence of subcutaneous bleeding and local inflammation at the injection sites. In addition, desirudin was immunogenic in dogs and formed antibody complexes resulting in prolonged half-life and accumulation. Desirudin showed sensitization potential in guinea pig immediate and delayed hypersensitivity models.
# Clinical Studies
- Iprivask was evaluated in two controlled, randomized, multicenter, clinical efficacy trials and a controlled, double-blind, dose-finding study. In the efficacy studies, Iprivask was compared to subcutaneously administered unfractionated heparin or enoxaparin sodium for the reduction of the risk of venous thromboembolic events (VTE) in patients undergoing total hip replacement surgery. In all studies Iprivask was initiated prior to surgery and continued for 8 to 12 days postoperatively (median duration 10 days). Patients who received Iprivask had a lower incidence of VTE. The efficacy studies are described below.
- In the first study, Iprivask 15 mg subcutaneously administered every 12 hours was compared to unfractionated heparin 5000 IU subcutaneously administered every 8 hours. A total of 445 patients were randomized in the study, 436 patients were treated, and 85 of the treated patients were excluded from efficacy analysis, mainly because of no phlebography or inadequate reading of phlebography. Patients ranged in age from 34 to 89 years (mean age 68.4 years) with 41.8% men and 58.2% women. All enrolled patients were Caucasian. Iprivask significantly reduced the number of total VTE compared to unfractionated heparin: Evaluable population: Iprivask, 13/174 (7.5%) vs. heparin, 41/177 (23.2%); p value <0.001; Intent-to-Treat population: Iprivask 13/225 (5.8%) vs. heparin 42/220 (19.1%); p value <0.0001.]. Significantly fewer patients in the group treated with Iprivask experienced proximal DVT than those patients treated with heparin: Evaluable population: Iprivask 6/174 (3.4%) vs. heparin 29/177 (16.4%); p value <0.001: Intent-to-Treat population: Iprivask 6/225 (2.7%) vs. heparin 30/220 (13.6%); p value <0.0001.
- In a second study, Iprivask 15 mg subcutaneously administered every 12 hours was compared to enoxaparin sodium 40 mg subcutaneously administered every 24 hours. A total of 2079 patients were randomized in the study, 2049 patients were treated, and 508 of the treated patients were excluded from efficacy analysis mainly because of no phlebography or inadequate reading of phlebography. Patients ranged in age from 18 to 90 years (mean age 68.5 years) with 41.7% men and 58.5% women. All enrolled patients were Caucasian. In both the evaluable patient population and the intent-to-treat population, patients who received Iprivask had a lower incidence of major VTE, total VTE, and proximal DVT than did patients who received enoxaparin (see table below).
- In a multicenter, double-blind, dose-finding study, Iprivask 10 mg, 15 mg, and 20 mg subcutaneously administered every 12 hours was compared to unfractionated heparin 5,000 IU administered every 8 hours SC in patients undergoing hip replacement surgery. A dose response was seen with regard to both effectiveness and bleeding complications. The 15-mg and 20-mg doses were superior to heparin and the 10-mg dose. In a smaller, open-labeled, dose-finding study of Iprivask 10 mg, 15 mg, 20 mg, and 40 mg subcutaneously administered every 12 hours in patients undergoing hip replacement surgery, the 40-mg dose was associated with unacceptable major bleeding.
# How Supplied
- Iprivask (desirudin for injection) is supplied as a single dose (15.75 mg) lyophilized powder with an accompanying sterile, non-pyrogenic diluent [0.6 mL of Mannitol USP (3%) in Water for Injection].
- Each Iprivask Vial contains 15.75 mg desirudin and the following inactive ingredients: 1.31 mg anhydrous magnesium chloride USP, sodium hydroxide for injection USP.
- Each carton (NDC 42998-715-10) of Iprivask (desirudin for injection) contains 10 individual doses of Iprivask, each in a separate tray.
- Each tray of Iprivask (desirudin for injection) contains:
- One (1) x 15.75 mg Single Dose Vial
- One (1) x 0.6 mL Prefilled syringe of Diluent
- One (1) Eclipse™ needle
- One (1) Vial Adapter
- Each prefilled syringe of diluent contains 0.6 mL Mannitol USP (3% w/v) in Water for Injection provided for reconstitution of the desirudin lyophilized powder.
- Storage: Protect from light.
- Unopened vials or prefilled syringes: Store at 25°C (77°F); excursions permitted to 15–30°C (59-86°F). [See USP Controlled Room Temperature.]
- Keep this and all medicines out of the reach of children.
## Storage
There is limited information regarding Desirudin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients to watch carefully for any signs of bleeding or bruising and to report these to their health care provider when they occur.
- Advise patients to discuss with their health care provider their use of any other medications, including over-the-counter medications or herbal products, prior to Iprivask use. Examples of other medications that should not be taken with Iprivask are aspirin, non-steroidal anti-inflammatory drugs including ketorolac, acetylsalicylic acid ticlopidine, dipyridamole, sulfinpyrazone, clopidogrel, abciximab and other glycoprotein IIb/IIIa antagonists.
- Advise patients to read the FDA-approved patient labeling (Product Assembly Instructions for Use).
# Precautions with Alcohol
- Alcohol-Desirudin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Iprivask®[7]
# Look-Alike Drug Names
- N/A[8]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Desirudin | |
d751f07960728e308be210b2bcd6e5998e8cfce2 | wikidoc | Desmosome | Desmosome
# Overview
A desmosome, also known as macula adherens (Latin: adhering spot), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adhesions randomly arranged on the lateral sides of plasma membranes.
Desmosomes help to resist shearing forces and are found in simple and stratified squamous epithelium. The intercellular space is very wide (about 30nm). Desmosomes are also found in muscle tissue where they bind muscles cells to one another.
# Structure
They are molecular complexes of cell adhesion proteins and linking proteins that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments.
The cell adhesion proteins of the desmosome are members of the cadherin family of cell adhesion molecules.
They are transmembrane proteins that bridge the space between adjacent epithelial cells by way of homophilic binding of their extracellular domains to other desmosomal cadherins on the adjacent cell.
On the cytoplasmic side of the plasma membrane is a disk-like structure (attachment plaque) composed of very dense materials.
The main desmosomal linking proteins, desmoplakins and plakoglobins, bind to the intracellular domain of cadherins and form a connecting bridge to the cytoskeleton.
# Blistering diseases
If the desmosomes connecting adjacent epithelial cells of the skin are not functioning correctly, layers of the skin can pull apart and allow abnormal movements of fluid within the skin, resulting in blisters and other tissue damage. Blistering diseases such as Pemphigus vulgaris can be due to genetic defects in desmosomal proteins or due to an autoimmune response. These patients are often found to have antibodies that bind to the desmosomal cadherins and disrupt the desmosomes.
# Hemidesmosomes
When visualized by electron microscopy, hemidesmosomes are similar in appearance to desmosomes. Rather than linking two cells, hemidesmosomes attach one cell to the extracellular matrix. Rather than using cadherins, hemidesmosomes use integrin cell adhesion proteins. Hemidesmosomes are asymmetrical and are found in epithelial cells connecting the basal face to other cells. | Desmosome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A desmosome, also known as macula adherens (Latin: adhering spot), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adhesions randomly arranged on the lateral sides of plasma membranes.
Desmosomes help to resist shearing forces and are found in simple and stratified squamous epithelium. The intercellular space is very wide (about 30nm). Desmosomes are also found in muscle tissue where they bind muscles cells to one another.
# Structure
They are molecular complexes of cell adhesion proteins and linking proteins that attach the cell surface adhesion proteins to intracellular keratin cytoskeletal filaments.
The cell adhesion proteins of the desmosome are members of the cadherin family of cell adhesion molecules.
They are transmembrane proteins that bridge the space between adjacent epithelial cells by way of homophilic binding of their extracellular domains to other desmosomal cadherins on the adjacent cell.
On the cytoplasmic side of the plasma membrane is a disk-like structure (attachment plaque) composed of very dense materials.
The main desmosomal linking proteins, desmoplakins and plakoglobins, bind to the intracellular domain of cadherins and form a connecting bridge to the cytoskeleton.
# Blistering diseases
If the desmosomes connecting adjacent epithelial cells of the skin are not functioning correctly, layers of the skin can pull apart and allow abnormal movements of fluid within the skin, resulting in blisters and other tissue damage. Blistering diseases such as Pemphigus vulgaris can be due to genetic defects in desmosomal proteins or due to an autoimmune response. These patients are often found to have antibodies that bind to the desmosomal cadherins and disrupt the desmosomes.
# Hemidesmosomes
When visualized by electron microscopy, hemidesmosomes are similar in appearance to desmosomes. Rather than linking two cells, hemidesmosomes attach one cell to the extracellular matrix. Rather than using cadherins, hemidesmosomes use integrin cell adhesion proteins. Hemidesmosomes are asymmetrical and are found in epithelial cells connecting the basal face to other cells. | https://www.wikidoc.org/index.php/Desmosome | |
9aacf7dfe3dce7144dda36bced1adbc1d43e61d4 | wikidoc | Trazodone | Trazodone
- Immediate-release tablets, initial 150 mg/day orally in divided doses; may increase dosage by 50 mg/day every 3 to 4 days; MAX, 400 mg/day for outpatients and 600 mg/day for inpatients.
- Extended-release tablets, initial 150 mg Orally once daily in the evening, preferably at bedtime; may increase by 75 mg once daily every 3 days; MAX, 375 mg/day; dose may be gradually reduced once adequate response achieved.
- 50 to 100 mg orally, 1 hour prior to bedtime has been used in clinical trials.
- 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 – 24) with 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 4,400 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 1,000 patients treated) are provided in Table
- 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.
- 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 trazodone should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
## Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
- The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (includingSSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors ), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.
- Treatment with trazodone hydrochloride tablets and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated.
- Trazodone hydrochloride tablets should not be used within 14 days of an MAOI .
- If concomitant treatment with trazodone hydrochloride tablets and an SSRI, SNRI or a 5- hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- The concomitant use of trazodone hydrochloride tablets with serotonin precursors (such as tryptophan) is not recommended.
## Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania
- 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 for clinical worsening and suicide risk 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 trazodone hydrochloride tablets is not approved for use in treating bipolar depression.
## QT Prolongation and Risk of Sudden Death
- Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QTc prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QTc.
- Although Torsades de Pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk. However, there have been postmarketing reports of Torsades de Pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.
## Use in Patients with Heart Disease
- Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction.
- Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias.
- QT prolongation has been reported with trazodone therapy . Clinical studies in patients with pre-existing cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and Torsades de Pointes. Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone.
- Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.
## Orthostatic Hypotension and Syncope
- Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride. Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug.
## Abnormal Bleeding
- Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding. While no association between trazodone and bleeding events, in particular GI bleeding, was shown, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
## Interaction with MAOIs
- In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that trazodone hydrochloride tablets should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping trazodone hydrochloride tablets before starting an MAOI.
## Priapism
- Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention .
- Trazodone should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease).
## Hyponatremia
- Hyponatremia may occur as a result of treatment with antidepressants. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with antidepressants. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of trazodone hydrochloride tablets 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 can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
## Potential for Cognitive and Motor Impairment
- Trazodone hydrochloride tablets may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.
## Discontinuation Symptoms
- Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone. Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.
- Clinical Worsening and Suicide Risk
- Serotonin Syndrome or NMS-like Reactions
- QT Prolongation and Risk of Sudden Death
- Orthostatic Hypotension
- Abnormal bleeding events
- Priapism
- Hyponatremia
- Cognitive and Motor Impairment
- Discontinuation symptoms
- The most common adverse reactions (reported in ≥5% and at twice the rate of placebo) are: Somnolence/sedation, dizziness, constipation, vision blurred.
- Table 2 presents the summary of adverse events (AEs) leading to discontinuation of trazodone hydrochloride tablets treatment with an incidence of at least 1% and at least twice that for placebo.
- The table below is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of trazodone hydrochloride.
- The figures cited cannot be used to predict concisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those which prevailed in the clinical trials. These incidence figures, also, cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials is conducted under a different set of conditions.
- Occasional sinus bradycardia has occurred in long-term studies.
- In addition to the relatively common (i.e., greater than 1%) untoward events enumerated above, the following adverse events have been reported to occur in association with the use of trazodone hydrochloride in the controlled clinical studies: akathisia, allergic reaction, anemia, chest pain, delayed urine flow, early menses, flatulence, hallucinations/delusions, hematuria, hyper-salivation, hypomania, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, and retrograde ejaculation.
- Cardiovascular system effects which have been reported include the following: conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. In postmarketing surveillance, prolonged QT interval, Torsades de Pointes, and ventricular tachycardia have been reported with the immediate-release form of trazodone at doses of 100 mg per day or less .
- MAOIs should not be used within 14 days of trazodone .
- Central Nervous System (CNS) Depressants
- Trazodone may enhance the response to alcohol, barbiturates, and other CNS depressants.
- Cytochrome P450 3A4 Inhibitors
- In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with cytochrome P450 3A4 (CYP3A4) inhibitors. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of trazodone increased by 34%, the AUC increased 2.4-fold, the half-life increased by 2.2-fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were co-administered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, the risk of cardiac arrhythmia may be increased and a lower dose of trazodone should be considered.
- Cytochrome P450 Inducers (e.g., carbamazepine)
- Carbamazepine induces CYP3A4. Following co-administration of carbamazepine 400 mg per day with trazodone 100 mg to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone and m- chlorophenlypiperazine (an active metabolite) by 76% and 60% respectively, compared to pre- carbamazepine values. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs.
- Digoxin and Phenytoin
- Increased serum digoxin or phenytoin levels have been reported in patients receiving trazodone concurrently with either of these drugs. Monitor serum levels and adjust dosages as needed.
- Serotonergic Drugs
- Based on the mechanism of action of trazodone and the potential for serotonin syndrome, caution is advised when trazodone is co-administered with other drugs that may affect the neurotransmitter systems .
- NSAIDs, Aspirin, or Other Drugs Affecting Coagulation or Bleeding
- Due to a possible association between serotonin modulating drugs and gastrointestinal bleeding, patients should be monitored for and cautioned about the potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding
- Warfarin
- There have been reports of altered (either increased or decreased) prothrombin times in taking both warfarin and trazodone.
- Antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients who may be at greater risk for this adverse reaction .
- Death from overdose has occurred in patients ingesting trazodone and other CNS depressant drugs concurrently (alcohol; alcohol and chloral hydrate and diazepam; amobarbital; chlordiazepoxide; or meprobamate).
- The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes, including QT prolongation. The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions.
- Management of Overdose
- There is no specific antidote for trazodone hydrochloride overdose.
- Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder.
- Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.
- General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Forced diuresis may be useful in facilitating elimination of the drug.
- 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.
Chemical Name: 2-propyl]-1,2,4-triazolopyridin-3(2H)-one hydrochloride
Structural Formula:
Molecular Formula: C19H22ClN5O HCl
Molecular Weight: 408.32
Each tablet, for oral administration, contains 50 mg, 100 mg, 150 mg or 300 mg of trazodone hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, and sodium starch glycolate.
Trazodone is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system.
Trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension.
- In humans, trazodone hydrochloride is well absorbed after oral administration without selective localization in any tissue. When trazodone hydrochloride is taken shortly after ingestion of food, there may be an increase in the amount of drug absorbed, a decrease in maximum concentration and a lengthening in the time to maximum concentration. Peak plasma levels occur approximately one hour after dosing when trazodone hydrochloride is taken on an empty stomach or 2 hours after dosing when taken with food.
- Metabolism
- In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.
- Elimination
- In some patients trazodone may accumulate in the plasma
- Protein Binding
- Trazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans.
- No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone in daily oral doses up to 300 mg/kg for 18 months.
Bottles of 30 NDC 13668-330-30
Bottles of 100 NDC 13668-330-01
Bottles of 500 NDC 13668-330-05
Bottles of 1000 NDC 13668-330-10
100 Unit dose Tablets NDC 13668-330-74
Trazodone Hydrochloride Tablets, USP 100 mg are available for oral administration as white to off white, round, biconvex, uncoated tablets debossed with "13" bisect "31" on one side and plain on other side.
Bottles of 30 NDC 13668-331-30
Bottles of 100 NDC 13668-331-01
Bottles of 500 NDC 13668-331-05
Bottles of 1000 NDC 13668-331-10
100 Unit dose Tablets NDC 13668-331-74
Trazodone Hydrochloride Tablets, USP 150 mg are available for oral administration as white to off white, oval, flat faced beveled edge uncoated tablets with a full bisect and two partial trisects. Debossed "13" bisect "32" on one side and "50 50 50" on other side.
Bottles of 30 NDC 13668-332-30
Bottles of 100 NDC 13668-332-01
Bottles of 500 NDC 13668-332-05
Bottles of 1000 NDC 13668-332-10
100 Unit dose Tablets NDC 13668-332-74
Directions for using the correct score when breaking the tablet, please refer to the following:
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
- Read the Medication Guide that comes with trazodone hydrochloride tablets before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider or pharmacist if there is something you do not understand or you want to learn about trazodone hydrochloride tablets.
## What is the most important information I should know about trazodone hydrochloride?
- Antidepressant medicines, depression or other serious mental illnesses, and suicidal thoughts or actions: Talk to your healthcare provider about:
- All risks and benefits of treatment with antidepressant medicines
- All treatment choices for depression or other serious mental illnesses
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
- Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a higher risk of having suicidal thoughts or actions. These include people who have or have a family history of bipolar illness (also called manic- depressive illness) or suicidal thoughts or actions.
## How can I watch for and try to prevent suicidal thoughts and actions?
- Pay close attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:
- Thoughts about suicide or dying
- Attempts to commit suicide
- New or worse depression
- New or worse anxiety
- Feeling very agitated or restless
- Panic attacks
- Trouble sleeping (insomnia)
- New or worse irritability
- Acting aggressive, being angry or violent
- Acting on dangerous impulses
- An extreme increase in activity and talking (mania)
- Other unusual changes in behavior or mood
## What else do I need to know about antidepressant medicines?
- Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
- Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider, not just the use of antidepressants.
- Antidepressant medicines have other side effects. Talk to your healthcare provider about the side effects of your medicines.
- Antidepressant medicines can interact with other medicines. Know all of the medicines that you take. Keep a list of all medicines to show your healthcare provider. Do not start new medicines without first checking with your healthcare provider.
- Trazodone hydrochloride tablets are not approved for use in children. Talk to your healthcare provider for more information.
# =What are trazodone hydrochloride tablets?
- Trazodone hydrochloride tablets are a prescription medicine used to treat major depressive disorder in adults.
- What should I tell my healthcare provider before taking trazodone hydrochloride tablets?
- Before you take trazodone hydrochloride tablets tell your healthcare provider if you:
- Have heart problems, including QT prolongation or a family history of it
- Have ever had a heart attack
- Have bipolar disorder
- Have liver or kidney problems
- Have other serious medical conditions
- Are pregnant or plan to become pregnant. Trazodone hydrochloride tablets may harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
- Are breastfeeding or plan to breastfeed. It is not known if trazodone hydrochloride tablets passes into your breast milk. You and your healthcare provider should decide if you will take trazodone hydrochloride tablets or breastfeed.
- Have taken a Monoamine Oxidase Inhibitor (MAOI) or if you have stopped taking an MAOI in the last 2 weeks.
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Using trazodone hydrochloride tablets with certain other medicines can affect each other causing serious side effects.
- Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
## How should I take trazodone hydrochloride tablets?
- Take trazodone hydrochloride tablets exactly as your healthcare provider tells you.
- Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.
- If you feel drowsy after taking trazodone hydrochloride tablets, talk to your healthcare provider. Your healthcare provider may change your dose or the time of day you take your trazodone hydrochloride tablets.
- Do not stop taking trazodone hydrochloride tablets without talking to your healthcare provider.
- Trazodone hydrochloride tablets should be swallowed whole or broken in half along the score line. Do not chew or crush trazodone hydrochloride tablets. Tell your healthcare provider if you cannot swallow trazodone either whole or as a half tablet.
- If you take too much trazodone hydrochloride, call your doctor or go to the nearest emergency room right away.
## What should I avoid while taking trazodone hydrochloride tablets?
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how trazodone hydrochloride tablets affects you. Trazodone hydrochloride tablets can slow your thinking and motor skills.
- Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking trazodone hydrochloride tablets until you talk with your healthcare provider. Trazodone hydrochloride tablets may make your sleepiness or dizziness worse if you take it with alcohol or other medicines that cause sleepiness or dizziness.
## What are the possible side effects of trazodone hydrochloride tablets?
- Trazodone hydrochloride tablets can cause serious side effects or death. See "What is the most important information I should know about trazodone hydrochloride tablets?"
- Serious side effects include:
- Serotonin syndrome. Symptoms of serotonin syndrome include: agitation, hallucinations, problems with coordination, fast heartbeat, tight muscles, trouble walking, nausea, vomiting, diarrhea.
- Feeling high or in a very good mood, then becoming irritable, or having too much energy, feeling like you have to keep talking or do not sleep (Mania).
- Irregular or fast heartbeat or faint (QT prolongation).
- Low blood pressure. You feel dizzy or faint when you change positions (go from sitting to standing).
- Unusual bruising or bleeding.
- Erection lasting for more than 6 hours (Priapism).
- Low sodium in your blood (Hyponatremia). Symptoms of hyponatremia include: headache, feeling weak, feeling confused, trouble concentrating, memory problems and feeling unsteady when you walk.
- Withdrawal symptoms. Symptoms of withdrawal can include anxiety, agitation, and sleep problems. Do not stop taking trazodone hydrochloride tablets without talking to your healthcare provider.
- Get medical help right away, if you have any of the symptoms listed above.
- The most common side effects of trazodone hydrochloride tablets include:
- Sleepiness
- Dizziness
- Constipation
- Blurry vision
- Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
- These are not all the possible side effects of trazodone hydrochloride tablets. For more information, ask your healthcare provider or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.
## How should I store trazodone hydrochloride tablets?
- Store trazodone hydrochloride tablets between between 68°F to 77°F (20° C to 25°C).
- Keep in tight container
- Keep out of the light
- Safely throw away medicine that is out of date or no longer needed.
- Keep trazodone hydrochloride tablets and all medicines out of the reach of children.
## General information about the safe and effective use of trazodone hydrochloride tablets
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use trazodone hydrochloride tablets for a condition for which it was not prescribed. Do not give trazodone hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them.
- This Medication Guide summarizes the most important information about trazodone hydrochloride tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about trazodone hydrochloride tablets that is written for health professionals.
- For more information go to www.torrentpharma.com or call 1-800-FDA-1088
## What are the ingredients in trazodone hydrochloride tablets?
- Active ingredient: trazodone hydrochloride, USP
- Inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, and sodium starch glycolate.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
- ↑ Jump up to: 1.0 1.1 1.2 1.3 Truven Health Analytics, Inc. DrugPoint® System (Internet) . Greenwood Village, CO: Thomsen Healthcare; 2013. | Trazodone
- Immediate-release tablets, initial 150 mg/day orally in divided doses; may increase dosage by 50 mg/day every 3 to 4 days; MAX, 400 mg/day for outpatients and 600 mg/day for inpatients.
- Extended-release tablets, initial 150 mg Orally once daily in the evening, preferably at bedtime; may increase by 75 mg once daily every 3 days; MAX, 375 mg/day; dose may be gradually reduced once adequate response achieved.
- 50 to 100 mg orally, 1 hour prior to bedtime has been used in clinical trials.
- 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 – 24) with 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 4,400 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 1,000 patients treated) are provided in Table
- 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.
- 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 trazodone should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
### Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
- The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (includingSSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.
- Treatment with trazodone hydrochloride tablets and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated.
- Trazodone hydrochloride tablets should not be used within 14 days of an MAOI [see Warnings and Precautions and Drug Interactions].
- If concomitant treatment with trazodone hydrochloride tablets and an SSRI, SNRI or a 5- hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- The concomitant use of trazodone hydrochloride tablets with serotonin precursors (such as tryptophan) is not recommended.
### Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania
- 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 for clinical worsening and suicide risk 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 trazodone hydrochloride tablets is not approved for use in treating bipolar depression.
### QT Prolongation and Risk of Sudden Death
- Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QTc prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QTc.
- Although Torsades de Pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk. However, there have been postmarketing reports of Torsades de Pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.
### Use in Patients with Heart Disease
- Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction.
- Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias.
- QT prolongation has been reported with trazodone therapy [see Warnings and Precautions]. Clinical studies in patients with pre-existing cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and Torsades de Pointes. Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone.
- Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.
### Orthostatic Hypotension and Syncope
- Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride. Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug.
### Abnormal Bleeding
- Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding. While no association between trazodone and bleeding events, in particular GI bleeding, was shown, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.
### Interaction with MAOIs
- In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that trazodone hydrochloride tablets should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping trazodone hydrochloride tablets before starting an MAOI.
### Priapism
- Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions and Overdosage].
- Trazodone should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease).
### Hyponatremia
- Hyponatremia may occur as a result of treatment with antidepressants. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with antidepressants. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of trazodone hydrochloride tablets 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 can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
### Potential for Cognitive and Motor Impairment
- Trazodone hydrochloride tablets may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.
### Discontinuation Symptoms
- Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone. Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.
- Clinical Worsening and Suicide Risk [see Boxed Warning and Warnings and Precautions]
- Serotonin Syndrome or NMS-like Reactions [see Warnings and Precautions]
- QT Prolongation and Risk of Sudden Death [see Warnings and Precautions]
- Orthostatic Hypotension [see Warnings and Precautions]
- Abnormal bleeding events [see Warnings and Precautions]
- Priapism [see Warnings and Precautions]
- Hyponatremia [see Warnings and Precautions]
- Cognitive and Motor Impairment [see Warnings and Precautions]
- Discontinuation symptoms [see Warnings and Precautions]
- The most common adverse reactions (reported in ≥5% and at twice the rate of placebo) are: Somnolence/sedation, dizziness, constipation, vision blurred.
- Table 2 presents the summary of adverse events (AEs) leading to discontinuation of trazodone hydrochloride tablets treatment with an incidence of at least 1% and at least twice that for placebo.
- The table below is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of trazodone hydrochloride.
- The figures cited cannot be used to predict concisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those which prevailed in the clinical trials. These incidence figures, also, cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials is conducted under a different set of conditions.
- Occasional sinus bradycardia has occurred in long-term studies.
- In addition to the relatively common (i.e., greater than 1%) untoward events enumerated above, the following adverse events have been reported to occur in association with the use of trazodone hydrochloride in the controlled clinical studies: akathisia, allergic reaction, anemia, chest pain, delayed urine flow, early menses, flatulence, hallucinations/delusions, hematuria, hyper-salivation, hypomania, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, and retrograde ejaculation.
- Cardiovascular system effects which have been reported include the following: conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. In postmarketing surveillance, prolonged QT interval, Torsades de Pointes, and ventricular tachycardia have been reported with the immediate-release form of trazodone at doses of 100 mg per day or less [see Warnings and Precautions ].
- MAOIs should not be used within 14 days of trazodone [see Warnings and Precautions].
- Central Nervous System (CNS) Depressants
- Trazodone may enhance the response to alcohol, barbiturates, and other CNS depressants.
- Cytochrome P450 3A4 Inhibitors
- In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with cytochrome P450 3A4 (CYP3A4) inhibitors. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of trazodone increased by 34%, the AUC increased 2.4-fold, the half-life increased by 2.2-fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were co-administered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, the risk of cardiac arrhythmia may be increased [see Warnings and Precautions] and a lower dose of trazodone should be considered.
- Cytochrome P450 Inducers (e.g., carbamazepine)
- Carbamazepine induces CYP3A4. Following co-administration of carbamazepine 400 mg per day with trazodone 100 mg to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone and m- chlorophenlypiperazine (an active metabolite) by 76% and 60% respectively, compared to pre- carbamazepine values. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs.
- Digoxin and Phenytoin
- Increased serum digoxin or phenytoin levels have been reported in patients receiving trazodone concurrently with either of these drugs. Monitor serum levels and adjust dosages as needed.
- Serotonergic Drugs
- Based on the mechanism of action of trazodone and the potential for serotonin syndrome, caution is advised when trazodone is co-administered with other drugs that may affect the neurotransmitter systems [see Warnings and Precautions].
- NSAIDs, Aspirin, or Other Drugs Affecting Coagulation or Bleeding
- Due to a possible association between serotonin modulating drugs and gastrointestinal bleeding, patients should be monitored for and cautioned about the potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Warnings and Precautions]
- Warfarin
- There have been reports of altered (either increased or decreased) prothrombin times in taking both warfarin and trazodone.
- Antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients who may be at greater risk for this adverse reaction [see Warnings and Precautions ].
- Death from overdose has occurred in patients ingesting trazodone and other CNS depressant drugs concurrently (alcohol; alcohol and chloral hydrate and diazepam; amobarbital; chlordiazepoxide; or meprobamate).
- The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes, including QT prolongation. The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions.
- Management of Overdose
- There is no specific antidote for trazodone hydrochloride overdose.
- Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder.
- Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.
- General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Forced diuresis may be useful in facilitating elimination of the drug.
- 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.
Chemical Name: 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one hydrochloride
Structural Formula:
Molecular Formula: C19H22ClN5O HCl
Molecular Weight: 408.32
Each tablet, for oral administration, contains 50 mg, 100 mg, 150 mg or 300 mg of trazodone hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, and sodium starch glycolate.
Trazodone is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system.
Trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension.
- In humans, trazodone hydrochloride is well absorbed after oral administration without selective localization in any tissue. When trazodone hydrochloride is taken shortly after ingestion of food, there may be an increase in the amount of drug absorbed, a decrease in maximum concentration and a lengthening in the time to maximum concentration. Peak plasma levels occur approximately one hour after dosing when trazodone hydrochloride is taken on an empty stomach or 2 hours after dosing when taken with food.
- Metabolism
- In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.
- Elimination
- In some patients trazodone may accumulate in the plasma
- Protein Binding
- Trazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans.
- No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone in daily oral doses up to 300 mg/kg for 18 months.
Bottles of 30 NDC 13668-330-30
Bottles of 100 NDC 13668-330-01
Bottles of 500 NDC 13668-330-05
Bottles of 1000 NDC 13668-330-10
100 Unit dose Tablets NDC 13668-330-74
Trazodone Hydrochloride Tablets, USP 100 mg are available for oral administration as white to off white, round, biconvex, uncoated tablets debossed with "13" bisect "31" on one side and plain on other side.
Bottles of 30 NDC 13668-331-30
Bottles of 100 NDC 13668-331-01
Bottles of 500 NDC 13668-331-05
Bottles of 1000 NDC 13668-331-10
100 Unit dose Tablets NDC 13668-331-74
Trazodone Hydrochloride Tablets, USP 150 mg are available for oral administration as white to off white, oval, flat faced beveled edge uncoated tablets with a full bisect and two partial trisects. Debossed "13" bisect "32" on one side and "50 50 50" on other side.
Bottles of 30 NDC 13668-332-30
Bottles of 100 NDC 13668-332-01
Bottles of 500 NDC 13668-332-05
Bottles of 1000 NDC 13668-332-10
100 Unit dose Tablets NDC 13668-332-74
Directions for using the correct score when breaking the tablet, please refer to the following:
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
- Read the Medication Guide that comes with trazodone hydrochloride tablets before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider or pharmacist if there is something you do not understand or you want to learn about trazodone hydrochloride tablets.
### What is the most important information I should know about trazodone hydrochloride?
- Antidepressant medicines, depression or other serious mental illnesses, and suicidal thoughts or actions: Talk to your healthcare provider about:
- All risks and benefits of treatment with antidepressant medicines
- All treatment choices for depression or other serious mental illnesses
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
- Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a higher risk of having suicidal thoughts or actions. These include people who have or have a family history of bipolar illness (also called manic- depressive illness) or suicidal thoughts or actions.
### How can I watch for and try to prevent suicidal thoughts and actions?
- Pay close attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts or feelings.
- Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
- Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:
- Thoughts about suicide or dying
- Attempts to commit suicide
- New or worse depression
- New or worse anxiety
- Feeling very agitated or restless
- Panic attacks
- Trouble sleeping (insomnia)
- New or worse irritability
- Acting aggressive, being angry or violent
- Acting on dangerous impulses
- An extreme increase in activity and talking (mania)
- Other unusual changes in behavior or mood
### What else do I need to know about antidepressant medicines?
- Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
- Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider, not just the use of antidepressants.
- Antidepressant medicines have other side effects. Talk to your healthcare provider about the side effects of your medicines.
- Antidepressant medicines can interact with other medicines. Know all of the medicines that you take. Keep a list of all medicines to show your healthcare provider. Do not start new medicines without first checking with your healthcare provider.
- Trazodone hydrochloride tablets are not approved for use in children. Talk to your healthcare provider for more information.
## =What are trazodone hydrochloride tablets?
- Trazodone hydrochloride tablets are a prescription medicine used to treat major depressive disorder in adults.
- What should I tell my healthcare provider before taking trazodone hydrochloride tablets?
- Before you take trazodone hydrochloride tablets tell your healthcare provider if you:
- Have heart problems, including QT prolongation or a family history of it
- Have ever had a heart attack
- Have bipolar disorder
- Have liver or kidney problems
- Have other serious medical conditions
- Are pregnant or plan to become pregnant. Trazodone hydrochloride tablets may harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
- Are breastfeeding or plan to breastfeed. It is not known if trazodone hydrochloride tablets passes into your breast milk. You and your healthcare provider should decide if you will take trazodone hydrochloride tablets or breastfeed.
- Have taken a Monoamine Oxidase Inhibitor (MAOI) or if you have stopped taking an MAOI in the last 2 weeks.
- Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Using trazodone hydrochloride tablets with certain other medicines can affect each other causing serious side effects.
- Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
### How should I take trazodone hydrochloride tablets?
- Take trazodone hydrochloride tablets exactly as your healthcare provider tells you.
- Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.
- If you feel drowsy after taking trazodone hydrochloride tablets, talk to your healthcare provider. Your healthcare provider may change your dose or the time of day you take your trazodone hydrochloride tablets.
- Do not stop taking trazodone hydrochloride tablets without talking to your healthcare provider.
- Trazodone hydrochloride tablets should be swallowed whole or broken in half along the score line. Do not chew or crush trazodone hydrochloride tablets. Tell your healthcare provider if you cannot swallow trazodone either whole or as a half tablet.
- If you take too much trazodone hydrochloride, call your doctor or go to the nearest emergency room right away.
### What should I avoid while taking trazodone hydrochloride tablets?
- Do not drive, operate heavy machinery, or do other dangerous activities until you know how trazodone hydrochloride tablets affects you. Trazodone hydrochloride tablets can slow your thinking and motor skills.
- Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking trazodone hydrochloride tablets until you talk with your healthcare provider. Trazodone hydrochloride tablets may make your sleepiness or dizziness worse if you take it with alcohol or other medicines that cause sleepiness or dizziness.
### What are the possible side effects of trazodone hydrochloride tablets?
- Trazodone hydrochloride tablets can cause serious side effects or death. See "What is the most important information I should know about trazodone hydrochloride tablets?"
- Serious side effects include:
- Serotonin syndrome. Symptoms of serotonin syndrome include: agitation, hallucinations, problems with coordination, fast heartbeat, tight muscles, trouble walking, nausea, vomiting, diarrhea.
- Feeling high or in a very good mood, then becoming irritable, or having too much energy, feeling like you have to keep talking or do not sleep (Mania).
- Irregular or fast heartbeat or faint (QT prolongation).
- Low blood pressure. You feel dizzy or faint when you change positions (go from sitting to standing).
- Unusual bruising or bleeding.
- Erection lasting for more than 6 hours (Priapism).
- Low sodium in your blood (Hyponatremia). Symptoms of hyponatremia include: headache, feeling weak, feeling confused, trouble concentrating, memory problems and feeling unsteady when you walk.
- Withdrawal symptoms. Symptoms of withdrawal can include anxiety, agitation, and sleep problems. Do not stop taking trazodone hydrochloride tablets without talking to your healthcare provider.
- Get medical help right away, if you have any of the symptoms listed above.
- The most common side effects of trazodone hydrochloride tablets include:
- Sleepiness
- Dizziness
- Constipation
- Blurry vision
- Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
- These are not all the possible side effects of trazodone hydrochloride tablets. For more information, ask your healthcare provider or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088.
### How should I store trazodone hydrochloride tablets?
- Store trazodone hydrochloride tablets between between 68°F to 77°F (20° C to 25°C).
- Keep in tight container
- Keep out of the light
- Safely throw away medicine that is out of date or no longer needed.
- Keep trazodone hydrochloride tablets and all medicines out of the reach of children.
### General information about the safe and effective use of trazodone hydrochloride tablets
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use trazodone hydrochloride tablets for a condition for which it was not prescribed. Do not give trazodone hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them.
- This Medication Guide summarizes the most important information about trazodone hydrochloride tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about trazodone hydrochloride tablets that is written for health professionals.
- For more information go to www.torrentpharma.com or call 1-800-FDA-1088
### What are the ingredients in trazodone hydrochloride tablets?
- Active ingredient: trazodone hydrochloride, USP
- Inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, and sodium starch glycolate.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
- ↑ Jump up to: 1.0 1.1 1.2 1.3 Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Oct 1]. Greenwood Village, CO: Thomsen Healthcare; 2013. | https://www.wikidoc.org/index.php/Desyrel | |
76b6c14e3fa298594b74d8b00e54eaa7992d9cb1 | wikidoc | Detergent | Detergent
# Overview
Detergent is a compound, or a mixture of compounds, intended to assist cleaning. The term is often used to differentiate between soap and other chemical surfactants used for cleaning purposes.
# Composition
Detergents, especially those made for use with water, often include different components such as:
- Surfactants to 'cut' grease and to wet surfaces
- Abrasive to scour
- Substances to modify pH or to affect performance or stability of other ingredients, acids for descaling or caustics to breakdown organic compounds
- Water softeners to counteract the effect of "hardness" ions on other ingredients
- oxidants (oxidizers) for bleaching, disinfection, and breaking down organic compounds
- Non-surfactant materials that keep dirt in suspension
- Enzymes to digest proteins, fats, or carbohydrates in stains or to modify fabric feel
- Ingredients that modify the foaming properties of the cleaning surfactants, to either stabilize or counteract foam
- Ingredients that affect the aesthetic properties, such as optical brighteners, fabric softeners, colors, perfumes, etc.
- Washing agents may contain soap for the purpose of reducing foam rather than cleaning fabric.
# Types
There are several factors that dictate what compositions of detergent should be used, including the material to be cleaned, the apparatus to be used, and tolerance for and type of dirt. For instance, all of the following are used to clean glass. The sheer range of different detergents that can be used demonstrates the importance of context in the selection of an appropriate glass-cleaning agent:
- a chromic acid solution—to get glass very clean for certain precision-demanding purposes, namely in analytical chemistry
- a high-foaming mixture of surfactants with low skin irritation—for hand-washing of drink glasses in a sink or dishpan
- other surfactant-based compositions—for washing windows with a squeegee, followed by rinsing
- any of various non-foaming compositions—for glasses in a dishwashing machine
- an ammonia-containing solution—for cleaning windows with no additional dilution and no rinsing
- ethanol or methanol in Windshield washer fluid—used for a vehicle in motion, with no additional dilution.
# Terminology
Sometimes the word detergent is used to be distinguished from soap. For a while during the infancy of other surfactants as commercial detergent products, the term syndet, short for synthetic detergent was promoted to indicate the distinction, but never caught on very well, and is incorrect because of the production of soap via saponification of glycerides. The term soapless soap also saw a brief vogue. There is no accurate term for detergents not made of soap other than soapless detergent or non-soap detergent.
Also, the term detergent is sometimes used for surfactants in general, even when they are not used for cleaning. As can be seen above, this too is terminology that should be avoided as long as the term surfactant itself is available.
It can be noted that plain water, if used for cleaning, is a detergent. Probably the most widely-used detergents other than water are soaps or mixtures composed chiefly of soaps. However, not all soaps have significant detergency. Often the word "soap" is used to indicate any detergent, especially those that have characteristics similar to those of soap. | Detergent
# Overview
Detergent is a compound, or a mixture of compounds, intended to assist cleaning. The term is often used to differentiate between soap and other chemical surfactants used for cleaning purposes.
# Composition
Detergents, especially those made for use with water, often include different components such as:
- Surfactants to 'cut' grease and to wet surfaces
- Abrasive to scour
- Substances to modify pH or to affect performance or stability of other ingredients, acids for descaling or caustics to breakdown organic compounds
- Water softeners to counteract the effect of "hardness" ions on other ingredients
- oxidants (oxidizers) for bleaching, disinfection, and breaking down organic compounds
- Non-surfactant materials that keep dirt in suspension
- Enzymes to digest proteins, fats, or carbohydrates in stains or to modify fabric feel
- Ingredients that modify the foaming properties of the cleaning surfactants, to either stabilize or counteract foam
- Ingredients that affect the aesthetic properties, such as optical brighteners, fabric softeners, colors, perfumes, etc.
- Washing agents may contain soap for the purpose of reducing foam rather than cleaning fabric.
# Types
There are several factors that dictate what compositions of detergent should be used, including the material to be cleaned, the apparatus to be used, and tolerance for and type of dirt. For instance, all of the following are used to clean glass. The sheer range of different detergents that can be used demonstrates the importance of context in the selection of an appropriate glass-cleaning agent:
- a chromic acid solution—to get glass very clean for certain precision-demanding purposes, namely in analytical chemistry
- a high-foaming mixture of surfactants with low skin irritation—for hand-washing of drink glasses in a sink or dishpan
- other surfactant-based compositions—for washing windows with a squeegee, followed by rinsing
- any of various non-foaming compositions—for glasses in a dishwashing machine
- an ammonia-containing solution—for cleaning windows with no additional dilution and no rinsing
- ethanol or methanol in Windshield washer fluid—used for a vehicle in motion, with no additional dilution.
# Terminology
Sometimes the word detergent is used to be distinguished from soap. For a while during the infancy of other surfactants as commercial detergent products, the term syndet, short for synthetic detergent was promoted to indicate the distinction, but never caught on very well, and is incorrect because of the production of soap via saponification of glycerides. The term soapless soap also saw a brief vogue. There is no accurate term for detergents not made of soap other than soapless detergent or non-soap detergent.
Also, the term detergent is sometimes used for surfactants in general, even when they are not used for cleaning. As can be seen above, this too is terminology that should be avoided as long as the term surfactant itself is available.
It can be noted that plain water, if used for cleaning, is a detergent. Probably the most widely-used detergents other than water are soaps or mixtures composed chiefly of soaps. However, not all soaps have significant detergency. Often the word "soap" is used to indicate any detergent, especially those that have characteristics similar to those of soap. | https://www.wikidoc.org/index.php/Detergent | |
100a7360e7a88762661f41f165f6cadcf1bd4d67 | wikidoc | Deuterium | Deuterium
Deuterium, also called heavy hydrogen, is a stable isotope of hydrogen with a natural abundance in the oceans of Earth of approximately one atom in 6500 of hydrogen (~154 PPM). Deuterium thus accounts for approximately 0.015% (on a weight basis, 0.030%) of all naturally occurring hydrogen in the oceans on Earth (see VSMOW; the abundance changes slightly from one kind of natural water to another). Deuterium abundance on Jupiter is about 6 atoms in 10,000 (0.06% atom basis); these ratios presumably reflect the early solar nebula ratios, and those after the Big Bang. There is little deuterium in the interior of the Sun, since thermonuclear reactions destroy it. However, it continues to persist in the outer solar atmosphere at roughly the same concentration as in Jupiter.
The nucleus of deuterium, called a deuteron, contains one proton and one neutron, whereas the far more common hydrogen nucleus contains no neutrons. The isotope name is formed from the Greek deuteros meaning "second", to denote the two particles comprising the nucleus.
# Differences between deuterium and common hydrogen (protium)
## Chemical symbol
Deuterium is frequently represented by the chemical symbol D. Since it is an isotope of hydrogen with mass number 2, it is also represented by ²H. IUPAC allows both D and ²H, although ²H is preferred. The reason deuterium has a distinct chemical symbol may be its large mass difference with protium (¹H); deuterium has a mass of 2.014 u, compared to the mean hydrogen atomic weight of 1.007947 u, and protium's mass of 1.007825 u. The isotope weight ratios within other chemical elements are largely insignificant in this regard, explaining the lack of unique isotope symbols elsewhere.
## Natural abundance
Deuterium occurs in trace amounts naturally as deuterium gas, written ²H2 or D2, but most natural occurrence in the universe is bonded with a typical ¹H atom, a gas called hydrogen deuteride (HD or ¹H²H).
The existence of deuterium on Earth, elsewhere in the solar system (as confirmed by planetary probes), and in the spectra of stars, is an important datum in cosmology. Stellar fusion destroys deuterium, and there are no known natural processes (for example, see the rare cluster decay), other than the Big Bang nucleosynthesis, which might have produced deuterium at anything close to the observed natural abundance of deuterium. This abundance seems to be a very similar fraction of hydrogen, wherever hydrogen is found. Thus, the existence of deuterium is one of the arguments in favor of the Big Bang theory over the steady state theory of the universe.
The world's leading "producer" of deuterium (technically, merely enricher or concentrator of deuterium) was Canada, until 1997 when the last plant was shut down (see more in the heavy water article). Canada uses heavy water as a neutron moderator for the operation of the CANDU reactor design. India is now probably the world's largest concentrator of heavy water, also used in nuclear power reactors.
# Physical properties
The physical properties of deuterium compounds can be different from the hydrogen analogs; for example, D2O is more viscous than H2O.
Deuterium behaves chemically similarly to ordinary hydrogen, but there are differences in bond energy and length for compounds of heavy hydrogen isotopes which are larger than the isotopic differences in any other element. Bonds involving deuterium and tritium are somewhat stronger than the corresponding bonds in light hydrogen, and these differences are enough to make significant changes in biological reactions (see heavy water).
Deuterium can replace the normal hydrogen in water molecules to form heavy water (D2O), which is about 10.6% more dense than normal water (enough that ice made from it sinks in ordinary water). Heavy water is slightly toxic in eukaryotic animals, with 25% substitution of the body water causing cell division problems and sterility, and 50% substitution causing death by cytotoxic syndrome (bone marrow failure and gastrointestinal lining failure). Prokaryotic organisms, however, can survive and grow in pure heavy water (though they grow more slowly). Consumption of heavy water would not pose a health threat to humans unless very large quantities (in excess of 10 liters) were consumed over many days. Small doses of heavy water (a few grams in humans, containing an amount of deuterium comparable to that normally present in the body) are routinely used as harmless metabolic tracers in humans and animals.
# Quantum properties
The deuteron has spin +1 and is thus a boson. The NMR frequency of deuterium is significantly different from common light hydrogen. Infrared spectroscopy also easily differentiates many deuterated compounds, due to the large difference in IR absorption frequency seen in the vibration of a chemical bond containing deuterium, versus light hydrogen. The two stable isotopes of hydrogen can also be distinguished by using mass spectrometry.
# Nuclear properties
Deuterium is one of only four stable nuclides with an odd number of protons and odd number of neutrons. (2H, 6Li, 10B, 14N; also, the long-lived radioactive nuclides 40K, 50V, 138La, 180mTa occur naturally.) Most odd-odd nuclei are unstable with respect to beta decay, because the decay products are even-even, and are therefore more strongly bound, due to nuclear pairing effects. Deuterium, however, benefits from having its proton and neutron coupled to a spin-1 state, which gives a stronger nuclear attraction; the corresponding state does not exist in the two-neutron or two-proton system, due to the Pauli exclusion principle which would require one or the other particle to have some orbital angular momentum. But that would require orbital angular momentum and kinetic energy, so that they have a higher total energy (both due to their kinetic energy and because their distance would be larger and their binding energy lower). In both cases, this causes the di-proton and di-neutron nucleus to be unstable.
## Deuterium as an isospin singlet
Due to the similarity in mass and nuclear properties between the proton and neutron, they are sometimes considered as two symmetric types of the same object, a nucleon. While only the proton has an electric charge, this is often negligible due of the weakness of the electromagnetic interaction relative to the strong nuclear interaction. The symmetry relating the proton and neutron is known as isospin and denoted \tau.
Isospin is an SU(2) symmetry, like ordinary spin, so is completely analogous to it. The proton and neutron form an isospin doublet, with a "down" state \downarrow being a neutron, and an "up" state \uparrow being a proton.
A pair of nucleons can either be in an antisymmetric state of isospin called singlet, or in a symmetric state called triplet. In terms of the "down" state and "up" state, the singlet is
This is a nucleus with one proton and one neutron, i.e. a deuterium nucleus.
The triplet is
\left(
\begin{array}{ll}
\uparrow\uparrow\\
\frac{1}{\sqrt{2}}(\uparrow\downarrow + \downarrow\uparrow)\\
\downarrow\downarrow
\end{array}
\right)
And thus consists of three types of nuclei, which are supposed to be symmetric - a deuterium nucleus (actually a highly excited state of it), a nucleus with two protons, and a nucleus with two neutrons. The latter two nuclei are not stable or nearly stable, and therefore so is this type of deuterium (meaning that it is indeed a highly excited state of deuterium).
## Approximated wavefunction of the deuteron
The total wavefunction of both the proton and neutron must be antisymmetric, because they are both fermions. Apart from their isospin, the two nucleons also have spin and spatial distributions of their wavefunction. The latter is symmetric if the deuteron is symmetric under parity (i.e. have an "even" or "positive" parity) , and antisymmetric if the deuteron is antisymmetric under parity (i.e. have an "odd" or "negative" parity). The parity is fully determined by the total orbital angular momentum of the two nucleons: if it is even then the parity is even (positive), and if it is odd then the parity is odd (negative).
The deuteron, being an isospin singlet, is antisymmetric under nucleons exchange due to isospin, and therefore must be symmetric under the double exchange of their spin and location. Therefore it can be in either of the following two different states:
- Symmetric spin and symmetric under parity. In this case, the exchange of the two nucleons will multiply the deuterium wavefunction by (-1) from isospin exchange, (+1) from spin exchange and (+1) from parity (location exchange), for a total of (-1) as needed for antisymmetry.
- Antisymmetric spin and antisymmetric under parity. In this case, the exchange of the two nucleons will multiply the deuterium wavefunction by (-1) from isospin exchange, (-1) from spin exchange and (-1) from parity (location exchange), again for a total of (-1) as needed for antisymmetry.
In the first case the deuteron has is a Spin triplet, so that its total spin s is 1. It also has an even parity and therefore even orbital angular momentum l ; The lower its orbital angular momentum, the lower its energy. Therefore the lowest possible energy state has s =1, l =0.
In the second case the deuteron has is a spin singlet, so that its total spin s is 0. It also has an odd parity and therefore odd orbital angular momentum l . Therefore the lowest possible energy state has s =0, l =1.
Since s =1 gives a stronger nuclear attraction, the deuterium ground state is in the s =1, l =0 state.
The same considerations lead to the possible states of an isospin triplet having s =0, l =even or s =1, l =odd. Thus the state of lowest energy has s =1, l =1, higher than that of the isospin singlet.
The analysis just given is in fact only approximate, both because isospin is not an exact symmetry, and more importantly because the strong nuclear interaction between the two nucleons is related to angular momentum in a way that mixes different s and l states. That is, s and l are not constant in time (they do not commute with the Hamiltonian), and over time a state such as s =1, l =0 may become a state of s =1, l =2. Parity is still constant in time so these do not mix with odd l states (such as s =0, l =1).
Therefore the quantum state of the deuterium is a superposition (a linear combination) of the s =1, l =0 state and the s =1, l =2 state, even though the first component is much bigger. Since the total angular momentum j is also a good quantum number (it is a constant in time), both components must have the same j, and therefore j =1. This is the total spin of the deuterium nucleus.
To summarize, the deuterium nucleus is antisymmetric in terms of isospin, and has spin 1 and even (+1) parity. The relative angular momentum of its nucleons l is not well defined, and the deuterium is a superposition of mostly l =0 with some l =2.
## Magnetic and electric multipoles
In order to find theoretically the deuterium magnetic dipole moment \mu, one uses the formula for a nuclear magnetic moment
{1\over (j+1)}\langle(l,s),j,m_j=j|\overrightarrow{\mu}\cdot \overrightarrow{j}|(l,s),j,m_j=j\rangle
with
g(l) and g(s) are g-factors of the nucleons.
Since the proton and neutron have different values for g(l) and g(s), one must separate their contributions. Each gets half of the deuterium orbital angular momentum \overrightarrow{l} and spin \overrightarrow{s}. One arrives at
{1\over (j+1)}\langle(l,s),j,m_j=j|\left({1\over 2}\overrightarrow{l} {g^{(l)}}_p + {1\over 2}\overrightarrow{s} ({g^{(s)}}_p + {g^{(s)}}_n)\right)\cdot \overrightarrow{j}|(l,s),j,m_j=j\rangle
where subscripts p and n stand for the proton and neutron, and g(l)n = 0.
By using the same identities as here and using the value g(l)p = 1 in nuclear magneton units, we arrive at the following result, in nuclear magneton units
{1\over 4 (j+1)}\left
For the s =1, l =0 state j =1 and we get, in nuclear magneton units
For the s =1, l =2 state with j =1 we get, in nuclear magneton units
The measured value of the deuterium magnetic dipole moment, in nuclear magneton units, is 0.857. This suggests that the state of the deuterium is indeed only approximately s =1, l =0 state, and is actually a linear combination of (mostly) this state with s =1, l =2 state.
The electric dipole is zero as usual.
The measured electric quadropole of the deuterium is 0.2859 e fm², where e is the proton electric charge and fm is fermi. While the order of magnitude is reasonable, since the deuterium radius is of order of 1 fermi (see below) and its electric charge is e, the above model does not suffice for its computation. More specifically, the electric quadropole does not get a contribution from the l =0 state (which is the dominant one) and does get a contribution from a term mixing the l =0 and the l =2 states, because the electric quadrupole operator does not commute with angular momentum.
The latter contribution is dominant in the absence of a pure l =0 contribution, but cannot be calculated without knowing the exact spatial form of the nucleons wavefunction inside the deuterium.
Higher magnetic and electric multipole moments cannot be calculated by the above model, for similar reasons.
## Deuterium radius
The square root of the average squared radius of the deuterium, measured experimentally, is
\sqrt{\langle r^2 \rangle} = 0.96 fermi (= 0.96 fm).
# Applications
Deuterium is useful in nuclear fusion reactions, especially in combination with tritium, because of the large reaction rate (or nuclear cross section) and high energy yield of the D-T reaction. There is an even higher-yield D-He3 fusion reaction, though the breakeven point of D-He3 is higher than that of most other fusion reactions; together with the scarcity of He3, this makes it implausible as a practical power source until at least D-T and D-D fusion reactions have been performed on a commercial scale. Unlike protium, deuterium undergoes fusion purely via the strong interaction, making its use for commercial power plausible.
In chemistry and biochemistry, deuterium is used as a non-radioactive isotopic tracer in molecules to study chemical reactions and metabolic pathways, because chemically it behaves similarly to ordinary hydrogen, but it can be distinguished from ordinary hydrogen by its mass, using mass spectrometry or infrared spectrometry.
Neutron scattering techniques particularly profit from availability of deuterated samples: The H and D cross sections are very distinct and different in sign, which allows contrast variation in such experiments. Further, a nuisance problem of ordinary hydrogen is its large incoherent neutron cross section, which is nil for D and delivers much clearer signals in deuterated samples. Hydrogen occurs in all materials of organic chemistry and life science, but cannot be seen by X-ray diffraction methods. Hydrogen can be seen by neutron diffraction and scattering, which makes neutron scattering, together with a modern deuteration facility, indispensable for many studies of macromolecules in biology and many other areas.
Deuterium is useful in hydrogen nuclear magnetic resonance spectroscopy (proton NMR). NMR ordinarily requires compounds of interest to be analyzed as dissolved in solution. Because of deuterium's nuclear spin properties which differ from the light hydrogen usually present in organic molecules, NMR spectra of hydrogen/protium are highly differentiable from that of deuterium, and in practice deuterium is not "seen" by an NMR instrument tuned to light-hydrogen. Deuterated solvents (including heavy water, but also compounds like deuterated chloroform CDCl3) are therefore routinely used in NMR spectroscopy, in order to allow only the light-hydrogen spectra of the compound of interest to be measured, without solvent-signal interference.
Deuterium can also be used for femtosecond infrared spectroscopy, since the mass difference drastically affects the frequency of molecular vibrations; deuterium-carbon bond vibrations are found in locations free of other signals.
Measurements of small variations in the natural abundances of deuterium, along with those of the stable heavy oxygen isotopes 17O and 18O, are of importance in hydrology, to trace the geographic origin of Earth's waters. The heavy isotopes of hydrogen and oxygen in rainwater (so-called meteoric water) are enriched as a function of the environmental temperature of the region in which the precipitation falls (and thus enrichment is related to mean latitude). The relative enrichment of the heavy isotopes in rainwater (as referenced to mean ocean water), when plotted against temperature falls predictably along a line called the global meteoric water line (GMWL). This plot allows samples of precipitation-originated water to be identified along with general information about the climate in which it originated. Evaporative and other processes in bodies of water, and also ground water processes, also differentially alter the ratios of heavy hydrogen and oxygen isotopes in fresh and salt waters, in characteristic and often regionally-distinctive ways.
The proton and neutron making up deuterium can be dissociated through neutral current interactions with neutrinos. The cross section for this interaction is comparatively large, and deuterium was successfully used as a neutrino target in the Sudbury Neutrino Observatory experiment.
# History
## Lighter element isotopes suspected
The existence of nonradioactive isotopes of lighter elements had been suspected in studies of neon as early as 1913, and proven by mass spectroscopy of light elements in 1920. The prevailing theory at the time, however, was that the isotopes were due to the existence of differing numbers of "nuclear electrons" in different atoms of an element. It was expected that hydrogen, with a measured average atomic mass very close to 1 u, and a nucleus thought to be composed of a single proton (a known particle), could not contain nuclear electrons, and thus could have no heavy isotopes.
## Deuterium predicted and finally detected
Deuterium was predicted in 1926 by Walter Russell, using his "spiral" periodic table. It was first detected spectroscopically in late 1931 by Harold Urey, a chemist at Columbia University. Urey's collaborator, Ferdinand Brickwedde, distilled five liters of cryogenically-produced liquid hydrogen to 1 mL of liquid, using the low-temperature physics laboratory that had recently been established at the National Bureau of Standards in Washington, DC (now the National Institute of Standards and Technology). This concentrated the fraction of the mass-2 isotope of hydrogen to a degree that made its spectroscopic identification unambiguous; Urey called the isotope "deuterium" from the Greek and Latin words for "two." The amount inferred for normal abundance of this heavy isotope was so small (only about 1 atom in 6400 hydrogen atoms in ocean water) that it had not noticeably affected previous measurements of (average) hydrogen atomic mass. Urey was also able to concentrate water to show partial enrichment of deuterium. Gilbert Newton Lewis prepared the first samples of pure heavy water in 1933. The discovery of deuterium, coming before the discovery of the neutron in 1932, was an experimental shock to theory, and after the neutron was reported, deuterium won Urey the Nobel Prize in chemistry in 1934.
## "Heavy water" experiments in World War II
Main Article: Heavy water
Shortly before the war, Hans von Halban and Lew Kowarski moved their research on neutron moderation from France to England, smuggling the entire global supply of heavy water (made in Norway) across in twenty-six steel drums.
During World War II, Nazi Germany was known to be conducting experiments using heavy water as moderator for a nuclear reactor design. (Heavy water is water in which the hydrogen is deuterium.) Such experiments were a source of concern because they might allow them to produce plutonium for an atomic bomb. Ultimately, it led to (what seemed to be important at that time) the Allied operation called the "Norwegian heavy water sabotage," the purpose of which was to destroy the Vemork deuterium production/enrichment facility in Norway.
After World War II ended, the Allies discovered that Germany was not putting as much serious effort into the program as has had been previously thought. The Germans had completed only a small, partly-built experimental reactor (which had been hidden away). By the end of the war, the Germans did not even have a fifth the amount of heavy water needed to run the reactor, partially due to the Norwegian heavy water sabotage operation. However, even had the Germans succeeded in getting a reactor operational (as the U.S. did with a graphite reactor in late 1942), they would still have been at least several years away from development of an atomic bomb with maximal effort. The engineering process, even with maximal effort and funding, required about two and a half years (from first critical reactor to bomb) in both the U.S. and U.S.S.R, for example.
# Data
- Density: 0.180 kg/m³ at STP (0 °C, 101.325 kPa).
- Atomic weight: 2.01355321270.
- Mean abundance in ocean water (see VSMOW) about 0.0156 % of H atoms = 1/6400 H atoms.
Data at approximately 18 K for D2 (triple point):
- Density:
- Liquid: 162.4 kg/m3
- Gas: 0.452 kg/m3
- Viscosity: 1.3 µPa·s
- Specific heat capacity at constant pressure cp:
- Solid: 2950 J/(kg·K)
- Gas: 5200 J/(kg·K)
# Anti-deuterium
An antideuteron is the antiparticle of the nucleus of deuterium, consisting of an antiproton and an antineutron. The antideuteron was first produced in 1965 at the Proton Synchrotron at CERN and the Alternating Gradient Synchrotron at Brookhaven National Laboratory. A complete atom, with a positron orbiting the nucleus, would be called antideuterium, but as of 2005 antideuterium has not yet been created. The symbol for antideuterium is the same as for deuterium, except with a bar over it. | Deuterium
Template:Tfd
Deuterium, also called heavy hydrogen, is a stable isotope of hydrogen with a natural abundance in the oceans of Earth of approximately one atom in 6500 of hydrogen (~154 PPM). Deuterium thus accounts for approximately 0.015% (on a weight basis, 0.030%) of all naturally occurring hydrogen in the oceans on Earth (see VSMOW; the abundance changes slightly from one kind of natural water to another). Deuterium abundance on Jupiter is about 6 atoms in 10,000 (0.06% atom basis)[1]; these ratios presumably reflect the early solar nebula ratios, and those after the Big Bang. There is little deuterium in the interior of the Sun, since thermonuclear reactions destroy it. However, it continues to persist in the outer solar atmosphere at roughly the same concentration as in Jupiter.
The nucleus of deuterium, called a deuteron, contains one proton and one neutron, whereas the far more common hydrogen nucleus contains no neutrons. The isotope name is formed from the Greek deuteros meaning "second", to denote the two particles comprising the nucleus.[2]
# Differences between deuterium and common hydrogen (protium)
## Chemical symbol
Deuterium is frequently represented by the chemical symbol D. Since it is an isotope of hydrogen with mass number 2, it is also represented by ²H. IUPAC allows both D and ²H, although ²H is preferred.[3] The reason deuterium has a distinct chemical symbol may be its large mass difference with protium (¹H); deuterium has a mass of 2.014 u, compared to the mean hydrogen atomic weight of 1.007947 u, and protium's mass of 1.007825 u. The isotope weight ratios within other chemical elements are largely insignificant in this regard, explaining the lack of unique isotope symbols elsewhere.[citation needed]
## Natural abundance
Deuterium occurs in trace amounts naturally as deuterium gas, written ²H2 or D2, but most natural occurrence in the universe is bonded with a typical ¹H atom, a gas called hydrogen deuteride (HD or ¹H²H).[4]
The existence of deuterium on Earth, elsewhere in the solar system (as confirmed by planetary probes), and in the spectra of stars, is an important datum in cosmology. Stellar fusion destroys deuterium, and there are no known natural processes (for example, see the rare cluster decay), other than the Big Bang nucleosynthesis, which might have produced deuterium at anything close to the observed natural abundance of deuterium. This abundance seems to be a very similar fraction of hydrogen, wherever hydrogen is found. Thus, the existence of deuterium is one of the arguments in favor of the Big Bang theory over the steady state theory of the universe.
The world's leading "producer" of deuterium (technically, merely enricher or concentrator of deuterium) was Canada, until 1997 when the last plant was shut down (see more in the heavy water article). Canada uses heavy water as a neutron moderator for the operation of the CANDU reactor design. India is now probably the world's largest concentrator of heavy water, also used in nuclear power reactors.
# Physical properties
The physical properties of deuterium compounds can be different from the hydrogen analogs; for example, D2O is more viscous than H2O.[citation needed]
Deuterium behaves chemically similarly to ordinary hydrogen, but there are differences in bond energy and length for compounds of heavy hydrogen isotopes which are larger than the isotopic differences in any other element. Bonds involving deuterium and tritium are somewhat stronger than the corresponding bonds in light hydrogen, and these differences are enough to make significant changes in biological reactions (see heavy water).
Deuterium can replace the normal hydrogen in water molecules to form heavy water (D2O), which is about 10.6% more dense than normal water (enough that ice made from it sinks in ordinary water). Heavy water is slightly toxic in eukaryotic animals, with 25% substitution of the body water causing cell division problems and sterility, and 50% substitution causing death by cytotoxic syndrome (bone marrow failure and gastrointestinal lining failure). Prokaryotic organisms, however, can survive and grow in pure heavy water (though they grow more slowly). Consumption of heavy water would not pose a health threat to humans unless very large quantities (in excess of 10 liters) were consumed over many days. Small doses of heavy water (a few grams in humans, containing an amount of deuterium comparable to that normally present in the body) are routinely used as harmless metabolic tracers in humans and animals.
# Quantum properties
The deuteron has spin +1 and is thus a boson. The NMR frequency of deuterium is significantly different from common light hydrogen. Infrared spectroscopy also easily differentiates many deuterated compounds, due to the large difference in IR absorption frequency seen in the vibration of a chemical bond containing deuterium, versus light hydrogen. The two stable isotopes of hydrogen can also be distinguished by using mass spectrometry.
# Nuclear properties
Deuterium is one of only four stable nuclides with an odd number of protons and odd number of neutrons. (2H, 6Li, 10B, 14N; also, the long-lived radioactive nuclides 40K, 50V, 138La, 180mTa occur naturally.) Most odd-odd nuclei are unstable with respect to beta decay, because the decay products are even-even, and are therefore more strongly bound, due to nuclear pairing effects. Deuterium, however, benefits from having its proton and neutron coupled to a spin-1 state, which gives a stronger nuclear attraction; the corresponding state does not exist in the two-neutron or two-proton system, due to the Pauli exclusion principle which would require one or the other particle to have some orbital angular momentum. But that would require orbital angular momentum and kinetic energy, so that they have a higher total energy (both due to their kinetic energy and because their distance would be larger and their binding energy lower). In both cases, this causes the di-proton and di-neutron nucleus to be unstable.
## Deuterium as an isospin singlet
Due to the similarity in mass and nuclear properties between the proton and neutron, they are sometimes considered as two symmetric types of the same object, a nucleon. While only the proton has an electric charge, this is often negligible due of the weakness of the electromagnetic interaction relative to the strong nuclear interaction. The symmetry relating the proton and neutron is known as isospin and denoted <math>\tau</math>.
Isospin is an SU(2) symmetry, like ordinary spin, so is completely analogous to it. The proton and neutron form an isospin doublet, with a "down" state <math>\downarrow</math> being a neutron, and an "up" state <math>\uparrow</math> being a proton.
A pair of nucleons can either be in an antisymmetric state of isospin called singlet, or in a symmetric state called triplet. In terms of the "down" state and "up" state, the singlet is
This is a nucleus with one proton and one neutron, i.e. a deuterium nucleus.
The triplet is
<math>
\left(
\begin{array}{ll}
\uparrow\uparrow\\
\frac{1}{\sqrt{2}}(\uparrow\downarrow + \downarrow\uparrow)\\
\downarrow\downarrow
\end{array}
\right)
</math>
And thus consists of three types of nuclei, which are supposed to be symmetric - a deuterium nucleus (actually a highly excited state of it), a nucleus with two protons, and a nucleus with two neutrons. The latter two nuclei are not stable or nearly stable, and therefore so is this type of deuterium (meaning that it is indeed a highly excited state of deuterium).
## Approximated wavefunction of the deuteron
The total wavefunction of both the proton and neutron must be antisymmetric, because they are both fermions. Apart from their isospin, the two nucleons also have spin and spatial distributions of their wavefunction. The latter is symmetric if the deuteron is symmetric under parity (i.e. have an "even" or "positive" parity) , and antisymmetric if the deuteron is antisymmetric under parity (i.e. have an "odd" or "negative" parity). The parity is fully determined by the total orbital angular momentum of the two nucleons: if it is even then the parity is even (positive), and if it is odd then the parity is odd (negative).
The deuteron, being an isospin singlet, is antisymmetric under nucleons exchange due to isospin, and therefore must be symmetric under the double exchange of their spin and location. Therefore it can be in either of the following two different states:
- Symmetric spin and symmetric under parity. In this case, the exchange of the two nucleons will multiply the deuterium wavefunction by (-1) from isospin exchange, (+1) from spin exchange and (+1) from parity (location exchange), for a total of (-1) as needed for antisymmetry.
- Antisymmetric spin and antisymmetric under parity. In this case, the exchange of the two nucleons will multiply the deuterium wavefunction by (-1) from isospin exchange, (-1) from spin exchange and (-1) from parity (location exchange), again for a total of (-1) as needed for antisymmetry.
In the first case the deuteron has is a Spin triplet, so that its total spin s is 1. It also has an even parity and therefore even orbital angular momentum l ; The lower its orbital angular momentum, the lower its energy. Therefore the lowest possible energy state has s =1, l =0.
In the second case the deuteron has is a spin singlet, so that its total spin s is 0. It also has an odd parity and therefore odd orbital angular momentum l . Therefore the lowest possible energy state has s =0, l =1.
Since s =1 gives a stronger nuclear attraction, the deuterium ground state is in the s =1, l =0 state.
The same considerations lead to the possible states of an isospin triplet having s =0, l =even or s =1, l =odd. Thus the state of lowest energy has s =1, l =1, higher than that of the isospin singlet.
The analysis just given is in fact only approximate, both because isospin is not an exact symmetry, and more importantly because the strong nuclear interaction between the two nucleons is related to angular momentum in a way that mixes different s and l states. That is, s and l are not constant in time (they do not commute with the Hamiltonian), and over time a state such as s =1, l =0 may become a state of s =1, l =2. Parity is still constant in time so these do not mix with odd l states (such as s =0, l =1).
Therefore the quantum state of the deuterium is a superposition (a linear combination) of the s =1, l =0 state and the s =1, l =2 state, even though the first component is much bigger. Since the total angular momentum j is also a good quantum number (it is a constant in time), both components must have the same j, and therefore j =1. This is the total spin of the deuterium nucleus.
To summarize, the deuterium nucleus is antisymmetric in terms of isospin, and has spin 1 and even (+1) parity. The relative angular momentum of its nucleons l is not well defined, and the deuterium is a superposition of mostly l =0 with some l =2.
## Magnetic and electric multipoles
In order to find theoretically the deuterium magnetic dipole moment <math>\mu</math>, one uses the formula for a nuclear magnetic moment
{1\over (j+1)}\langle(l,s),j,m_j=j|\overrightarrow{\mu}\cdot \overrightarrow{j}|(l,s),j,m_j=j\rangle</math>
with
g(l) and g(s) are g-factors of the nucleons.
Since the proton and neutron have different values for g(l) and g(s), one must separate their contributions. Each gets half of the deuterium orbital angular momentum <math>\overrightarrow{l}</math> and spin <math>\overrightarrow{s}</math>. One arrives at
{1\over (j+1)}\langle(l,s),j,m_j=j|\left({1\over 2}\overrightarrow{l} {g^{(l)}}_p + {1\over 2}\overrightarrow{s} ({g^{(s)}}_p + {g^{(s)}}_n)\right)\cdot \overrightarrow{j}|(l,s),j,m_j=j\rangle</math>
where subscripts p and n stand for the proton and neutron, and g(l)n = 0.
By using the same identities as here and using the value g(l)p = 1 in nuclear magneton units, we arrive at the following result, in nuclear magneton units
{1\over 4 (j+1)}\left[({g^{(s)}}_p + {g^{(s)}}_n)\big(j(j+1) - l(l+1) + s(s+1)\big) + \big(j(j+1) + l(l+1) - s(s+1)\big)\right]</math>
For the s =1, l =0 state j =1 and we get, in nuclear magneton units
For the s =1, l =2 state with j =1 we get, in nuclear magneton units
The measured value of the deuterium magnetic dipole moment, in nuclear magneton units, is 0.857. This suggests that the state of the deuterium is indeed only approximately s =1, l =0 state, and is actually a linear combination of (mostly) this state with s =1, l =2 state.
The electric dipole is zero as usual.
The measured electric quadropole of the deuterium is 0.2859 e fm², where e is the proton electric charge and fm is fermi. While the order of magnitude is reasonable, since the deuterium radius is of order of 1 fermi (see below) and its electric charge is e, the above model does not suffice for its computation. More specifically, the electric quadropole does not get a contribution from the l =0 state (which is the dominant one) and does get a contribution from a term mixing the l =0 and the l =2 states, because the electric quadrupole operator does not commute with angular momentum.
The latter contribution is dominant in the absence of a pure l =0 contribution, but cannot be calculated without knowing the exact spatial form of the nucleons wavefunction inside the deuterium.
Higher magnetic and electric multipole moments cannot be calculated by the above model, for similar reasons.
## Deuterium radius
The square root of the average squared radius of the deuterium, measured experimentally, is
<math>\sqrt{\langle r^2 \rangle} = 0.96</math> fermi (= 0.96 fm).
# Applications
Deuterium is useful in nuclear fusion reactions, especially in combination with tritium, because of the large reaction rate (or nuclear cross section) and high energy yield of the D-T reaction. There is an even higher-yield D-He3 fusion reaction, though the breakeven point of D-He3 is higher than that of most other fusion reactions; together with the scarcity of He3, this makes it implausible as a practical power source until at least D-T and D-D fusion reactions have been performed on a commercial scale. Unlike protium, deuterium undergoes fusion purely via the strong interaction, making its use for commercial power plausible.
In chemistry and biochemistry, deuterium is used as a non-radioactive isotopic tracer in molecules to study chemical reactions and metabolic pathways, because chemically it behaves similarly to ordinary hydrogen, but it can be distinguished from ordinary hydrogen by its mass, using mass spectrometry or infrared spectrometry.
Neutron scattering techniques particularly profit from availability of deuterated samples: The H and D cross sections are very distinct and different in sign, which allows contrast variation in such experiments. Further, a nuisance problem of ordinary hydrogen is its large incoherent neutron cross section, which is nil for D and delivers much clearer signals in deuterated samples. Hydrogen occurs in all materials of organic chemistry and life science, but cannot be seen by X-ray diffraction methods. Hydrogen can be seen by neutron diffraction and scattering, which makes neutron scattering, together with a modern deuteration facility, indispensable for many studies of macromolecules in biology and many other areas.
Deuterium is useful in hydrogen nuclear magnetic resonance spectroscopy (proton NMR). NMR ordinarily requires compounds of interest to be analyzed as dissolved in solution. Because of deuterium's nuclear spin properties which differ from the light hydrogen usually present in organic molecules, NMR spectra of hydrogen/protium are highly differentiable from that of deuterium, and in practice deuterium is not "seen" by an NMR instrument tuned to light-hydrogen. Deuterated solvents (including heavy water, but also compounds like deuterated chloroform CDCl3) are therefore routinely used in NMR spectroscopy, in order to allow only the light-hydrogen spectra of the compound of interest to be measured, without solvent-signal interference.
Deuterium can also be used for femtosecond infrared spectroscopy, since the mass difference drastically affects the frequency of molecular vibrations; deuterium-carbon bond vibrations are found in locations free of other signals.
Measurements of small variations in the natural abundances of deuterium, along with those of the stable heavy oxygen isotopes 17O and 18O, are of importance in hydrology, to trace the geographic origin of Earth's waters. The heavy isotopes of hydrogen and oxygen in rainwater (so-called meteoric water) are enriched as a function of the environmental temperature of the region in which the precipitation falls (and thus enrichment is related to mean latitude). The relative enrichment of the heavy isotopes in rainwater (as referenced to mean ocean water), when plotted against temperature falls predictably along a line called the global meteoric water line (GMWL). This plot allows samples of precipitation-originated water to be identified along with general information about the climate in which it originated. Evaporative and other processes in bodies of water, and also ground water processes, also differentially alter the ratios of heavy hydrogen and oxygen isotopes in fresh and salt waters, in characteristic and often regionally-distinctive ways.[5]
The proton and neutron making up deuterium can be dissociated through neutral current interactions with neutrinos. The cross section for this interaction is comparatively large, and deuterium was successfully used as a neutrino target in the Sudbury Neutrino Observatory experiment.
# History
## Lighter element isotopes suspected
The existence of nonradioactive isotopes of lighter elements had been suspected in studies of neon as early as 1913, and proven by mass spectroscopy of light elements in 1920. The prevailing theory at the time, however, was that the isotopes were due to the existence of differing numbers of "nuclear electrons" in different atoms of an element. It was expected that hydrogen, with a measured average atomic mass very close to 1 u, and a nucleus thought to be composed of a single proton (a known particle), could not contain nuclear electrons, and thus could have no heavy isotopes.
## Deuterium predicted and finally detected
Deuterium was predicted in 1926 by Walter Russell, using his "spiral" periodic table. It was first detected spectroscopically in late 1931 by Harold Urey, a chemist at Columbia University. Urey's collaborator, Ferdinand Brickwedde, distilled five liters of cryogenically-produced liquid hydrogen to 1 mL of liquid, using the low-temperature physics laboratory that had recently been established at the National Bureau of Standards in Washington, DC (now the National Institute of Standards and Technology). This concentrated the fraction of the mass-2 isotope of hydrogen to a degree that made its spectroscopic identification unambiguous; Urey called the isotope "deuterium" from the Greek and Latin words for "two." The amount inferred for normal abundance of this heavy isotope was so small (only about 1 atom in 6400 hydrogen atoms in ocean water) that it had not noticeably affected previous measurements of (average) hydrogen atomic mass. Urey was also able to concentrate water to show partial enrichment of deuterium. Gilbert Newton Lewis prepared the first samples of pure heavy water in 1933. The discovery of deuterium, coming before the discovery of the neutron in 1932, was an experimental shock to theory, and after the neutron was reported, deuterium won Urey the Nobel Prize in chemistry in 1934.
## "Heavy water" experiments in World War II
Main Article: Heavy water
Shortly before the war, Hans von Halban and Lew Kowarski moved their research on neutron moderation from France to England, smuggling the entire global supply of heavy water (made in Norway) across in twenty-six steel drums.[6][7]
During World War II, Nazi Germany was known to be conducting experiments using heavy water as moderator for a nuclear reactor design. (Heavy water is water in which the hydrogen is deuterium.) Such experiments were a source of concern because they might allow them to produce plutonium for an atomic bomb. Ultimately, it led to (what seemed to be important at that time) the Allied operation called the "Norwegian heavy water sabotage," the purpose of which was to destroy the Vemork deuterium production/enrichment facility in Norway.
After World War II ended, the Allies discovered that Germany was not putting as much serious effort into the program as has had been previously thought. The Germans had completed only a small, partly-built experimental reactor (which had been hidden away). By the end of the war, the Germans did not even have a fifth the amount of heavy water needed to run the reactor, partially due to the Norwegian heavy water sabotage operation. However, even had the Germans succeeded in getting a reactor operational (as the U.S. did with a graphite reactor in late 1942), they would still have been at least several years away from development of an atomic bomb with maximal effort. The engineering process, even with maximal effort and funding, required about two and a half years (from first critical reactor to bomb) in both the U.S. and U.S.S.R, for example.
# Data
- Density: 0.180 kg/m³ at STP (0 °C, 101.325 kPa).
- Atomic weight: 2.01355321270.
- Mean abundance in ocean water (see VSMOW) about 0.0156 % of H atoms = 1/6400 H atoms.
Data at approximately 18 K for D2 (triple point):
- Density:
- Liquid: 162.4 kg/m3
- Gas: 0.452 kg/m3
- Viscosity: 1.3 µPa·s
- Specific heat capacity at constant pressure cp:
- Solid: 2950 J/(kg·K)
- Gas: 5200 J/(kg·K)
# Anti-deuterium
An antideuteron is the antiparticle of the nucleus of deuterium, consisting of an antiproton and an antineutron. The antideuteron was first produced in 1965 at the Proton Synchrotron at CERN[8] and the Alternating Gradient Synchrotron at Brookhaven National Laboratory[9]. A complete atom, with a positron orbiting the nucleus, would be called antideuterium, but as of 2005 antideuterium has not yet been created. The symbol for antideuterium is the same as for deuterium, except with a bar over it. | https://www.wikidoc.org/index.php/Deuterium | |
208f3ba8d9b25d41bdb2f00284e8ee959c1cb19e | wikidoc | Dew point | Dew point
The dew point (sometimes spelled dewpoint) is the temperature to which a given parcel of air must be cooled, at constant barometric pressure, for water vapor to condense into water. The condensed water is called dew. The dew point is a saturation point.
When the dew point temperature falls below freezing it is often called the frost point, as the water vapor no longer creates dew but instead creates frost or hoarfrost by deposition.
The dew point is associated with relative humidity. A high relative humidity indicates that the dew point is closer to the current air temperature; if the relative humidity is 100%, the dew point is equal to the current temperature. Given a constant dew point, an increase in temperature will lead to a decrease in relative humidity.
At a given barometric pressure, independent of temperature, the dew point indicates the mole fraction of water vapor in the air, and therefore determines the specific humidity of the air.
The dew point is an important statistic for general aviation pilots, as it is used to calculate the likelihood of carburetor icing and fog, and estimate the height of the cloud base.
# Explanation
The graph above shows the maximum percentage (by mass) of water vapor that can exist in air at sea level across a range of temperatures. With higher temperatures, the equilibrium partial pressure of water vapor increases and more water evaporates. The behavior of water vapor does not depend on the presence of other gasses in air. The formation of dew would occur at the dew point even if the only gas present is water vapor. Dew point is a monotonic function of the partial pressure of water vapor, so dew point can be determined from partial pressure of water vapor alone, and vice versa.
## Constant pressure
At a given barometric pressure, independent of temperature, the dew point indicates the mole fraction of water vapor in the air, or, put differently, determines the specific humidity of the air. If the barometric pressure rises without changing this mole fraction, the dew point will rise accordingly, and water condenses at a higher temperature. Reducing the mole fraction ,i.e. making the air dryer, will bring the dew point back down to its initial value. In the same way, increasing the mole fraction after a pressure drop brings the dew point back up to its initial level. For this reason, the same dew point in New York and Denver (which is at a much higher altitude) will imply that a higher fraction of the air in Denver, CO consists of water vapor than in New York, NY.
## Varying pressure
At a given temperature but independent of barometric pressure, the dew point indicates the absolute humidity of the air. If the temperature rises without changing the absolute humidity, the dew point will rise accordingly, and water condenses at a higher pressure. Reducing the absolute humidity will bring the dew point back down to its initial value. In the same way, increasing the absolute humidity after a temperature drop brings the dew point back up to its initial level. Coming back to the New York - Denver example, this means that if the dew point and temperature in both cities are the same, then the mass of water vapor per cubic meter of air will also be the same in those cities.
# Human reaction to high dew points
Humans tend to react with discomfort to high dew points, as a high dew point corresponds with a high ambient temperature (causing the body to perspire and produce sweat) and/or a high relative humidity (which inhibits the evaporation of sweat, by which the body is cooled); as a result the body may overheat, resulting in discomfort.
A lower dew point, meanwhile, corresponds to a lower ambient temperature or lower relative humidity, either of which allow the body to more effectively regulate its temperature to avoid overheating.
Those accustomed to continental climates often begin to feel uncomfortable when the dew point reaches between 15 and 20 °C (59 to 68 °F). Most inhabitants of these areas will consider dew points above 21 °C (70 °F) to be oppressive.
# Record high dew point
The highest recorded dew point was 35°C (95°F), reported in Dhahran, Saudi Arabia at 3 p.m. July 8, 2003. The temperature was 42.2°C (108°F) resulting in an apparent temperature or Heat Index of 77.7°C (172°F).
# Calculating the dew point
A well-known approximation used to calculate the dew point Td given the relative humidity RH and the actual temperature T of air is:
T_d = \frac {b\ \gamma(T,RH)} {a - \gamma(T,RH)}
where
\gamma(T,RH) = \frac {a\ T} {b+T} + \ln (RH/100)
where the temperatures are in degrees Celsius and "ln" refers to the natural logarithm. The constants are:
This expression is based on the "Magnus" (or "Magnus-Tetens") approximation for the saturation vapor pressure of water in air as a function of temperature. It is considered valid for
## Simple approximation
There is also a very simple approximation which allows conversion between the dew point, the dry bulb temperature and the relative humidity, which is accurate to within about ±1 °C as long as the relative humidity is above 50%.
The equation is:
T_d = T - \frac {(100 - RH)} {5}
-r
RH = 100 - 5 (T - T_d)
This can be expressed as a simple rule of thumb:
For every 1 °C difference in the dew point and dry bulb temperatures, the relative humidity decreases by 5%, starting with RH=100% when the dew point equals the dry bulb temperature.
where in this case RH is in percent, and T and Td are in degrees Celsius.
The derivation of this, a discussion of its accuracy, comparisons to other approximations, and more information on the history and applications of the dew point are given in the Bulletin of the American Meteorological Society .
In Fahrenheit
Tf_d = Tf - \frac {(100 - RH)} {3.333}
For example, a relative humidity of 100% means dew point is same as air temp. For 90% RH dew point is 3 degrees Fahrenheit lower than air temp. For every 10 percent lower, dew point drops 3 °F.
Tfd is in degrees Fahrenheit; RH same as above. | Dew point
The dew point (sometimes spelled dewpoint) is the temperature to which a given parcel of air must be cooled, at constant barometric pressure, for water vapor to condense into water. The condensed water is called dew. The dew point is a saturation point.
When the dew point temperature falls below freezing it is often called the frost point, as the water vapor no longer creates dew but instead creates frost or hoarfrost by deposition.
The dew point is associated with relative humidity. A high relative humidity indicates that the dew point is closer to the current air temperature; if the relative humidity is 100%, the dew point is equal to the current temperature. Given a constant dew point, an increase in temperature will lead to a decrease in relative humidity.
At a given barometric pressure, independent of temperature, the dew point indicates the mole fraction of water vapor in the air, and therefore determines the specific humidity of the air.
The dew point is an important statistic for general aviation pilots, as it is used to calculate the likelihood of carburetor icing and fog, and estimate the height of the cloud base.
# Explanation
The graph above shows the maximum percentage (by mass) of water vapor that can exist in air at sea level across a range of temperatures. With higher temperatures, the equilibrium partial pressure of water vapor increases and more water evaporates. The behavior of water vapor does not depend on the presence of other gasses in air. The formation of dew would occur at the dew point even if the only gas present is water vapor. Dew point is a monotonic function of the partial pressure of water vapor, so dew point can be determined from partial pressure of water vapor alone, and vice versa.
## Constant pressure
At a given barometric pressure, independent of temperature, the dew point indicates the mole fraction of water vapor in the air, or, put differently, determines the specific humidity of the air. If the barometric pressure rises without changing this mole fraction, the dew point will rise accordingly, and water condenses at a higher temperature. Reducing the mole fraction ,i.e. making the air dryer, will bring the dew point back down to its initial value. In the same way, increasing the mole fraction after a pressure drop brings the dew point back up to its initial level. For this reason, the same dew point in New York and Denver (which is at a much higher altitude) will imply that a higher fraction of the air in Denver, CO consists of water vapor than in New York, NY.
## Varying pressure
At a given temperature but independent of barometric pressure, the dew point indicates the absolute humidity of the air. If the temperature rises without changing the absolute humidity, the dew point will rise accordingly, and water condenses at a higher pressure. Reducing the absolute humidity will bring the dew point back down to its initial value. In the same way, increasing the absolute humidity after a temperature drop brings the dew point back up to its initial level. Coming back to the New York - Denver example, this means that if the dew point and temperature in both cities are the same, then the mass of water vapor per cubic meter of air will also be the same in those cities.
# Human reaction to high dew points
Humans tend to react with discomfort to high dew points, as a high dew point corresponds with a high ambient temperature (causing the body to perspire and produce sweat) and/or a high relative humidity (which inhibits the evaporation of sweat, by which the body is cooled); as a result the body may overheat, resulting in discomfort.
A lower dew point, meanwhile, corresponds to a lower ambient temperature or lower relative humidity, either of which allow the body to more effectively regulate its temperature to avoid overheating.
Those accustomed to continental climates often begin to feel uncomfortable when the dew point reaches between 15 and 20 °C (59 to 68 °F). Most inhabitants of these areas will consider dew points above 21 °C (70 °F) to be oppressive.
[1]
# Record high dew point
The highest recorded dew point was 35°C (95°F), reported in Dhahran, Saudi Arabia at 3 p.m. July 8, 2003. The temperature was 42.2°C (108°F) resulting in an apparent temperature or Heat Index of 77.7°C (172°F).[2]
# Calculating the dew point
A well-known approximation used to calculate the dew point Td given the relative humidity RH and the actual temperature T of air is:
T_d = \frac {b\ \gamma(T,RH)} {a - \gamma(T,RH)}
</math>
where
\gamma(T,RH) = \frac {a\ T} {b+T} + \ln (RH/100)
</math>
where the temperatures are in degrees Celsius and "ln" refers to the natural logarithm. The constants are:
This expression is based on the "Magnus" (or "Magnus-Tetens") approximation for the saturation vapor pressure of water in air as a function of temperature.[3] It is considered valid for
## Simple approximation
There is also a very simple approximation which allows conversion between the dew point, the dry bulb temperature and the relative humidity, which is accurate to within about ±1 °C as long as the relative humidity is above 50%.
The equation is:
T_d = T - \frac {(100 - RH)} {5}
</math>
or
RH = 100 - 5 (T - T_d)
</math>
This can be expressed as a simple rule of thumb:
For every 1 °C difference in the dew point and dry bulb temperatures, the relative humidity decreases by 5%, starting with RH=100% when the dew point equals the dry bulb temperature.
where in this case RH is in percent, and T and Td are in degrees Celsius.
The derivation of this, a discussion of its accuracy, comparisons to other approximations, and more information on the history and applications of the dew point are given in the Bulletin of the American Meteorological Society [4].
In Fahrenheit
Tf_d = Tf - \frac {(100 - RH)} {3.333}
</math>
For example, a relative humidity of 100% means dew point is same as air temp. For 90% RH dew point is 3 degrees Fahrenheit lower than air temp. For every 10 percent lower, dew point drops 3 °F.
Tfd is in degrees Fahrenheit; RH same as above. | https://www.wikidoc.org/index.php/Dew_point | |
99dba05f74ceed7e5befd2491a86920931ae3389 | wikidoc | Diacerein | Diacerein
# Overview
Diacerein (INN), also known as diacetylrhein, is a slow-acting medicine of the class anthraquinone used to treat joint diseases such as osteoarthritis (swelling and pain in the joints). It works by inhibiting interleukin-1 beta. A 2005 Cochrane review found diacerein to be slightly, but significantly, more effective than placebo in improving pain and slowing the progress of osteoarthritis in the hip and knee.
Diacerein-containing medicines are currently authorized in the following European Union (EU) Member States: Austria, Czech Republic, France, Greece, Italy, Portugal, Slovakia and Spain.
# Pharmacology
Diacerein works by blocking the actions of interleukin-1 beta, a protein involved in the inflammation and destruction of cartilage that play a role in the development of symptoms of degenerative joint diseases such as osteoarthritis. Due to its specific mode of action, which does not involve the inhibition of prostaglandin synthesis, diacerein has been shown to have anti-osteoarthritis and cartilage stimulating properties in vitro and animal models. Due to its excellent gastro-intestinal tolerance, a combination therapy with an analgesic or a NSAID may be recommended during the first 2-4 weeks of treatment.
# Side effects
The most common side effects of diacerein treatment are gastrointestinal, such as diarrhea.Due to the risks associated with severe diarrhoea it is advisable to start treatment with half the normal dose (i.e. 50 mg per day) for the first 2 to 4 weeks, after which the recommended dose is 50 mg twice a day. Discoloration of urine (yellow or pink) is another side effect of Diacerein. This effect is due to the elimination of rhein metabolites via the urine and no clinical significance has been found; it may also be dependent on general fluid intake.
# Special warning
Diacerein should not be administered during pregnancy and lactation. It is also should not be used in any patient with liver disease or a history of liver disease.
# Dosage and administration
Diacerein should not be taken below 15 years of old as no clinical studies have been undertaken in this age group. The usual dosage of diacerein is 50 mg twice daily, after meals, for 3 years.
# Marketing
It is marketed in Egypt and the Middle East by Eva Pharma. The Original product company was TRB Ltd Swiss. In Pakistan, Bangladesh and India, Diacerein is marketed and sold as a single preparation or combination with Glucosamine Sulfate. In Greece it has been sold since 2001 by Faran Ltd under the trade name Verboril. | Diacerein
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Diacerein (INN), also known as diacetylrhein, is a slow-acting medicine of the class anthraquinone used to treat joint diseases such as osteoarthritis (swelling and pain in the joints).[1] It works by inhibiting interleukin-1 beta. A 2005 Cochrane review found diacerein to be slightly, but significantly, more effective than placebo in improving pain and slowing the progress of osteoarthritis in the hip and knee.[2]
Diacerein-containing medicines are currently authorized in the following European Union (EU) Member States: Austria, Czech Republic, France, Greece, Italy, Portugal, Slovakia and Spain.
# Pharmacology
Diacerein works by blocking the actions of interleukin-1 beta, a protein involved in the inflammation and destruction of cartilage that play a role in the development of symptoms of degenerative joint diseases such as osteoarthritis. Due to its specific mode of action, which does not involve the inhibition of prostaglandin synthesis, diacerein has been shown to have anti-osteoarthritis and cartilage stimulating properties in vitro and animal models. Due to its excellent gastro-intestinal tolerance, a combination therapy with an analgesic or a NSAID may be recommended during the first 2-4 weeks of treatment.
# Side effects
The most common side effects of diacerein treatment are gastrointestinal, such as diarrhea.[2]Due to the risks associated with severe diarrhoea it is advisable to start treatment with half the normal dose (i.e. 50 mg per day) for the first 2 to 4 weeks, after which the recommended dose is 50 mg twice a day.[3] Discoloration of urine (yellow or pink) is another side effect of Diacerein. This effect is due to the elimination of rhein metabolites via the urine and no clinical significance has been found; it may also be dependent on general fluid intake. [4]
# Special warning
Diacerein should not be administered during pregnancy and lactation. It is also should not be used in any patient with liver disease or a history of liver disease.[5]
# Dosage and administration
Diacerein should not be taken below 15 years of old as no clinical studies have been undertaken in this age group. The usual dosage of diacerein is 50 mg twice daily, after meals, for 3 years. [6]
# Marketing
It is marketed in Egypt and the Middle East by Eva Pharma.[7] The Original product company was TRB Ltd Swiss.[8] In Pakistan, Bangladesh and India, Diacerein is marketed and sold as a single preparation or combination with Glucosamine Sulfate. In Greece it has been sold since 2001 by Faran Ltd under the trade name Verboril.[9] | https://www.wikidoc.org/index.php/Diacerein | |
1e8489f67e6dbc45615335497f1230771f1e2268 | wikidoc | Diagnosis | Diagnosis
# Overview
In general, diagnosis (plural diagnoses) has two distinct dictionary definitions. The first definition is "the recognition of a disease or condition by its outward signs and symptoms", while the second definition is "the analysis of the underlying physiological/biochemical cause(s) of a disease or condition".
Diagnosis covers a broad spectrum, or spectra, of testing in some form of analysis; collective reasoning using such tests is called the method of diagnostics, leading then to the results of those tests by ideal (ethics) would then be considered a diagnosis, but not necessarily the correct one.
In medicine, diagnosis or diagnostics is the process of identifying a medical condition or disease by its signs, symptoms, and from the results of various diagnostic procedures. The conclusion reached through this process is called a diagnosis. The term "diagnostic criteria" designates the combination of symptoms which allows the doctor to ascertain the diagnosis of the respective disease.
Typically, someone with abnormal symptoms will consult a physician, who will then obtain a history of the patient's illness and examine him for signs of disease. The physician will formulate a hypothesis of likely diagnoses and in many cases will obtain further testing to confirm or clarify the diagnosis before providing treatment.
Medical tests commonly performed are measuring blood pressure, checking the pulse rate, listening to the heart with a stethoscope, urine tests, fecal tests, saliva tests, blood tests, medical imaging, electrocardiogram, hydrogen breath test and occasionally biopsy.
The word diagnosis is derived from the Greek words dia which means "by", and gnosis which means "knowledge". The verb is diagnose and a person diagnosing could be considered a diagnostician.
# Relationship of diagnosis to medical practice
A physician's job is to know the human body and its functions in terms of normality (homeostasis). The four cornerstones of diagnostic medicine, each essential for understanding homeostasis, are: anatomy (the structure of the human body), physiology (how the body works), pathology (what can go wrong with the anatomy and physiology) and psychology (thought and behavior). Once the doctor knows what is normal and can measure the patient's current condition against those norms, she or he can then determine the patient's particular departure from homeostasis and the degree of departure. This is called the diagnosis. Once a diagnosis has been reached, the doctor is able to propose a management plan, which will include treatment as well as plans for follow-up. From this point on, in addition to treating the patient's condition, the doctor educates the patient about the causes, progression, outcomes, and possible treatments of his ailments, as well as providing advice for maintaining health.
It should be noted however, that medical diagnosis in psychology or psychiatry is problematic. Apart from the fact that there are differing theoretical views toward mental conditions and that there are few "lab" tests available for various major disorders (e.g., clinical depression), a causal analysis with respect to symptomatology and disorder/disease is not always possible. As a result, most if not all mental conditions, function as both symptoms as well as disorders. There are often functional descriptions provided for psychological disorders and these are vulnerable to circular reasoning due to the etiological fuzziness inherent of these diagnostic categories. (BDG, 2006)
# Diagnostic procedure
Diagnosis is a fluid process in which the physician responds to information garnered from the patient and others, from a physical examination of the patient, and from medical tests performed upon the patient.
The doctor should consider the patient in his 'well' context rather than simply as a walking medical condition. This entails assessing the socio-political context of the patient (family, work, stress, beliefs), in addition to the patient's physical body, as this often offers vital clues to the patient's condition and its management.
The process of diagnosis begins when the patient consults the doctor and presents a set of complaints (the symptoms). If the patient is unconscious, this condition is the de facto complaint. The doctor then obtains further information from the patient himself (and from those who know him, if present) about the patient's symptoms, his previous state of health, living conditions, and so forth.
Rather than consider the myriad diseases that could afflict the patient, the physician narrows down the possibilities to the illnesses likely to account for the apparent symptoms, making a list of only those conditions that could account for what is wrong with the patient. These are generally ranked in order of probability.
The doctor then conducts a physical examination of the patient, studies the patient's medical record, and asks further questions as he goes, in an effort to rule out as many of the potential conditions as possible. When the list is narrowed down to a single condition, this is called the differential diagnosis, and provides the basis for a hypothesis of what is ailing the patient.
Unless the physician is certain of the condition present, further medical tests are performed or scheduled (such as medical imaging), in part to confirm or disprove the diagnosis but also to document the patient's status to keep the patient's medical history up to date. Consultations with other physicians and specialists in the field may be sought. If unexpected findings are made during this process, the initial hypothesis may be ruled out and the physician must then consider other hypotheses.
Despite all of these complexities, most patient consultations are relatively brief, because many diseases are obvious, or the physician's experience may enable him to recognize the condition quickly. Another factor is that the decision trees used for most diagnostic hypothesis testing are relatively short.
Once the physician has completed the diagnosis, he explains the prognosis to the patient and proposes a treatment plan which includes therapy and follow-up (further consultations and tests to monitor the condition and the progress of the treatment, if needed), usually according to the guideline provided by the medical field on the treatment of the particular illness.
Treatment itself may indicate a need for review of the diagnosis if there is a failure to respond to treatments that would normally work.
# History of medical diagnostics
The history of medical diagnosis began in earnest from the enlightened days of Hippocrates in ancient Greece but is far from perfect despite the enormous bounty of information made available by medical research including the sequencing of the human genome. The practice of diagnosis continues to be dominated by theories set down in the early 1900s.
## Ancient Greece
Over two thousand years ago, Hippocrates recorded the association between disease and heredity. In similar fashion, Pythagoras noted the association between metabolism and heredity (allergy to Fava beans). The medical community, however, has only recently acknowledged the importance of genetics and its relevance to mainstream medicine.
## The Oslerian ideal
The ideals of William Osler who transformed the practice of medicine in the early 1900s were based on the principles of the diagnosis and treatment of disease. According to Osler, the functions of a physician were to be able to identify disease and its manifestations, understand its mechanisms, how it may be prevented and how it may be cured. For his medical students he believed that the best textbook was the patient himself – analysis of morbid anatomy and pathology were the keys. The Oslerian ideal continues today, as the basis of the Doctor’s strategy is, "What disease does this patient have and what is the best way for treatment?" The emphasis is on the classification of the disease in order to use the remedies available for its effects to be reversed or ameliorated. The human being in question is representative of a class of people with this type of disease whereas the biological individuality of this person is not given any great weight.
## Garrod's view
The successor to William Osler as Regius Professor at Oxford was Archibald Garrod. Garrod echoed the observations of his Greek counterparts of two millennia ago, ...our chemical individualities are due to our chemical merits as well as our chemical shortcomings; and it is more nearly true to say that the factors which confer upon us our predispositions to and immunities from various mishaps which are spoken of as diseases, are inherent in our very chemical structure; and even in the molecular groupings which confer upon us our individualities, and which went into the making of the chromosomes from which we sprang. Considering that the time that he formulated these ideas were the early 1900's, and the knowledge of DNA encoding genes that in turn encoded proteins responsible for bodily structure and functions not being discovered until some fifty years later it took some time before medicine could fully appreciate the fundamental importance of his concept of diagnosis.
## Present-day Oslerian practice
Whereas Osler laid the founding principles by which medicine should be practiced, Garrod placed these principles in a greater context of a chemical individuality that is inherited and is subject to the mechanisms of evolutionary selection. The Oslerian ideal of medical practice continues to dominate medical philosophy today. The patient is a collective of symptoms to be characterized and analyzed algorithmically in order to draw a diagnosis and subsequently produce a strategy of treatment. Medicine is about problems based solutions. In keeping with this philosophy, today's pathology reports provide a momentary snapshot of the patient's biochemical profile, highlighting the end result of the disease process.
## Influence of DNA technology
Garrod's conception of biological individuality was confirmed with the advent of the sequencing of the human genome. Finally the subtle relationship between inheritance, individuality and environment became apparent via the variations detected in DNA. In each patient's DNA lies a script for how their bodies will change and become ill as well as how they will handle the assaults of the environment from the beginning of their life to its end. It is hoped that by knowing a patient's genes that the biological strengths and weaknesses in respect to these assaults will be revealed and disease processes can be predicted before they have the opportunity to manifest. Although knowledge in this area is far from complete, there are already medical interventions based on this. More importantly, the physician, forewarned with this knowledge can guide the patient towards appropriate lifestyle changes to anticipate and mitigate disease processes. | Diagnosis
To go back to the main page, click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Sumanth Khadke, MD[2]
# Overview
In general, diagnosis (plural diagnoses) has two distinct dictionary definitions. The first definition is "the recognition of a disease or condition by its outward signs and symptoms", while the second definition is "the analysis of the underlying physiological/biochemical cause(s) of a disease or condition".
Diagnosis covers a broad spectrum, or spectra, of testing in some form of analysis; collective reasoning using such tests is called the method of diagnostics, leading then to the results of those tests by ideal (ethics) would then be considered a diagnosis, but not necessarily the correct one.
In medicine, diagnosis or diagnostics is the process of identifying a medical condition or disease by its signs, symptoms, and from the results of various diagnostic procedures. The conclusion reached through this process is called a diagnosis. The term "diagnostic criteria" designates the combination of symptoms which allows the doctor to ascertain the diagnosis of the respective disease.
Typically, someone with abnormal symptoms will consult a physician, who will then obtain a history of the patient's illness and examine him for signs of disease. The physician will formulate a hypothesis of likely diagnoses and in many cases will obtain further testing to confirm or clarify the diagnosis before providing treatment.
Medical tests commonly performed are measuring blood pressure, checking the pulse rate, listening to the heart with a stethoscope, urine tests, fecal tests, saliva tests, blood tests, medical imaging, electrocardiogram, hydrogen breath test and occasionally biopsy.
The word diagnosis is derived from the Greek words dia which means "by", and gnosis which means "knowledge". The verb is diagnose and a person diagnosing could be considered a diagnostician.
# Relationship of diagnosis to medical practice
A physician's job is to know the human body and its functions in terms of normality (homeostasis). The four cornerstones of diagnostic medicine, each essential for understanding homeostasis, are: anatomy (the structure of the human body), physiology (how the body works), pathology (what can go wrong with the anatomy and physiology) and psychology (thought and behavior). Once the doctor knows what is normal and can measure the patient's current condition against those norms, she or he can then determine the patient's particular departure from homeostasis and the degree of departure. This is called the diagnosis. Once a diagnosis has been reached, the doctor is able to propose a management plan, which will include treatment as well as plans for follow-up. From this point on, in addition to treating the patient's condition, the doctor educates the patient about the causes, progression, outcomes, and possible treatments of his ailments, as well as providing advice for maintaining health.
It should be noted however, that medical diagnosis in psychology or psychiatry is problematic. Apart from the fact that there are differing theoretical views toward mental conditions and that there are few "lab" tests available for various major disorders (e.g., clinical depression), a causal analysis with respect to symptomatology and disorder/disease is not always possible. As a result, most if not all mental conditions, function as both symptoms as well as disorders. There are often functional descriptions provided for psychological disorders and these are vulnerable to circular reasoning due to the etiological fuzziness inherent of these diagnostic categories. (BDG, 2006)
# Diagnostic procedure
Diagnosis is a fluid process in which the physician responds to information garnered from the patient and others, from a physical examination of the patient, and from medical tests performed upon the patient.
The doctor should consider the patient in his 'well' context rather than simply as a walking medical condition. This entails assessing the socio-political context of the patient (family, work, stress, beliefs), in addition to the patient's physical body, as this often offers vital clues to the patient's condition and its management.
The process of diagnosis begins when the patient consults the doctor and presents a set of complaints (the symptoms). If the patient is unconscious, this condition is the de facto complaint. The doctor then obtains further information from the patient himself (and from those who know him, if present) about the patient's symptoms, his previous state of health, living conditions, and so forth.
Rather than consider the myriad diseases that could afflict the patient, the physician narrows down the possibilities to the illnesses likely to account for the apparent symptoms, making a list of only those conditions that could account for what is wrong with the patient. These are generally ranked in order of probability.
The doctor then conducts a physical examination of the patient, studies the patient's medical record, and asks further questions as he goes, in an effort to rule out as many of the potential conditions as possible. When the list is narrowed down to a single condition, this is called the differential diagnosis, and provides the basis for a hypothesis of what is ailing the patient.
Unless the physician is certain of the condition present, further medical tests are performed or scheduled (such as medical imaging), in part to confirm or disprove the diagnosis but also to document the patient's status to keep the patient's medical history up to date. Consultations with other physicians and specialists in the field may be sought. If unexpected findings are made during this process, the initial hypothesis may be ruled out and the physician must then consider other hypotheses.
Despite all of these complexities, most patient consultations are relatively brief, because many diseases are obvious, or the physician's experience may enable him to recognize the condition quickly. Another factor is that the decision trees used for most diagnostic hypothesis testing are relatively short.
Once the physician has completed the diagnosis, he explains the prognosis to the patient and proposes a treatment plan which includes therapy and follow-up (further consultations and tests to monitor the condition and the progress of the treatment, if needed), usually according to the guideline provided by the medical field on the treatment of the particular illness.
Treatment itself may indicate a need for review of the diagnosis if there is a failure to respond to treatments that would normally work.
# History of medical diagnostics
The history of medical diagnosis began in earnest from the enlightened days of Hippocrates in ancient Greece but is far from perfect despite the enormous bounty of information made available by medical research including the sequencing of the human genome. The practice of diagnosis continues to be dominated by theories set down in the early 1900s.
## Ancient Greece
Over two thousand years ago, Hippocrates recorded the association between disease and heredity. In similar fashion, Pythagoras noted the association between metabolism and heredity (allergy to Fava beans). The medical community, however, has only recently acknowledged the importance of genetics and its relevance to mainstream medicine.
## The Oslerian ideal
The ideals of William Osler who transformed the practice of medicine in the early 1900s were based on the principles of the diagnosis and treatment of disease. According to Osler, the functions of a physician were to be able to identify disease and its manifestations, understand its mechanisms, how it may be prevented and how it may be cured. For his medical students he believed that the best textbook was the patient himself – analysis of morbid anatomy and pathology were the keys. The Oslerian ideal continues today, as the basis of the Doctor’s strategy is, "What disease does this patient have and what is the best way for treatment?" The emphasis is on the classification of the disease in order to use the remedies available for its effects to be reversed or ameliorated. The human being in question is representative of a class of people with this type of disease whereas the biological individuality of this person is not given any great weight.
## Garrod's view
The successor to William Osler as Regius Professor at Oxford was Archibald Garrod. Garrod echoed the observations of his Greek counterparts of two millennia ago, ...our chemical individualities are due to our chemical merits as well as our chemical shortcomings; and it is more nearly true to say that the factors which confer upon us our predispositions to and immunities from various mishaps which are spoken of as diseases, are inherent in our very chemical structure; and even in the molecular groupings which confer upon us our individualities, and which went into the making of the chromosomes from which we sprang. Considering that the time that he formulated these ideas were the early 1900's, and the knowledge of DNA encoding genes that in turn encoded proteins responsible for bodily structure and functions not being discovered until some fifty years later it took some time before medicine could fully appreciate the fundamental importance of his concept of diagnosis.
## Present-day Oslerian practice
Whereas Osler laid the founding principles by which medicine should be practiced, Garrod placed these principles in a greater context of a chemical individuality that is inherited and is subject to the mechanisms of evolutionary selection. The Oslerian ideal of medical practice continues to dominate medical philosophy today. The patient is a collective of symptoms to be characterized and analyzed algorithmically in order to draw a diagnosis and subsequently produce a strategy of treatment. Medicine is about problems based solutions. In keeping with this philosophy, today's pathology reports provide a momentary snapshot of the patient's biochemical profile, highlighting the end result of the disease process.
## Influence of DNA technology
Garrod's conception of biological individuality was confirmed with the advent of the sequencing of the human genome. Finally the subtle relationship between inheritance, individuality and environment became apparent via the variations detected in DNA. In each patient's DNA lies a script for how their bodies will change and become ill as well as how they will handle the assaults of the environment from the beginning of their life to its end. It is hoped that by knowing a patient's genes that the biological strengths and weaknesses in respect to these assaults will be revealed and disease processes can be predicted before they have the opportunity to manifest. Although knowledge in this area is far from complete, there are already medical interventions based on this. More importantly, the physician, forewarned with this knowledge can guide the patient towards appropriate lifestyle changes to anticipate and mitigate disease processes. | https://www.wikidoc.org/index.php/Diagnose | |
5a3dae39cc4a7b2ff5bae4ac3fcc12d25b1e5fb3 | wikidoc | Dianazene | Dianazene
Dianazene was the name given by L. Ron Hubbard to a vitamin supplement containing iron, Vitamin C, and various B vitamins, including especially large doses of niacin. Hubbard promoted it as a form of protection against radiation poisoning during the 1950s, saying that "Dianazene runs out radiation - or what appears to be radiation. It also proofs a person against radiation in some degree. It also turns on and runs out incipient cancer."
In 1958, the Food and Drug Administration seized from a Scientology company, the Distribution Center, and destroyed, 21,000 Dianazene tablets because they were falsely labelled as a preventative and treatment for radiation sickness.
Vitamins continue to play a large role in the Scientology Purification Rundown and the secular version in the Narconon program, where it is similarly claimed that large quantities of niacin and other vitamins, combined with the heat in a sauna, can "purify" the body by allowing it to release toxins stored in cellular tissue and to "run out" or ameliorate prior radiation exposure including sunburn.
# Ingredients
A standard dose of Dianazene, according to Hubbard's 1957 book All About Radiation, contained the following ingredients:
- Vitamin B3 (Niacin): 200 mg
- Iron (Ferrous gluconate): 10 g
- Vitamin B1 (Thiamine): 25 mg
- Vitamin B2 (Riboflavin): 50 mg
- Vitamin C (Ascorbic acid): 200-500 mg
- Calcium (Dicalcium phosphate): 15-20 g
# Notes
- ↑ Jump up to: 1.0 1.1 Hubbard, L. Ron. All About Radiation. ISBN 9780884040620..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}
- ↑ Atack, Jon (1990). A Piece of Blue Sky. New York, NY: Carol Publishing Group. ISBN 0-8184-0499-X.
- ↑ Wallis, Roy. Sectarianism: Analyses of Religious and Non-Religious Sects, Page 92, 1975, ISBN 0470919108
- ↑ Clear Body, Clear Mind L. Ron Hubbard 1990 | Dianazene
Template:ScientologySeries
Dianazene was the name given by L. Ron Hubbard to a vitamin supplement containing iron, Vitamin C, and various B vitamins, including especially large doses of niacin. Hubbard promoted it as a form of protection against radiation poisoning during the 1950s, saying that "Dianazene runs out radiation - or what appears to be radiation. It also proofs a person against radiation in some degree. It also turns on and runs out incipient cancer." [1]
In 1958, the Food and Drug Administration seized from a Scientology company, the Distribution Center, and destroyed, 21,000 Dianazene tablets because they were falsely labelled as a preventative and treatment for radiation sickness.[2][3]
Vitamins continue to play a large role in the Scientology Purification Rundown and the secular version in the Narconon program, where it is similarly claimed that large quantities of niacin and other vitamins, combined with the heat in a sauna, can "purify" the body by allowing it to release toxins stored in cellular tissue and to "run out" or ameliorate prior radiation exposure including sunburn.[4]
# Ingredients
A standard dose of Dianazene, according to Hubbard's 1957 book All About Radiation, contained the following ingredients:
- Vitamin B3 (Niacin): 200 mg
- Iron (Ferrous gluconate): 10 g
- Vitamin B1 (Thiamine): 25 mg
- Vitamin B2 (Riboflavin): 50 mg
- Vitamin C (Ascorbic acid): 200-500 mg
- Calcium (Dicalcium phosphate): 15-20 g [1]
# Notes
- ↑ Jump up to: 1.0 1.1 Hubbard, L. Ron. All About Radiation. ISBN 9780884040620..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}
- ↑ Atack, Jon (1990). A Piece of Blue Sky. New York, NY: Carol Publishing Group. ISBN 0-8184-0499-X.
- ↑ Wallis, Roy. Sectarianism: Analyses of Religious and Non-Religious Sects, Page 92, 1975, ISBN 0470919108
- ↑ Clear Body, Clear Mind L. Ron Hubbard 1990 | https://www.wikidoc.org/index.php/Dianazene | |
66ef1760efefbe9fc17f6abb58558166a5411cc8 | wikidoc | Diazoxide | Diazoxide
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# Overview
Diazoxide is a potassium channel opener that is FDA approved for the treatment of hypoglycemia. Common adverse reactions include hypotension, hyperglycemia, nausea, vomiting, asthenia, and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- initial dosage: 3 mg/kg PO tid（approxmately 200 mg q24h for a adult）
- maitaing dosage: 3—8 mg/kg PO q8—12 h
- Patients should be under close clinical observation when treatment with proglycem is initiated. The clinical response and blood glucose level should be carefully monitored until the patient's condition has stabilized satisfactory; in most instances, this may be accomplished in several days. If administration of proglycem® is not effective after two or three weeks, the drug should be discontinued.
- The dosage of proglycem® must be individualized based on the severity of the hypoglycemic condition and the blood glucose level and clinical response of the patient. The dosage should be adjusted until the desired clinical and laboratory effects are produced with the least amount of the drug. Special care should be taken to assure accuracy of dosage in infants and young children.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Diazoxide in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 1.5 mg/kg IV (for over 5 minutes)
- Dosing Information
- 30—50 mg IV every 1 to 4 minutes or continuously
- Dosing Information
- 300 mg IV every 10 minutes (Total doses of DIAZOXIDE ranged from 450 to 900 mg)
- Dosing Information
- 4—6 mg/kg
- Dosing Information
- 2/3 mg/kg PO (max 200 mg/day) combined with 1260- (women) to 1570- (men) calorie diets
- Dosing Information
- 600 mg PO q24h
- Dosing Information
- 200 mg/day plus haloperidol 20 mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Initial dosage: 10 mg/kg tid
- Maintaining dosage； 8—15 mg/kg q8h or q12h
- Patients should be under close clinical observation when treatment with proglycem® is initiated. The clinical response and blood glucose level should be carefully monitored until the patient's condition has stabilized satisfactory; in most instances, this may be accomplished in several days. If administration of proglycem® is not effective after two or three weeks, the drug should be discontinued.
- The dosage of proglycem® must be individualized based on the severity of the hypoglycemic condition and the blood glucose level and clinical response of the patient. The dosage should be adjusted until the desired clinical and laboratory effects are produced with the least amount of the drug. Special care should be taken to assure accuracy of dosage in infants and young children.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Diazoxide in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- 10 mg/kg/day
# Contraindications
- The use of proglycem® for functional hypoglycemia is contraindicated. The drug should not be used in patients hypersensitive to diazoxide or to other thiazides unless the potential benefits outweigh the possible risks.
# Warnings
- The antidiuretic property of diazoxide may lead to significant fluid retention, which in patients with compromised cardiac reserve, may precipitate congestive heart failure. The fluid retention will respond to conventional therapy with diuretics.
- It should be noted that concomitantly administered thiazides may potentiate the hyperglycemic and hyperuricemic actions of diazoxide.
- Ketoacidosis and nonketotic hyperosmolar coma have been reported in patients treated with recommended doses of proglycem® usually during intercurrent illness. Prompt recognition and treatment are essential, and prolonged surveillance following the acute episode is necessary because of the long drug half-life of approximately 30 hours. The occurrence of these serious events may be reduced by careful education of patients regarding the need for monitoring the urine for sugar and ketones and for prompt reporting of abnormal findings and unusual symptoms to the physician. Transient cataracts occurred in association with hyperosmolar coma in an infant, and subsided on correction of the hyper-osmolarity. Cataracts have been observed in several animals receiving daily doses of intravenous or oral diazoxide.
- The development of abnormal facial features in four children treated chronically (>4 years) with proglycem® for hypoglycemia and hyperinsulinism in the same clinic has been reported.
## PRECAUTIONS
### General
- Treatment with proglycem® should be initiated under close clinical supervision, with careful monitoring of blood glucose and clinical response until the patient's condition has stabilized. This usually requires several days. If not effective in two to three weeks, the drug should be discontinued.
- Prolonged treatment requires regular monitoring of the urine for sugar and ketones, especially under stress conditions, with prompt reporting of any abnormalities to the physician. Additionally, blood sugar levels should be monitored periodically by the physician to determine the need for dose adjustment.
- The effects of diazoxide on the hematopoietic system and the level of serum uric acid should be kept in mind; the latter should be considered particularly in patients with hyperuricemia or a history of gout.
- In some patients, higher blood levels have been observed with the oral suspension than with the capsule formulation of proglycem®. Dosage should be adjusted as necessary in individual patients if changed from one formulation to the other.
- Since the plasma half-life of diazoxide is prolonged in patients with impaired renal function, a reduced dosage should be considered. Serum electrolyte levels should also be evaluated for such patients.
- The antihypertensive effect of other drugs may be enhanced by proglycem®, and this should be kept in mind when administering it concomitantly with antihypertensive agents.
- Because of the protein binding, administration of proglycem® with coumarin or its derivatives may require reduction in the dosage of the anticoagulant, although there has been no reported evidence of excessive anticoagulant effect. In addition, proglycem® may possibly displace bilirubin from albumin; this should be kept in mind particularly when treating newborns with increased bilirubinemia.
# Adverse Reactions
## Clinical Trials Experience
There is limited information about the clinical trial experience.
## Postmarketing Experience
- Sodium and fluid retention is most common in young infants and in adults and may precipitate congestive heart failure in patients with compromised cardiac reserve. It usually responds to diuretic therapy.
- Diabetic ketoacidosis and hyperosmolar nonketotic coma may develop very rapidly. Conventional therapy with insulin and restoration of fluid and electrolyte balance is usually effective if instituted promptly. Prolonged surveillance is essential in view of the long half-life of proglycem®.
- Hirsutism of the lanugo type, mainly on the forehead, back and limbs, occurs most commonly in children and women and may be cosmetically unacceptable. It subsides on discontinuation of the drug.
- Hyperglycemia or glycosuria may require reduction in dosage in order to avoid progression to ketoacidosis or hyperosmolar coma.
- Gastrointestinal intolerance may include anorexia, nausea, vomiting, abdominal pain, ileus, diarrhea, transient loss of taste.
- Tachycardia, palpitations, increased levels of serum uric acid are common.
- Thrombocytopenia with or without purpura may require discontinuation of the drug. Neutropenia is transient, is not associated with increased susceptibility to infection, and ordinarily does not require discontinuation of the drug. Skin rash, headache, weakness, and malaise may also occur.
- Other adverse reactions which have been observed are
Cardiovascular
Hypotension occurs occasionally, which may be augmented by thiazide diuretics given concurrently. A few cases of transient hypertension, for which no explanation is apparent, have been noted. Chest pain has been reported rarely.
Hematologic
Eosinophilia; decreased hemoglobin / hematocrit; excessive bleeding, decreased IgG.
Hepato-renal
Increased AST, alkaline phosphatase; azotemia, decreased creatinine clearance, reversible nephrotic syndrome, decreased urinary output, hematuria, albuminuria.
Neurologic
Anxiety, dizziness, insomnia, polyneuritis, paresthesia, pruritus, extrapyramidal signs.
Ophthalmologic
Transient cataracts, subconjunctival hemorrhage, ring scotoma, blurred vision, diplopia, lacrimation. Skeletal, integumentary; monilial dermatitis, herpes, advance in bone age; loss of scalp hair.
Systemic
Fever, lymphadenopathy. Other; gout acute pancreatitis/pancreatic necrosis, galactorrhea, enlargement of lump in breast.
# Drug Interactions
- Since diazoxide is highly bound to serum proteins, it may displace other substances which are also bound to protein, such as bilirubin or coumarinand its derivatives, resulting in higher blood levels of these substances. Concomitant administration of oral diazoxide and diphenylhydantoin may result in a loss of seizure control. These potential interactions must be considered when administering proglycem® Capsules or Suspension.
- The concomitant administration of thiazides or other commonly used diuretics may potentiate the hyperglycemic and hyperuricemic effects of diazoxide.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Reproduction studies using the oral preparation in rats have revealed increased fetal resorptions and delayed parturition, as well as fetal skeletal anomalies; evidence of skeletal and cardiac teratogenic effects in rabbits has been noted with intravenous administration. The drug has also been demonstrated to cross the placental barrier in animals and to cause degeneration of the fetal pancreatic beta cells. Since there are no adequate data on fetal effects of this drug when given to pregnant women, safety in pregnancy has not been established. When the use of proglycem® is considered, the indications should be limited to those specified above for adults, and the potential benefits to the mother must be weighed against possible harmful effects to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Diazoxide in women who are pregnant.
### Labor and Delivery
- Since intravenous administration of the drug during labor may cause cessation of uterine contractions, and administration of oxytocic agents may be required to reinstate labor, caution is advised in administering proglycem® at that time.
### Nursing Mothers
- Information is not available concerning the passage of diazoxide in breast milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions from diazoxide in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
(See INDICATIONS AND USAGE).
### Geriatic Use
There is no FDA guidance on the use of Diazoxide in geriatric settings.
### Gender
There is no FDA guidance on the use of Diazoxide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Diazoxide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Diazoxide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Diazoxide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Diazoxide crosses the placental barrier and appears in cord blood. When given to the mother prior to delivery of the infant, the drug may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism, and possibly other side effects that have occurred in adults.
- Alopecia and hypertrichosis lanuginosa have occurred in infants whose mothers received oral diazoxide during the last 19 to 60 days of pregnancy.
### Immunocompromised Patients
There is no FDA guidance one the use of Diazoxide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Patients should be under close clinical observation when treatment with proglycem® is initiated. The clinical response and blood glucose level should be carefully monitored until the patient's condition has stabilized satisfactory; in most instances, this may be accomplished in several days. If administration of proglycem® is not effective after two or three weeks, the drug should be discontinued.
- The dosage of proglycem® must be individualized based on the severity of the hypoglycemic condition and the blood glucose level and clinical response of the patient. The dosage should be adjusted until the desired clinical and laboratory effects are produced with the least amount of the drug. Special care should be taken to assure accuracy of dosage in infants and young children.
### Monitoring
- The occurrence of these serious events may be reduced by careful education of patients regarding the need for monitoring the urine for sugar and ketones and for prompt reporting of abnormal findings and unusual symptoms to the physician.
- Prolonged treatment requires regular monitoring of the urine for sugar and ketones, especially under stress conditions, with prompt reporting of any abnormalities to the physician.
- Additionally, blood sugar levels should be monitored periodically by the physician to determine the need for dose adjustment.
- The following procedures may be especially important in patient monitoring (not necessarily inclusive); blood glucose determinations (recommended at periodic intervals in patients taking diazoxide orally for treatment of hypoglycemia, until stabilized); blood urea nitrogen (BUN) determinations and creatinine clearance determinations; hematocrit determinations; platelet count determinations; total and differential leukocyte counts; serum aspartate aminotransferase (AST) level determinations; serum uric acid level determinations; and urine testing for glucose and ketones (in patients being treated with diazoxide for hypoglycemia, semiquantitative estimation of sugar and ketones in serum performed by the patient and reported to the physician provides frequent and relatively inexpensive monitoring of the condition).
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
- An overdosage of proglycem® causes marked hyperglycemia which may be associated with ketoacidosis. It will respond to prompt insulin administration and restoration of fluid and electrolyte balance. Because of the drug's long half-life (approximately 30 hours), the symptoms of overdosage require prolonged surveillance for periods up to seven days until the blood sugar level stabilizes within the normal range. One investigator reported successful lowering of diazoxide blood levels by peritoneal dialysis in one patient and by hemodialysis in another.
# Pharmacology
## Mechanism of Action
- Diazoxide administered orally produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic effect.
## Structure
- Proglycem® (diazoxide) is a nondiuretic benzothiadiazine derivative taken orally for the management of symptomatic hypoglycemia. Proglycem® Capsulescontain 50 mg diazoxide, USP. The Suspension contains 50 mg of diazoxide, USP in each milliliter and has a chocolate-mint flavor; alcohol content is approximately 7.25%. Other ingredients: Sorbitol solution, chocolate cream flavor, propylene glycol, magnesium aluminum silicate, carboxymethycellulose sodium, mint flavor, sodium benzoate, methylparaben, poloxamer 188, propylparaben, and purified water. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
- Diazoxide has the following structural formula:
## Pharmacodynamics
- The hyperglycemic effect begins within an hour and generally lasts no more than eight hours in the presence of normal renal function.
- Proglycem® decreases the excretion of sodium and water, resulting in fluid retention which may be clinically significant.
- The hypotensive effect of diazoxide on blood pressure is usually not marked with the oral preparation. This contrasts with the intravenous preparation of diazoxide.
- Other pharmacologic actions of proglycem® include increased pulse rate; increased serum uric acid levels due to decreased excretion; increased serum levels of free fatty acids' decreased chloride excretion; decreased para-aminohippuric acid; (PAH) clearance with no appreciable effect on glomerular filtration rate.
- The concomitant administration of a benzothiazide diuretic may intensify the hyperglycemic and hyperuricemic effects of proglycem®. In the presence of hypokalemia, hyperglycemic effects are also potentiated.
- Proglycem®-induced hyperglycemia is reversed by the administration of insulin or tolbutamide. The inhibition of insulin release by proglycem® is antagonized by alpha-adrenergic blocking agents.
- Proglycem® is extensively bound (more than 90%) to serum proteins, and is excreted in the kidneys. The plasma half-life following I.V. administration is 28 ± 8.3 hours. Limited data on oral administration revealed a half-life of 24 and 36 hours in two adults. In four children aged four months to six years, the plasma half-life varied from 9.5 to 24 hours on long-term oral administration. The half-life may be prolonged following overdosage, and in patients with impaired renal function.
## Pharmacokinetics
There is limited information regarding Diazoxide Pharmacokinetics in the drug label.
## Nonclinical Toxicology
- Oral diazoxide in the mouse, rat, rabbit, dog, pig, and monkey produces a rapid and transient rise in blood glucose levels. In dogs, increased blood glucose is accompanied by increased free fatty acids, lactate, and pyruvate in the serum. In mice, a marked decrease in liver glycogen and an increase in the blood urea nitrogen level occur.
- In acute toxicity studies the LD50 for oral diazoxide suspension is >5000 mg/kg in the rat, >522 mg/kg in the neonatal rat, between 1900 and 2572 mg/kg in the mouse, and 219 mg/kg in the guinea pig. Although the oral LD50 was not determined in the dog, a dosage of up to 500 mg/kg was well tolerated.
- In subacute oral toxicity studies, diazoxide at 400 mg/kg in the rat produced growth retardation, edema, increases in liver and kidney weights, and adrenal hypertrophy. Daily dosages up to 1080 mg/kg for three months produced hyperglycemia, an increase in liver weight and an increase in mortality. In dogs given oral diazoxide at approximately 40 mg/kg/day for one month, no biologically significant gross or microscopic abnormalities were observed. Cataracts, attributed to markedly disturbed carbohydrate metabolism, have been observed in a few dogs given repeated daily doses of oral or intravenous diazoxide. The lenticular changes resembled those which occur experimentally in animals with increased blood glucose levels. In chronic toxicity studies, rats given a daily dose of 200 mg/kg diazoxide for 52 weeks had a decrease in weight gain and an increase in heart, liver, adrenal and thyroid weights. Mortality in drug-treated and control groups was not different. Dogs treated with diazoxide at dosages of 50, l00, and 200 mg/kg/day for 82 weeks had higher blood glucose levels than controls. Mild bone marrow stimulation and increased pancreas weights were evident in the drug-treated dogs; several developed inguinal hernias, one had a testicular seminoma, and another had a mass near the penis. Two females had inguinal mammary swellings. The etiology of these changes was not established. There was no difference in mortality between drug-treated and control groups. In a second chronic oral toxicity study, dogs given milled diazoxide at 50, l00, and 200 mg/kg/day had anorexia and sever weight loss, causing death in a few. Hematologic, biochemical, and histologic examination did not indicate any cause of death other than inanition. After one year of treatment, there is no evidence of herniation or tissue swelling in any of the dogs.
- When diazoxide was administered at high dosages concomitantly with either chlorothiazide to rats or trichlormethiazide to dogs, increased toxicity was observed. In rats, the combination was nephrotoxic; epithelial hyperplasia was observed in the collecting tubules. In dogs, a diabetic syndrome was produced which resulted in ketosis and death. Neither of the drugs given alone produced these effects.
- Although the data are inconclusive, reproduction and teratology studies in several species of animals indicate that diazoxide, when administered during the critical period of embryo formation, may interfere with normal fetal development, possibly through altered glucose metabolism. Parturition was occasionally prolonged in animals treated at term. Intravenous administration of diazoxide to pregnant sheep, goats, and swine produced in the fetus an appreciable increase in blood glucose level and degeneration of the beta cells of the Islets of Langerhans. The reversibility of these effects was not studied.
# Clinical Studies
- Diazoxide administered orally produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic effect.
- The hyperglycemic effect begins within an hour and generally lasts no more than eight hours in the presence of normal renal function.
- Proglycem® decreases the excretion of sodium and water, resulting in fluid retention which may be clinically significant.
- The hypotensive effect of diazoxide on blood pressure is usually not marked with the oral preparation. This contrasts with the intravenous preparation of diazoxide.
- Other pharmacologic actions of proglycem® include increased pulse rate; increased serum uric acid levels due to decreased excretion; increased serum levels of free fatty acids' decreased chloride excretion; decreased para-aminohippuric acid; (PAH) clearance with no appreciable effect on glomerular filtration rate.
- The concomitant administration of a benzothiazide diuretic may intensify the hyperglycemic and hyperuricemic effects of proglycem®. In the presence of hypokalemia, hyperglycemic effects are also potentiated.
- Proglycem®-induced hyperglycemia is reversed by the administration of insulin or tolbutamide. The inhibition of insulin release by proglycem® is antagonized by alpha-adrenergic blocking agents.
- Proglycem® is extensively bound (more than 90%) to serum proteins, and is excreted in the kidneys. The plasma half-life following I.V. administration is 28 ± 8.3 hours. Limited data on oral administration revealed a half-life of 24 and 36 hours in two adults. In four children aged four months to six years, the plasma half-life varied from 9.5 to 24 hours on long-term oral administration. The half-life may be prolonged following overdosage, and in patients with impaired renal function.
# How Supplied
- Proglycem® (diazoxide capsules, USP), 50 mg, half opaque orange and half clear capsules, branded in black with BNP 6000: bottle of 100 (NDC 0575-6000-01).
- Proglycem® suspension, 50 mg/mL, a chocolate-mint flavored suspension; bottle of 30 ml (NDC 0575-6200-30), with dropper calibrated to deliver 10, 20, 30, 40 and 50 mg diazoxide. Shake well before each use. Protect from light. Store in carton until contents are used. Store in light resistant container as defined in the USP.
## Storage
- Store proglycem® Capsules and Suspension at 25°C (77°F) excursions permitted 15°-30°C (59-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- During treatment with proglycem® the patient should be advised to consult regularly with the physician and to cooperate in the periodic monitoring of his condition by laboratory tests. In addition, the patient should be advised:
- to take the drug on a regular schedule as prescribed, not to skip doses, not to take extra doses;
- not to use this drug with other medications unless this is done with the physician's advice;
- not to allow anyone else to take this medication;
- to follow dietary instructions;
- to report promptly any adverse effects (i.e., increased urinary frequency, increased thirst, fruity breath odor);
- to report pregnancy or to discuss plans for pregnancy.
# Precautions with Alcohol
Alcohol-Diazoxide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Diazoxide Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price | Diazoxide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
# Disclaimer
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# Overview
Diazoxide is a potassium channel opener that is FDA approved for the treatment of hypoglycemia. Common adverse reactions include hypotension, hyperglycemia, nausea, vomiting, asthenia, and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- initial dosage: 3 mg/kg PO tid（approxmately 200 mg q24h for a adult）
- maitaing dosage: 3—8 mg/kg PO q8—12 h
- Patients should be under close clinical observation when treatment with proglycem is initiated. The clinical response and blood glucose level should be carefully monitored until the patient's condition has stabilized satisfactory; in most instances, this may be accomplished in several days. If administration of proglycem® is not effective after two or three weeks, the drug should be discontinued.
- The dosage of proglycem® must be individualized based on the severity of the hypoglycemic condition and the blood glucose level and clinical response of the patient. The dosage should be adjusted until the desired clinical and laboratory effects are produced with the least amount of the drug. Special care should be taken to assure accuracy of dosage in infants and young children.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Diazoxide in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 1.5 mg/kg IV (for over 5 minutes) [1]
- Dosing Information
- 30—50 mg IV every 1 to 4 minutes or continuously
- Dosing Information
- 300 mg IV every 10 minutes (Total doses of DIAZOXIDE ranged from 450 to 900 mg) [2]
- Dosing Information
- 4—6 mg/kg [3]
- Dosing Information
- 2/3 mg/kg PO (max 200 mg/day) combined with 1260- (women) to 1570- (men) calorie diets[4]
- Dosing Information
- 600 mg PO q24h
- Dosing Information
- 200 mg/day plus haloperidol 20 mg/day [5]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Initial dosage: 10 mg/kg tid
- Maintaining dosage； 8—15 mg/kg q8h or q12h
- Patients should be under close clinical observation when treatment with proglycem® is initiated. The clinical response and blood glucose level should be carefully monitored until the patient's condition has stabilized satisfactory; in most instances, this may be accomplished in several days. If administration of proglycem® is not effective after two or three weeks, the drug should be discontinued.
- The dosage of proglycem® must be individualized based on the severity of the hypoglycemic condition and the blood glucose level and clinical response of the patient. The dosage should be adjusted until the desired clinical and laboratory effects are produced with the least amount of the drug. Special care should be taken to assure accuracy of dosage in infants and young children.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Diazoxide in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- 10 mg/kg/day [6]
# Contraindications
- The use of proglycem® for functional hypoglycemia is contraindicated. The drug should not be used in patients hypersensitive to diazoxide or to other thiazides unless the potential benefits outweigh the possible risks.
# Warnings
- The antidiuretic property of diazoxide may lead to significant fluid retention, which in patients with compromised cardiac reserve, may precipitate congestive heart failure. The fluid retention will respond to conventional therapy with diuretics.
- It should be noted that concomitantly administered thiazides may potentiate the hyperglycemic and hyperuricemic actions of diazoxide.
- Ketoacidosis and nonketotic hyperosmolar coma have been reported in patients treated with recommended doses of proglycem® usually during intercurrent illness. Prompt recognition and treatment are essential, and prolonged surveillance following the acute episode is necessary because of the long drug half-life of approximately 30 hours. The occurrence of these serious events may be reduced by careful education of patients regarding the need for monitoring the urine for sugar and ketones and for prompt reporting of abnormal findings and unusual symptoms to the physician. Transient cataracts occurred in association with hyperosmolar coma in an infant, and subsided on correction of the hyper-osmolarity. Cataracts have been observed in several animals receiving daily doses of intravenous or oral diazoxide.
- The development of abnormal facial features in four children treated chronically (>4 years) with proglycem® for hypoglycemia and hyperinsulinism in the same clinic has been reported.
## PRECAUTIONS
### General
- Treatment with proglycem® should be initiated under close clinical supervision, with careful monitoring of blood glucose and clinical response until the patient's condition has stabilized. This usually requires several days. If not effective in two to three weeks, the drug should be discontinued.
- Prolonged treatment requires regular monitoring of the urine for sugar and ketones, especially under stress conditions, with prompt reporting of any abnormalities to the physician. Additionally, blood sugar levels should be monitored periodically by the physician to determine the need for dose adjustment.
- The effects of diazoxide on the hematopoietic system and the level of serum uric acid should be kept in mind; the latter should be considered particularly in patients with hyperuricemia or a history of gout.
- In some patients, higher blood levels have been observed with the oral suspension than with the capsule formulation of proglycem®. Dosage should be adjusted as necessary in individual patients if changed from one formulation to the other.
- Since the plasma half-life of diazoxide is prolonged in patients with impaired renal function, a reduced dosage should be considered. Serum electrolyte levels should also be evaluated for such patients.
- The antihypertensive effect of other drugs may be enhanced by proglycem®, and this should be kept in mind when administering it concomitantly with antihypertensive agents.
- Because of the protein binding, administration of proglycem® with coumarin or its derivatives may require reduction in the dosage of the anticoagulant, although there has been no reported evidence of excessive anticoagulant effect. In addition, proglycem® may possibly displace bilirubin from albumin; this should be kept in mind particularly when treating newborns with increased bilirubinemia.
# Adverse Reactions
## Clinical Trials Experience
There is limited information about the clinical trial experience.
## Postmarketing Experience
- Sodium and fluid retention is most common in young infants and in adults and may precipitate congestive heart failure in patients with compromised cardiac reserve. It usually responds to diuretic therapy.
- Diabetic ketoacidosis and hyperosmolar nonketotic coma may develop very rapidly. Conventional therapy with insulin and restoration of fluid and electrolyte balance is usually effective if instituted promptly. Prolonged surveillance is essential in view of the long half-life of proglycem®.
- Hirsutism of the lanugo type, mainly on the forehead, back and limbs, occurs most commonly in children and women and may be cosmetically unacceptable. It subsides on discontinuation of the drug.
- Hyperglycemia or glycosuria may require reduction in dosage in order to avoid progression to ketoacidosis or hyperosmolar coma.
- Gastrointestinal intolerance may include anorexia, nausea, vomiting, abdominal pain, ileus, diarrhea, transient loss of taste.
- Tachycardia, palpitations, increased levels of serum uric acid are common.
- Thrombocytopenia with or without purpura may require discontinuation of the drug. Neutropenia is transient, is not associated with increased susceptibility to infection, and ordinarily does not require discontinuation of the drug. Skin rash, headache, weakness, and malaise may also occur.
- Other adverse reactions which have been observed are
Cardiovascular
Hypotension occurs occasionally, which may be augmented by thiazide diuretics given concurrently. A few cases of transient hypertension, for which no explanation is apparent, have been noted. Chest pain has been reported rarely.
Hematologic
Eosinophilia; decreased hemoglobin / hematocrit; excessive bleeding, decreased IgG.
Hepato-renal
Increased AST, alkaline phosphatase; azotemia, decreased creatinine clearance, reversible nephrotic syndrome, decreased urinary output, hematuria, albuminuria.
Neurologic
Anxiety, dizziness, insomnia, polyneuritis, paresthesia, pruritus, extrapyramidal signs.
Ophthalmologic
Transient cataracts, subconjunctival hemorrhage, ring scotoma, blurred vision, diplopia, lacrimation. Skeletal, integumentary; monilial dermatitis, herpes, advance in bone age; loss of scalp hair.
Systemic
Fever, lymphadenopathy. Other; gout acute pancreatitis/pancreatic necrosis, galactorrhea, enlargement of lump in breast.
# Drug Interactions
- Since diazoxide is highly bound to serum proteins, it may displace other substances which are also bound to protein, such as bilirubin or coumarinand its derivatives, resulting in higher blood levels of these substances. Concomitant administration of oral diazoxide and diphenylhydantoin may result in a loss of seizure control. These potential interactions must be considered when administering proglycem® Capsules or Suspension.
- The concomitant administration of thiazides or other commonly used diuretics may potentiate the hyperglycemic and hyperuricemic effects of diazoxide.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Reproduction studies using the oral preparation in rats have revealed increased fetal resorptions and delayed parturition, as well as fetal skeletal anomalies; evidence of skeletal and cardiac teratogenic effects in rabbits has been noted with intravenous administration. The drug has also been demonstrated to cross the placental barrier in animals and to cause degeneration of the fetal pancreatic beta cells. Since there are no adequate data on fetal effects of this drug when given to pregnant women, safety in pregnancy has not been established. When the use of proglycem® is considered, the indications should be limited to those specified above for adults, and the potential benefits to the mother must be weighed against possible harmful effects to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Diazoxide in women who are pregnant.
### Labor and Delivery
- Since intravenous administration of the drug during labor may cause cessation of uterine contractions, and administration of oxytocic agents may be required to reinstate labor, caution is advised in administering proglycem® at that time.
### Nursing Mothers
- Information is not available concerning the passage of diazoxide in breast milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions from diazoxide in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
(See INDICATIONS AND USAGE).
### Geriatic Use
There is no FDA guidance on the use of Diazoxide in geriatric settings.
### Gender
There is no FDA guidance on the use of Diazoxide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Diazoxide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Diazoxide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Diazoxide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Diazoxide crosses the placental barrier and appears in cord blood. When given to the mother prior to delivery of the infant, the drug may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism, and possibly other side effects that have occurred in adults.
- Alopecia and hypertrichosis lanuginosa have occurred in infants whose mothers received oral diazoxide during the last 19 to 60 days of pregnancy.
### Immunocompromised Patients
There is no FDA guidance one the use of Diazoxide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Patients should be under close clinical observation when treatment with proglycem® is initiated. The clinical response and blood glucose level should be carefully monitored until the patient's condition has stabilized satisfactory; in most instances, this may be accomplished in several days. If administration of proglycem® is not effective after two or three weeks, the drug should be discontinued.
- The dosage of proglycem® must be individualized based on the severity of the hypoglycemic condition and the blood glucose level and clinical response of the patient. The dosage should be adjusted until the desired clinical and laboratory effects are produced with the least amount of the drug. Special care should be taken to assure accuracy of dosage in infants and young children.
### Monitoring
- The occurrence of these serious events may be reduced by careful education of patients regarding the need for monitoring the urine for sugar and ketones and for prompt reporting of abnormal findings and unusual symptoms to the physician.
- Prolonged treatment requires regular monitoring of the urine for sugar and ketones, especially under stress conditions, with prompt reporting of any abnormalities to the physician.
- Additionally, blood sugar levels should be monitored periodically by the physician to determine the need for dose adjustment.
- The following procedures may be especially important in patient monitoring (not necessarily inclusive); blood glucose determinations (recommended at periodic intervals in patients taking diazoxide orally for treatment of hypoglycemia, until stabilized); blood urea nitrogen (BUN) determinations and creatinine clearance determinations; hematocrit determinations; platelet count determinations; total and differential leukocyte counts; serum aspartate aminotransferase (AST) level determinations; serum uric acid level determinations; and urine testing for glucose and ketones (in patients being treated with diazoxide for hypoglycemia, semiquantitative estimation of sugar and ketones in serum performed by the patient and reported to the physician provides frequent and relatively inexpensive monitoring of the condition).
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
- An overdosage of proglycem® causes marked hyperglycemia which may be associated with ketoacidosis. It will respond to prompt insulin administration and restoration of fluid and electrolyte balance. Because of the drug's long half-life (approximately 30 hours), the symptoms of overdosage require prolonged surveillance for periods up to seven days until the blood sugar level stabilizes within the normal range. One investigator reported successful lowering of diazoxide blood levels by peritoneal dialysis in one patient and by hemodialysis in another.
# Pharmacology
## Mechanism of Action
- Diazoxide administered orally produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic effect.
## Structure
- Proglycem® (diazoxide) is a nondiuretic benzothiadiazine derivative taken orally for the management of symptomatic hypoglycemia. Proglycem® Capsulescontain 50 mg diazoxide, USP. The Suspension contains 50 mg of diazoxide, USP in each milliliter and has a chocolate-mint flavor; alcohol content is approximately 7.25%. Other ingredients: Sorbitol solution, chocolate cream flavor, propylene glycol, magnesium aluminum silicate, carboxymethycellulose sodium, mint flavor, sodium benzoate, methylparaben, poloxamer 188, propylparaben, and purified water. Hydrochloric acid or sodium hydroxide may be added to adjust pH.
- Diazoxide has the following structural formula:
## Pharmacodynamics
- The hyperglycemic effect begins within an hour and generally lasts no more than eight hours in the presence of normal renal function.
- Proglycem® decreases the excretion of sodium and water, resulting in fluid retention which may be clinically significant.
- The hypotensive effect of diazoxide on blood pressure is usually not marked with the oral preparation. This contrasts with the intravenous preparation of diazoxide.
- Other pharmacologic actions of proglycem® include increased pulse rate; increased serum uric acid levels due to decreased excretion; increased serum levels of free fatty acids' decreased chloride excretion; decreased para-aminohippuric acid; (PAH) clearance with no appreciable effect on glomerular filtration rate.
- The concomitant administration of a benzothiazide diuretic may intensify the hyperglycemic and hyperuricemic effects of proglycem®. In the presence of hypokalemia, hyperglycemic effects are also potentiated.
- Proglycem®-induced hyperglycemia is reversed by the administration of insulin or tolbutamide. The inhibition of insulin release by proglycem® is antagonized by alpha-adrenergic blocking agents.
- Proglycem® is extensively bound (more than 90%) to serum proteins, and is excreted in the kidneys. The plasma half-life following I.V. administration is 28 ± 8.3 hours. Limited data on oral administration revealed a half-life of 24 and 36 hours in two adults. In four children aged four months to six years, the plasma half-life varied from 9.5 to 24 hours on long-term oral administration. The half-life may be prolonged following overdosage, and in patients with impaired renal function.
## Pharmacokinetics
There is limited information regarding Diazoxide Pharmacokinetics in the drug label.
## Nonclinical Toxicology
- Oral diazoxide in the mouse, rat, rabbit, dog, pig, and monkey produces a rapid and transient rise in blood glucose levels. In dogs, increased blood glucose is accompanied by increased free fatty acids, lactate, and pyruvate in the serum. In mice, a marked decrease in liver glycogen and an increase in the blood urea nitrogen level occur.
- In acute toxicity studies the LD50 for oral diazoxide suspension is >5000 mg/kg in the rat, >522 mg/kg in the neonatal rat, between 1900 and 2572 mg/kg in the mouse, and 219 mg/kg in the guinea pig. Although the oral LD50 was not determined in the dog, a dosage of up to 500 mg/kg was well tolerated.
- In subacute oral toxicity studies, diazoxide at 400 mg/kg in the rat produced growth retardation, edema, increases in liver and kidney weights, and adrenal hypertrophy. Daily dosages up to 1080 mg/kg for three months produced hyperglycemia, an increase in liver weight and an increase in mortality. In dogs given oral diazoxide at approximately 40 mg/kg/day for one month, no biologically significant gross or microscopic abnormalities were observed. Cataracts, attributed to markedly disturbed carbohydrate metabolism, have been observed in a few dogs given repeated daily doses of oral or intravenous diazoxide. The lenticular changes resembled those which occur experimentally in animals with increased blood glucose levels. In chronic toxicity studies, rats given a daily dose of 200 mg/kg diazoxide for 52 weeks had a decrease in weight gain and an increase in heart, liver, adrenal and thyroid weights. Mortality in drug-treated and control groups was not different. Dogs treated with diazoxide at dosages of 50, l00, and 200 mg/kg/day for 82 weeks had higher blood glucose levels than controls. Mild bone marrow stimulation and increased pancreas weights were evident in the drug-treated dogs; several developed inguinal hernias, one had a testicular seminoma, and another had a mass near the penis. Two females had inguinal mammary swellings. The etiology of these changes was not established. There was no difference in mortality between drug-treated and control groups. In a second chronic oral toxicity study, dogs given milled diazoxide at 50, l00, and 200 mg/kg/day had anorexia and sever weight loss, causing death in a few. Hematologic, biochemical, and histologic examination did not indicate any cause of death other than inanition. After one year of treatment, there is no evidence of herniation or tissue swelling in any of the dogs.
- When diazoxide was administered at high dosages concomitantly with either chlorothiazide to rats or trichlormethiazide to dogs, increased toxicity was observed. In rats, the combination was nephrotoxic; epithelial hyperplasia was observed in the collecting tubules. In dogs, a diabetic syndrome was produced which resulted in ketosis and death. Neither of the drugs given alone produced these effects.
- Although the data are inconclusive, reproduction and teratology studies in several species of animals indicate that diazoxide, when administered during the critical period of embryo formation, may interfere with normal fetal development, possibly through altered glucose metabolism. Parturition was occasionally prolonged in animals treated at term. Intravenous administration of diazoxide to pregnant sheep, goats, and swine produced in the fetus an appreciable increase in blood glucose level and degeneration of the beta cells of the Islets of Langerhans. The reversibility of these effects was not studied.
# Clinical Studies
- Diazoxide administered orally produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas, and also to an extrapancreatic effect.
- The hyperglycemic effect begins within an hour and generally lasts no more than eight hours in the presence of normal renal function.
- Proglycem® decreases the excretion of sodium and water, resulting in fluid retention which may be clinically significant.
- The hypotensive effect of diazoxide on blood pressure is usually not marked with the oral preparation. This contrasts with the intravenous preparation of diazoxide.
- Other pharmacologic actions of proglycem® include increased pulse rate; increased serum uric acid levels due to decreased excretion; increased serum levels of free fatty acids' decreased chloride excretion; decreased para-aminohippuric acid; (PAH) clearance with no appreciable effect on glomerular filtration rate.
- The concomitant administration of a benzothiazide diuretic may intensify the hyperglycemic and hyperuricemic effects of proglycem®. In the presence of hypokalemia, hyperglycemic effects are also potentiated.
- Proglycem®-induced hyperglycemia is reversed by the administration of insulin or tolbutamide. The inhibition of insulin release by proglycem® is antagonized by alpha-adrenergic blocking agents.
- Proglycem® is extensively bound (more than 90%) to serum proteins, and is excreted in the kidneys. The plasma half-life following I.V. administration is 28 ± 8.3 hours. Limited data on oral administration revealed a half-life of 24 and 36 hours in two adults. In four children aged four months to six years, the plasma half-life varied from 9.5 to 24 hours on long-term oral administration. The half-life may be prolonged following overdosage, and in patients with impaired renal function.
# How Supplied
- Proglycem® (diazoxide capsules, USP), 50 mg, half opaque orange and half clear capsules, branded in black with BNP 6000: bottle of 100 (NDC 0575-6000-01).
- Proglycem® suspension, 50 mg/mL, a chocolate-mint flavored suspension; bottle of 30 ml (NDC 0575-6200-30), with dropper calibrated to deliver 10, 20, 30, 40 and 50 mg diazoxide. Shake well before each use. Protect from light. Store in carton until contents are used. Store in light resistant container as defined in the USP.
## Storage
- Store proglycem® Capsules and Suspension at 25°C (77°F) excursions permitted 15°-30°C (59-86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- During treatment with proglycem® the patient should be advised to consult regularly with the physician and to cooperate in the periodic monitoring of his condition by laboratory tests. In addition, the patient should be advised:
- to take the drug on a regular schedule as prescribed, not to skip doses, not to take extra doses;
- not to use this drug with other medications unless this is done with the physician's advice;
- not to allow anyone else to take this medication;
- to follow dietary instructions;
- to report promptly any adverse effects (i.e., increased urinary frequency, increased thirst, fruity breath odor);
- to report pregnancy or to discuss plans for pregnancy.
# Precautions with Alcohol
Alcohol-Diazoxide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Diazoxide Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Diazoxide | |
b4331b966ee7b3bdf600c97ecf98a59abafff641 | wikidoc | Dibucaine | Dibucaine
# 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.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Dibucaine is a Local analgesic ointment that is FDA approved for the treatment of pain and itching due to hemorrhoids or other anorectal disorders, Sunburn, minor burns, minor cuts. Common adverse reactions include unusual warmth or flushing of skin, Contact dermatitis, Photosensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- temporarily relieves pain and itching due to:
- hemorrhoids or other anorectal disorders, sunburn, minor burns, minor cuts
- scrapes, Insect Bites, minor skin irritation
### Dosage
- if possible clean the affected area with mild soap and warm water and rinse thoroughly
- gently dry by patting or blotting with toilet tissue or a soft cloth before applying
- Adults and children 12 and over - apply externally to the affected area up to 3 to 4 times a day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dibucaine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dibucaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Children under 2 - 12 years of age - ask a doctor
- Infants under 2 years of age - DO NOT USE
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dibucaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dibucaine in pediatric patients.
# Contraindications
There is limited information regarding Dibucaine Contraindications in the drug label.
# Warnings
- For external use only.
- Allergy alert - certain persons san develop allergic reactions to ingredients in this product
- Do not use
- in or near the eyes
- do not get into the eyes
- in infants under 2 years of age
- in large quantities, particularly over raw surfaces or blistered areas
- do not put this product into rectum by using fingers or any mechanical device
- Stop use and ask a doctor if
- condition worsens, or does not improve within 7 days
- the symptom being treated does not subside or if redness, irritation, swelling, bleeding or other symptoms develop or increase
- If pregnant or breast feeding, as a health care professional before use
- Keep out of the reach of children. If swallowed, get medical help or contact a Poison Control Center right away
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding clinical trial experience of Dibucaine in the drug label.
## Postmarketing Experience
- unusual warmth or flushing of skin
- Contact dermatitis
- Photosensitivity
- Chest pain
- fast or irregular heartbeat
- tightness in the chest
- Hypersensitivity reaction
# Drug Interactions
There is limited information regarding Dibucaine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- If pregnant or breast feeding, as a health care professional before use
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dibucaine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dibucaine during labor and delivery.
### Nursing Mothers
- If pregnant or breast feeding, as a health care professional before use
### Pediatric Use
There is no FDA guidance on the use of Dibucaine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Dibucaine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Dibucaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dibucaine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dibucaine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dibucaine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dibucaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dibucaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- topical
### Monitoring
There is limited information regarding Monitoring of Dibucaine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Dibucaine in the drug label.
# Overdosage
- Keep out of the reach of children. If swallowed, get medical help or contact a Poison Control Center right away
# Pharmacology
## Mechanism of Action
There is limited information regarding Dibucaine Mechanism of Action in the drug label.
## Structure
- Active ingredients - Dibucaine 1%
- Inactive Ingredients - acetone sodium bisulfite, lanolin, light mineral oil, purified water, white petrolatum
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dibucaine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Dibucaine in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Dibucaine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Dibucaine in the drug label.
# How Supplied
There is limited information regarding Dibucaine How Supplied in the drug label.
## Storage
store at controlled room temperature 20 degrees to 25 degrees c
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
to secure child resistant cap; screw cap tightly. Then turn cap in opposite direction.
If clicking sound is not heard, repeat procedure.
- see crimp of tube for lot number and expiration date
# Precautions with Alcohol
- Alcohol-Dibucaine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DIBUCAINE®
# Look-Alike Drug Names
There is limited information regarding the look alike names.
# Drug Shortage Status
# Price | Dibucaine
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.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Dibucaine is a Local analgesic ointment that is FDA approved for the treatment of pain and itching due to hemorrhoids or other anorectal disorders, Sunburn, minor burns, minor cuts. Common adverse reactions include unusual warmth or flushing of skin, Contact dermatitis, Photosensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- temporarily relieves pain and itching due to:
- hemorrhoids or other anorectal disorders, sunburn, minor burns, minor cuts
- scrapes, Insect Bites, minor skin irritation
### Dosage
- if possible clean the affected area with mild soap and warm water and rinse thoroughly
- gently dry by patting or blotting with toilet tissue or a soft cloth before applying
- Adults and children 12 and over - apply externally to the affected area up to 3 to 4 times a day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dibucaine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dibucaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Children under 2 - 12 years of age - ask a doctor
- Infants under 2 years of age - DO NOT USE
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dibucaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dibucaine in pediatric patients.
# Contraindications
There is limited information regarding Dibucaine Contraindications in the drug label.
# Warnings
- For external use only.
- Allergy alert - certain persons san develop allergic reactions to ingredients in this product
- Do not use
- in or near the eyes
- do not get into the eyes
- in infants under 2 years of age
- in large quantities, particularly over raw surfaces or blistered areas
- do not put this product into rectum by using fingers or any mechanical device
- Stop use and ask a doctor if
- condition worsens, or does not improve within 7 days
- the symptom being treated does not subside or if redness, irritation, swelling, bleeding or other symptoms develop or increase
- If pregnant or breast feeding, as a health care professional before use
- Keep out of the reach of children. If swallowed, get medical help or contact a Poison Control Center right away
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding clinical trial experience of Dibucaine in the drug label.
## Postmarketing Experience
- unusual warmth or flushing of skin
- Contact dermatitis
- Photosensitivity
- Chest pain
- fast or irregular heartbeat
- tightness in the chest
- Hypersensitivity reaction
# Drug Interactions
There is limited information regarding Dibucaine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- If pregnant or breast feeding, as a health care professional before use
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dibucaine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dibucaine during labor and delivery.
### Nursing Mothers
- If pregnant or breast feeding, as a health care professional before use
### Pediatric Use
There is no FDA guidance on the use of Dibucaine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Dibucaine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Dibucaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dibucaine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dibucaine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dibucaine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dibucaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dibucaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- topical
### Monitoring
There is limited information regarding Monitoring of Dibucaine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Dibucaine in the drug label.
# Overdosage
- Keep out of the reach of children. If swallowed, get medical help or contact a Poison Control Center right away
# Pharmacology
## Mechanism of Action
There is limited information regarding Dibucaine Mechanism of Action in the drug label.
## Structure
- Active ingredients - Dibucaine 1%
- Inactive Ingredients - acetone sodium bisulfite, lanolin, light mineral oil, purified water, white petrolatum
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Dibucaine in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Dibucaine in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Dibucaine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Dibucaine in the drug label.
# How Supplied
There is limited information regarding Dibucaine How Supplied in the drug label.
## Storage
store at controlled room temperature 20 degrees to 25 degrees c
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
to secure child resistant cap; screw cap tightly. Then turn cap in opposite direction.
If clicking sound is not heard, repeat procedure.
- see crimp of tube for lot number and expiration date
# Precautions with Alcohol
- Alcohol-Dibucaine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DIBUCAINE®[1]
# Look-Alike Drug Names
There is limited information regarding the look alike names.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Dibucaine | |
24ebd13a8978ccff1bbdf304c41557d706f8ae89 | wikidoc | Dichogamy | Dichogamy
# Overview
Dichogamy is the separation in time of gender expression in a hermaphroditic organism, a characteristic of some fishes, gastropods, and most flowering plants.
# In flowering plants
In the context of the flowering plants (angiosperms), there are two forms of dichogamy: protogyny—female function precedes male function—and protandry—male function precedes female function.
Historically, dichogamy has been regarded as a mechanism for reducing inbreeding (e.g., Darwin, 1862). However, a survey of the angiosperms found that self-incompatible (SI) plants, which are incapable of inbreeding, were as likely to be dichogamous as were self-compatible (SC) plants (Bertin, 1993). This finding led to a reinterpretation of dichogamy as a more general mechanism for reducing the impact of pollen-pistil interference on pollen import and export (reviewed in Lloyd & Webb, 1986; Barrett, 2002). Unlike the inbreeding-avoidance hypothesis, which focused on female function, this interference-avoidance hypothesis considers both gender functions.
In many hermaphroditic species, the close physical proximity of anthers and stigma makes interference unavoidable, either within a flower or between flowers on an inflorescence. Within-flower interference, which occurs when either the pistil interrupts pollen removal or the anthers prevent pollen deposition, can result in autonomous or facilitated self-pollination (Lloyd & Webb, 1986; Lloyd & Schoen, 1992). Between-flower interference results from similar mechanisms, except that the interfering structures occur on different flowers within the same inflorescence and it requires pollinator activity. This results in geitonogamous pollination, the transfer of pollen between flowers of the same individual (Lloyd & Schoen, 1992; de Jong et al., 1993). In contrast to within-flower interference, geitonogamy necessarily involves the same processes as outcrossing: pollinator attraction, reward provisioning, and pollen removal. Therefore, between-flower interference not only carries the cost of self-fertilization (inbreeding depression; Charlesworth & Charlesworth, 1987; Husband & Schemske, 1996), but also reduces the amount of pollen available for export (so-called "pollen discounting"; Harder & Wilson, 1998]). Because pollen discounting diminishes outcross siring success, interference avoidance may be an important evolutionary force in floral biology (Harder & Barrett, 1995, 1996; Harder & Wilson, 1998; Barrett, 2002).
Dichogamy may reduce between-flower interference by minimizing the temporal overlap between stigma and anthers within an inflorescence. Large inflorescences attract more pollinators, potentially enhancing reproductive success by increasing pollen import and export (Schemske, 1980; Queller, 1983; Bell, 1985; Geber, 1985; Schmid-Hempel & Speiser, 1988; Klinkhamer & de Jong, 1990). However, large inflorescences also increase the opportunities for both geitonogamy and pollen discounting, so that the opportunity for between-flower interference increases with inflorescence size (Harder & Barrett, 1996). Consequently, the evolution of floral display size may represent a compromise between maximizing pollinator visitation and minimizing geitonogamy and pollen discounting (Klinkhamer & de Jong, 1993; Barrett et al, 1994; Holsinger, 1996; Snow et al., 1996).
Protandry may be particularly relevant to this compromise, because it often results in an inflorescence structure with female phase flowers positioned below male phase flowers (Bertin & Newman, 1993). Given the tendency of many insect pollinators to forage upwards through inflorescences (Galen & Plowright, 1988), protandry may enhance pollen export by reducing between-flower interference (Darwin, 1862; Harder et al, 2000). Furthermore, this enhanced pollen export should increase as floral display size increases, because between-flower interference should increase with floral display size. These effects of protandry on between-flower interference may decouple the benefits of large inflorescences from the consequences of geitonogamy and pollen discounting. Such a decoupling would provide a significant reproductive advantage through increased pollinator visitation and siring success.
Harder et al. (2000) demonstrated experimentally that dichogamy both reduced rates of self-fertilization and enhanced outcross siring success through reductions in geitonogamy and pollen discounting, respectively. Routley & Husband (2003)examined the influence of inflorescence size on this siring advantage and found a bimodal distribution with increased siring success with both small and large display sizes. | Dichogamy
# Overview
Dichogamy is the separation in time of gender expression in a hermaphroditic organism, a characteristic of some fishes, gastropods, and most flowering plants.
# In flowering plants
In the context of the flowering plants (angiosperms), there are two forms of dichogamy: protogyny—female function precedes male function—and protandry—male function precedes female function.
Historically, dichogamy has been regarded as a mechanism for reducing inbreeding (e.g., Darwin, 1862). However, a survey of the angiosperms found that self-incompatible (SI) plants, which are incapable of inbreeding, were as likely to be dichogamous as were self-compatible (SC) plants (Bertin, 1993). This finding led to a reinterpretation of dichogamy as a more general mechanism for reducing the impact of pollen-pistil interference on pollen import and export (reviewed in Lloyd & Webb, 1986; Barrett, 2002). Unlike the inbreeding-avoidance hypothesis, which focused on female function, this interference-avoidance hypothesis considers both gender functions.
In many hermaphroditic species, the close physical proximity of anthers and stigma makes interference unavoidable, either within a flower or between flowers on an inflorescence. Within-flower interference, which occurs when either the pistil interrupts pollen removal or the anthers prevent pollen deposition, can result in autonomous or facilitated self-pollination (Lloyd & Webb, 1986; Lloyd & Schoen, 1992). Between-flower interference results from similar mechanisms, except that the interfering structures occur on different flowers within the same inflorescence and it requires pollinator activity. This results in geitonogamous pollination, the transfer of pollen between flowers of the same individual (Lloyd & Schoen, 1992; de Jong et al., 1993). In contrast to within-flower interference, geitonogamy necessarily involves the same processes as outcrossing: pollinator attraction, reward provisioning, and pollen removal. Therefore, between-flower interference not only carries the cost of self-fertilization (inbreeding depression; Charlesworth & Charlesworth, 1987; Husband & Schemske, 1996), but also reduces the amount of pollen available for export (so-called "pollen discounting"; Harder & Wilson, 1998]). Because pollen discounting diminishes outcross siring success, interference avoidance may be an important evolutionary force in floral biology (Harder & Barrett, 1995, 1996; Harder & Wilson, 1998; Barrett, 2002).
Dichogamy may reduce between-flower interference by minimizing the temporal overlap between stigma and anthers within an inflorescence. Large inflorescences attract more pollinators, potentially enhancing reproductive success by increasing pollen import and export (Schemske, 1980; Queller, 1983; Bell, 1985; Geber, 1985; Schmid-Hempel & Speiser, 1988; Klinkhamer & de Jong, 1990). However, large inflorescences also increase the opportunities for both geitonogamy and pollen discounting, so that the opportunity for between-flower interference increases with inflorescence size (Harder & Barrett, 1996). Consequently, the evolution of floral display size may represent a compromise between maximizing pollinator visitation and minimizing geitonogamy and pollen discounting (Klinkhamer & de Jong, 1993; Barrett et al, 1994; Holsinger, 1996; Snow et al., 1996).
Protandry may be particularly relevant to this compromise, because it often results in an inflorescence structure with female phase flowers positioned below male phase flowers (Bertin & Newman, 1993). Given the tendency of many insect pollinators to forage upwards through inflorescences (Galen & Plowright, 1988), protandry may enhance pollen export by reducing between-flower interference (Darwin, 1862; Harder et al, 2000). Furthermore, this enhanced pollen export should increase as floral display size increases, because between-flower interference should increase with floral display size. These effects of protandry on between-flower interference may decouple the benefits of large inflorescences from the consequences of geitonogamy and pollen discounting. Such a decoupling would provide a significant reproductive advantage through increased pollinator visitation and siring success.
Harder et al. (2000) demonstrated experimentally that dichogamy both reduced rates of self-fertilization and enhanced outcross siring success through reductions in geitonogamy and pollen discounting, respectively. Routley & Husband (2003)examined the influence of inflorescence size on this siring advantage and found a bimodal distribution with increased siring success with both small and large display sizes. | https://www.wikidoc.org/index.php/Dichogamy | |
b6f1402302f77f18052ad58ff76e33be7df9afba | wikidoc | Dicumarol | Dicumarol
# Overview
Dicoumarol (INN) or dicumarol (USAN) is a naturally occurring anticoagulant that functions as a functional vitamin K depleter (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases.
Dicoumarol is a natural chemical substance of combined plant and fungal origin. It is a derivative of coumarin, a bitter tasting but sweet-smelling substance made by plants that does not itself affect coagulation, but which is (classically) transformed in mouldy feeds or silages by a number of species of fungi, into active dicoumarol. Dicoumarol does affect coagulation, and was discovered in mouldy wet sweet-clover hay, as the cause of a naturally occurring bleeding disease in cattle. See warfarin for a more detailed discovery history.
Identified in 1940, dicoumarol became the prototype of the 4-hydroxycoumarin derivative anticoagulant drug class. Dicoumarol itself, for a short time, was employed as a medicinal anticoagulant drug, but since the mid-1950s has been replaced by its simpler derivative warfarin, and other 4-hydroxycoumarin drugs.
It is given orally, and it acts within two days.
# Mechanism of Action
Like all 4-hydroxycoumarin drugs it is a competitive inhibitor of vitamin K epoxide reductase, an enzyme that recycles vitamin K, thus causing depletion of active vitamin K in blood. This prevents the formation of the active form of prothrombin and several other coagulant enzymes.
These compounds are not direct antagonists (in the pharmaceutical sense) of vitamin K itself, but rather act to deplete reduced vitamin K in tissues. For this reason vitamin K antagonizes their effect (rather than the reverse), and this has led to the loose terminology of vitamin K antagonism.
Administration of vitamin K is therefore the antidote for dicoumarol toxicity. The action and toxicity of the drug and the antidote effectiveness are measured with the prothrombin time (PT) blood test.
# Uses
Dicoumarol was used along with heparin, for the treatment of deep venous thrombosis. Unlike heparin, this class of drugs may be used for months or years.
# Poisoning
Overdose results in serious, sometimes fatal uncontrolled hemorrhage. | Dicumarol
For patient information, click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dicoumarol (INN) or dicumarol (USAN) is a naturally occurring anticoagulant that functions as a functional vitamin K depleter (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases.
Dicoumarol is a natural chemical substance of combined plant and fungal origin. It is a derivative of coumarin, a bitter tasting but sweet-smelling substance made by plants that does not itself affect coagulation, but which is (classically) transformed in mouldy feeds or silages by a number of species of fungi, into active dicoumarol. Dicoumarol does affect coagulation, and was discovered in mouldy wet sweet-clover hay, as the cause of a naturally occurring bleeding disease in cattle.[1] See warfarin for a more detailed discovery history.
Identified in 1940, dicoumarol became the prototype of the 4-hydroxycoumarin derivative anticoagulant drug class. Dicoumarol itself, for a short time, was employed as a medicinal anticoagulant drug, but since the mid-1950s has been replaced by its simpler derivative warfarin, and other 4-hydroxycoumarin drugs.
It is given orally, and it acts within two days.
# Mechanism of Action
Like all 4-hydroxycoumarin drugs it is a competitive inhibitor of vitamin K epoxide reductase, an enzyme that recycles vitamin K, thus causing depletion of active vitamin K in blood. This prevents the formation of the active form of prothrombin and several other coagulant enzymes.
These compounds are not direct antagonists (in the pharmaceutical sense) of vitamin K itself, but rather act to deplete reduced vitamin K in tissues. For this reason vitamin K antagonizes their effect (rather than the reverse), and this has led to the loose terminology of vitamin K antagonism.
Administration of vitamin K is therefore the antidote for dicoumarol toxicity. The action and toxicity of the drug and the antidote effectiveness are measured with the prothrombin time (PT) blood test.
# Uses
Dicoumarol was used along with heparin, for the treatment of deep venous thrombosis. Unlike heparin, this class of drugs may be used for months or years.
# Poisoning
Overdose results in serious, sometimes fatal uncontrolled hemorrhage. | https://www.wikidoc.org/index.php/Dicoumarol | |
bf5252c7a5badf223d3a0778c4da4d78a35b5b15 | wikidoc | Dictamnus | Dictamnus
Dictamnus is a genus of flowering plant in the family Rutaceae, with a single species, Dictamnus albus. It is known variously as Burning-bush, False Dittany, White Dittany, and Gas-plant. It is a perennial herb, native to southern Europe, north Africa and southern and central Asia.
# Description
This plant grows about 60 cm high. Its flowers form a loose pyramidal spike and vary in colour from pale purple to white. It normally grows in woods in warm places. It is a popular garden plant both for its flowers and for its fragrance. It bears large elegant flowers of various colours: red, white, striped or blue. Its leaves resemble those of an Ash tree. Outside its natural range it is planted in gardens and grows well in warm places. It can also be found in sheltered places in woodlands.
In the summer months, the whole plant is covered with a kind of flammable substance, which is gluey to the touch, and has a very fragrant smell; but if it takes fire, it goes off with a flash all over the plant.
The name "Burning-bush" derives from the volatile oils produced by the plant, which can catch fire readily in hot weather, leading to comparisons with the burning bush of the Bible, including the suggestion that this is the plant involved there.
# Historical medical uses
Some use has been made of the plant (chiefly the powdered root) in herbalism. However, as the alternative name "False dittany" implies, it is unrelated to the Dittany found in Crete, which has a much more significant history of medicinal use. Like Dittany of Crete they were believed to be useful for cordial and cephalic ailments, to help resist poison and combat putrefaction, and to be useful in malignant and pestilential fevers. They were also used for cases of hysteria. While the volatile oil does have anti-inflammatory properties, it isn't used for such ailments today.
An infusion of the tops of the plant was also used as a pleasant and efficacious medicine in the gravel. It was believed to work powerfully by provoking urine and easing colicky pains which frequently accompany that disorder. The root was considered a sure remedy for epilepsies, and other diseases of the head, opening obstructions of the womb and procuring the discharges of the uterus. The plant is known to have emmenagogic properties, but the use of such plants to procure onset of menses is generally considered obsolete today.
# Modern medical uses
Today the plant is not used much, but has some modern uses. The plant is more commonly known today as the Burning Bush. It is the essential oil, which has a lemon-like smell, that is flammable. The herb is not much used these days, but is classified as a stomach tonic. A simple infusion of the leaves may be used as a substitute for tea and as a remedy for nervous complaints. The powdered root combined in equal parts with Peppermint has been administered in doses of 2 drams (4 g) for epilepsy.
# Edibility
The plant is inedible: the leaves have a bitter and unpalatable taste. Despite the lemon-like smell, the plant is acrid when eaten.
ca:Dictamnus
de:Diptam | Dictamnus
Dictamnus is a genus of flowering plant in the family Rutaceae, with a single species, Dictamnus albus. It is known variously as Burning-bush, False Dittany, White Dittany, and Gas-plant. It is a perennial herb, native to southern Europe, north Africa and southern and central Asia.
# Description
This plant grows about 60 cm high. Its flowers form a loose pyramidal spike and vary in colour from pale purple to white. It normally grows in woods in warm places. It is a popular garden plant both for its flowers and for its fragrance. It bears large elegant flowers of various colours: red, white, striped or blue. Its leaves resemble those of an Ash tree. Outside its natural range it is planted in gardens and grows well in warm places. It can also be found in sheltered places in woodlands.
In the summer months, the whole plant is covered with a kind of flammable substance, which is gluey to the touch, and has a very fragrant smell; but if it takes fire, it goes off with a flash all over the plant.
The name "Burning-bush" derives from the volatile oils produced by the plant, which can catch fire readily in hot weather, leading to comparisons with the burning bush of the Bible, including the suggestion that this is the plant involved there.
# Historical medical uses
Some use has been made of the plant (chiefly the powdered root) in herbalism. However, as the alternative name "False dittany" implies, it is unrelated to the Dittany found in Crete, which has a much more significant history of medicinal use. Like Dittany of Crete they were believed to be useful for cordial and cephalic ailments, to help resist poison and combat putrefaction, and to be useful in malignant and pestilential fevers. They were also used for cases of hysteria. While the volatile oil does have anti-inflammatory properties, it isn't used for such ailments today.
An infusion of the tops of the plant was also used as a pleasant and efficacious medicine in the gravel. It was believed to work powerfully by provoking urine and easing colicky pains which frequently accompany that disorder. The root was considered a sure remedy for epilepsies, and other diseases of the head, opening obstructions of the womb and procuring the discharges of the uterus. The plant is known to have emmenagogic properties, but the use of such plants to procure onset of menses is generally considered obsolete today.
# Modern medical uses
Today the plant is not used much, but has some modern uses. The plant is more commonly known today as the Burning Bush. It is the essential oil, which has a lemon-like smell, that is flammable. The herb is not much used these days, but is classified as a stomach tonic. A simple infusion of the leaves may be used as a substitute for tea and as a remedy for nervous complaints. The powdered root combined in equal parts with Peppermint has been administered in doses of 2 drams (4 g) for epilepsy.
# Edibility
The plant is inedible: the leaves have a bitter and unpalatable taste. Despite the lemon-like smell, the plant is acrid when eaten.
ca:Dictamnus
de:Diptam | https://www.wikidoc.org/index.php/Dictamnus | |
f17c945890ab6a59299f797183c4cdb093042864 | wikidoc | Dienogest | Dienogest
Dienogest is an orally active synthetic progesterone (or progestin). It is available for use as an oral contraceptive in combination with ethinylestradiol. It has antiandrogenic activity and as a result can improve androgenic symptoms. It is a non-ethinylated progestin which is structurally related to testosterone.
# History
Dienogest was discovered in 1979 in Jena, Germany and first named STS 557. It was found that its potency was 10 times that of levonorgestrel.The first product on the market to contain dienogest as a contraceptive pill Valette in 1995 made by Jenapharm. It has been little used outside of Germany.
# Indications
## Contraception
Dienogest is used primarily as a contraceptive in combination with ethinylestradiol. It is given as a tablet containing 2mg of dienogest and 30μg of ethinylestradiol.
# Pharmacodynamics
## Progestational Activity
Dienogest has moderate affinity for the progesterone receptor in human uterus tissue, in vitro, about 10% that of progesterone.
## Inhibition of Ovulation
The minimum effective dose of oral dienogest required to inhibit ovulation is 1 mg/day. The inhibition of ovulation by dienogest occurs mainly via peripheral action as opposed to central action on gonadotrophin secretion.
Oral treatment of dienogest 2mg/day in cyclical women reduced serum progesterone levels to anovulatory levels, however serum levels of lutenising hormone and follicle-stimulating hormone are not significantly altered.
# Adverse effects
Adverse effects associated with dienogest are the same as those expected of a progestogen. These include weight gain, increased blood pressure, breast tenderness and nausea. It produces no androgenic side effects and has little effect on metabolic and lipid haemostatic parameters. | Dienogest
Dienogest is an orally active synthetic progesterone (or progestin).[5] It is available for use as an oral contraceptive in combination with ethinylestradiol. It has antiandrogenic activity and as a result can improve androgenic symptoms.[2] It is a non-ethinylated progestin which is structurally related to testosterone.[6]
# History
Dienogest was discovered in 1979 in Jena, Germany and first named STS 557. It was found that its potency was 10 times that of levonorgestrel.[7]The first product on the market to contain dienogest as a contraceptive pill Valette in 1995 made by Jenapharm. It has been little used outside of Germany. [8]
# Indications
## Contraception
Dienogest is used primarily as a contraceptive in combination with ethinylestradiol. It is given as a tablet containing 2mg of dienogest and 30μg of ethinylestradiol.[9]
# Pharmacodynamics
## Progestational Activity
Dienogest has moderate affinity for the progesterone receptor in human uterus tissue, in vitro, about 10% that of progesterone.[10]
## Inhibition of Ovulation
The minimum effective dose of oral dienogest required to inhibit ovulation is 1 mg/day. [11] The inhibition of ovulation by dienogest occurs mainly via peripheral action as opposed to central action on gonadotrophin secretion.[2]
Oral treatment of dienogest 2mg/day in cyclical women reduced serum progesterone levels to anovulatory levels, however serum levels of lutenising hormone and follicle-stimulating hormone are not significantly altered.[11]
# Adverse effects
Adverse effects associated with dienogest are the same as those expected of a progestogen.[2] These include weight gain, increased blood pressure, breast tenderness and nausea.[12] It produces no androgenic side effects and has little effect on metabolic and lipid haemostatic parameters. | https://www.wikidoc.org/index.php/Dienogest | |
aef2634b256cfb9ba2c4291c55531f97537562d0 | wikidoc | Dietitian | Dietitian
A dietitian (sometimes spelled dietician) is an expert in food and nutrition. Dietitians help promote good health through proper eating. They also supervise the preparation and service of food, develop modified diets, participate in research, and educate individuals and groups on good nutritional habits. The goals of the dietary department are to obtain, prepare, and serve flavorsome, attractive, and nutritious food to patients, family members, and health care providers.
In the US nutrition professionals include the registered dietitian (RD) and the dietetic technician, registered (DTR). These terms, as well as simply dietitian, are legally protected terms regulated by the American Dietetic Association (ADA). Some RDs or DTRs call themselves nutritionists. However, the term nutritionist is not regulated, as dietitian is. Persons may call themselves nutritionists without the educational and professional requirements of registered dietitians. Dietetic technicians are not the same as dietitians in terms of responsibilities and qualifications. Different professional terms are used in other countries.
In the U.S., dietitians are registered with the Commission on Dietetic Registration (the certifying agency of the ADA) and are only able to use the label "Registered Dietitian" when they have met strict, specific educational and professional prerequisites and passed a national registration examination.
# Types of dietitians
The majority of dietitians are clinical, or therapeutic, dietitians. Clinical dietitians review medical charts and talk with patients' families. They work with other health care professionals and community groups to provide nourishment, nutritional programs and instructional presentations to benefit people of all ages, and with a variety of health conditions. This is accomplished by developing individual plans to meet nutritional needs. These plans include nourishment, tube feedings (called enteral nutrition), intravenous feedings (called parenteral nutrition) such as total parenteral nutrition (TPN) or peripheral parenteral nutrition (PPN), diets, and education. Clinical dietitians provide individual and group educational programs for patients and family members about their nutrition and health.
## Clinical dietitians
Clinical dietitians work in hospitals and other health care facilities to provide medical nutrition therapy to patients according to the disease processes, provide individual dietary consultations to patients and their family members and also conduct group educations for other health workers, patients and the public. They coordinate both medical records and nutritional needs to asess the patients and make a plan based on their findings.Some clinical dietitians have dual responsibilities with medical nutrition therapy and in foodservice, described below. In addition, clinical dietitians in smaller facilities will also provide or create outpatient education programs. They work as a team with the physicians, physical therapists, occupational therapists, pharmacists, speech therapists, social workers and nurses to provide care to the patients.
## Community dietitians
Community dietitians work with wellness programs and international health organizations. These dietitians apply and distribute knowledge about food and nutrition to specific life-styles and geographic areas. They coordinate nutritional programs in public health agencies, daycare centers, health clubs, and recreational camps and resorts. Some community dietitians carry out clinical based patient care in the form of home visits for patients who are too physically ill to attend consultation in health facilities.
## Foodservice dietitians
Foodservice dietitians or managers are responsible for large-scale food planning and service. They coordinate, assess and plan foodservice processes in health care facilities, school food service programs, prisons, cafeterias and restaurants. These dietitians will also perform audits of their departments, train other food service workers and use marketing skills to launch new menus and various programs within their institution. They direct and manage the operational and nutrition services staffs such as kitchen staffs, delivery staffs and dietary assistants or diet aides.
## Gerontological dietitians
Gerontological dietitians are specialist in nutrition and aging. They are Board certified in Gerontological Nutrition with the American Dietetic Association. They work in government agencies in aging policy, and in a regulatory capacity in the oversight of nursing homes and community-based care facilities. They work as Consultants in Nursing Homes, and in higher education in the field of Gerontology (the study of Aging.)
## Research dietitians
Research dietitians are mostly involved with dietary related research in the clinical aspect of nutrition in disease states, public aspect on primary, secondary and sometimes tertiary health prevention and foodservice aspect in issues involving the food prepared for patients. Many registered dietitians also work with the biochemical aspects of nutrient interaction within the body. Research Dietitians normally work in a hospital or university research facilities. It should be noted that some Clinical dietitian's roles also involve research other than the normal clinical workload. Quality improvement in dietetics services is also one area of research.
## Administrative dietitians
Administrative, or manager or Director of Dietetics Department or Nutrition Services are sometimes also known as Manager instead of Director depending on the size, number of dietitians in the department and also the organizational structure adopted by the Health facilities or Hospital. Director or Manager acts as head of the dietitians. They also hire, train, direct and supervise employees and manage dietary departments. Administrative dietitians may also apply procedure and policy as part of their management job.
## Business dietitians
Business dietitians serve as resource people for the media. Dietitians' expertise in nutrition is often taped for TV, radio, and newspapers -- either as an expert guest opinion, regular columnist or guest, or for resource, restaurant, or recipe development and critique. Dietitians have served as show hosts on major television stations and as drive-time radio news anchors. Dietitians write books, appear on television cooking channels, and author corporate newsletters on nutrition and wellness. They also work as sales representatives for food manufacturing companies that provide nutritional supplements and tube feeding supplies.
## Consultant dietitians
Consultant dietitians work under private practice. They contract independently to provide nutrition services and educational programs to individuals, nursing homes, and in health care facilities. As recent studies have shown the importance of diet in both preventing and managing disease, many US states have moved towards covering medical nutrition therapy under the Medicaid/Medicare making consulting a much more lucrative option for dietitians due to insurance reimbursement.
# Other nutrition workers
These designations apply principally to the US although the generic classifications are likely to be applicable elsewhere.
## Dietetic Technicians
Dietetic Technicians or diet tech are a registered and licensed support professional responsible for assisting and carry out medical nutrition therapy under the direct supervision of a registerd dietitian. Most are employed with hospitals or long term care facilities.
## Dietary assistants
Dietary assistants or dietary aides are responsible for assisting and carrying out the medical nutrition therapy prescribed by the Dietitians and to ensure that food for the patients as instructed by the Dietitians are carried out correctly by checking menus against recent diet orders before tray assembly begins and being physically present in the kitchen plating-lines at meal hours. Dietary aides in some countries might also carry out a simple initial health screening for newly admitted patients and only inform the Dietitians if any screened patients requires a dietitian's expertise for further assessments or interventions.
## Dietary clerks
Dietary clerks perform clerical tasks such as entry and maintenance of dietary requirements to a database. They also track financial information, such as the number of meals served each day.
## Dietary managers
Dietary managers are responsible for retail, catering and tray lines. If an operation is large, there may be one or more managers to help in directing the dietary workers.
## Dietary workers
Dietary workers prepare the food and meal trays in the kitchen. They check for accuracy and completeness. They also maintain the storage area for food supplies and ensure practice of sanitary procedures. Dietary workers are trained on the job and can work in any commercial kitchen.
## Dietary hosts
Dietary hosts or hostesses deliver and bring back the meal trays to patients. They distribute and collect menus and help the patients to make complete selections.
## USA
A dietitian's education in health science involves significant scientific based knowledge in anatomy, chemistry, biochemistry, biology, physiology, nutrition, medical science. It is these strong foundations in advanced scientific knowledge and a internship that equipped with counseling skills and aspects of psychology enable a Registered Dietitian to assess, analyze, intervene, and educate a patient in relation to the diet and disease.
It can be said that in an interdisciplinary team (consisting of the physician, dietitian, speech therapist, physiotherapist, occupational therapist, social worker, and nurses), the physician and the dietitian are the two health professionals with the most well-rounded knowledge on human biochemistry and physiology.
There are a few different academic routes to becoming a fully qualified registrable dietitian:
- A professional bachelor degree in Dietetics which requires four years of studies
-r
- A bachelor of science degree and a postgraduate diploma in Dietetics
-r
- A bachelor of science degree and a master's degree in Dietetics
Besides academic education, registered dietitians must complete up to a year long dietetic internship of at least 900 hours through and accredited program before they can sit for the registration examination. The dietetic internship requires the intern to complete several areas of competency including rotations in clinical, community, long-term care nutrition as well as food service, public health and a variety of other worksites.
Once the degree is earned, the internship completed, and registration examination passed, the individual can now use the nationally recognized legal term, Registered Dietitian and is able to work in a variety of professional settings. Most states require additional licensure to work in most settings. To maintain, the RD credential, professionals must participate in and earn continuing education units 75 hours every 5 years.
# Professional associations
## USA & Canada
In the United States and Canada, the Dietitian, Registered Dietitian (RD), etc. are similarly protected titles. The professional association in Canada is the Dietitians of Canada. The US equivalent of it is The American Dietetic Association.
# Australia
In Australia, the qualified dietitian is called Accredited Practising Dietitian (APD) | Dietitian
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A dietitian (sometimes spelled dietician) is an expert in food and nutrition. Dietitians help promote good health through proper eating. They also supervise the preparation and service of food, develop modified diets, participate in research, and educate individuals and groups on good nutritional habits. The goals of the dietary department are to obtain, prepare, and serve flavorsome, attractive, and nutritious food to patients, family members, and health care providers.
In the US nutrition professionals include the registered dietitian (RD) and the dietetic technician, registered (DTR). These terms, as well as simply dietitian, are legally protected terms regulated by the American Dietetic Association (ADA). Some RDs or DTRs call themselves nutritionists. However, the term nutritionist is not regulated, as dietitian is. Persons may call themselves nutritionists without the educational and professional requirements of registered dietitians. Dietetic technicians are not the same as dietitians in terms of responsibilities and qualifications. Different professional terms are used in other countries.
In the U.S., dietitians are registered with the Commission on Dietetic Registration (the certifying agency of the ADA) and are only able to use the label "Registered Dietitian" when they have met strict, specific educational and professional prerequisites and passed a national registration examination.
# Types of dietitians
The majority of dietitians are clinical, or therapeutic, dietitians. Clinical dietitians review medical charts and talk with patients' families. They work with other health care professionals and community groups to provide nourishment, nutritional programs and instructional presentations to benefit people of all ages, and with a variety of health conditions. This is accomplished by developing individual plans to meet nutritional needs. These plans include nourishment, tube feedings (called enteral nutrition), intravenous feedings (called parenteral nutrition) such as total parenteral nutrition (TPN) or peripheral parenteral nutrition (PPN), diets, and education. Clinical dietitians provide individual and group educational programs for patients and family members about their nutrition and health.
## Clinical dietitians
Clinical dietitians work in hospitals and other health care facilities to provide medical nutrition therapy to patients according to the disease processes, provide individual dietary consultations to patients and their family members and also conduct group educations for other health workers, patients and the public. They coordinate both medical records and nutritional needs to asess the patients and make a plan based on their findings.Some clinical dietitians have dual responsibilities with medical nutrition therapy and in foodservice, described below. In addition, clinical dietitians in smaller facilities will also provide or create outpatient education programs. They work as a team with the physicians, physical therapists, occupational therapists, pharmacists, speech therapists, social workers and nurses to provide care to the patients.
## Community dietitians
Community dietitians work with wellness programs and international health organizations. These dietitians apply and distribute knowledge about food and nutrition to specific life-styles and geographic areas. They coordinate nutritional programs in public health agencies, daycare centers, health clubs, and recreational camps and resorts. Some community dietitians carry out clinical based patient care in the form of home visits for patients who are too physically ill to attend consultation in health facilities.
## Foodservice dietitians
Foodservice dietitians or managers are responsible for large-scale food planning and service. They coordinate, assess and plan foodservice processes in health care facilities, school food service programs, prisons, cafeterias and restaurants. These dietitians will also perform audits of their departments, train other food service workers and use marketing skills to launch new menus and various programs within their institution. They direct and manage the operational and nutrition services staffs such as kitchen staffs, delivery staffs and dietary assistants or diet aides.
## Gerontological dietitians
Gerontological dietitians are specialist in nutrition and aging. They are Board certified in Gerontological Nutrition with the American Dietetic Association. They work in government agencies in aging policy, and in a regulatory capacity in the oversight of nursing homes and community-based care facilities. They work as Consultants in Nursing Homes, and in higher education in the field of Gerontology (the study of Aging.)
## Research dietitians
Research dietitians are mostly involved with dietary related research in the clinical aspect of nutrition in disease states, public aspect on primary, secondary and sometimes tertiary health prevention and foodservice aspect in issues involving the food prepared for patients. Many registered dietitians also work with the biochemical aspects of nutrient interaction within the body. Research Dietitians normally work in a hospital or university research facilities. It should be noted that some Clinical dietitian's roles also involve research other than the normal clinical workload. Quality improvement in dietetics services is also one area of research.
## Administrative dietitians
Administrative, or manager or Director of Dietetics Department or Nutrition Services are sometimes also known as Manager instead of Director depending on the size, number of dietitians in the department and also the organizational structure adopted by the Health facilities or Hospital. Director or Manager acts as head of the dietitians. They also hire, train, direct and supervise employees and manage dietary departments. Administrative dietitians may also apply procedure and policy as part of their management job.
## Business dietitians
Business dietitians serve as resource people for the media. Dietitians' expertise in nutrition is often taped for TV, radio, and newspapers -- either as an expert guest opinion, regular columnist or guest, or for resource, restaurant, or recipe development and critique. Dietitians have served as show hosts on major television stations and as drive-time radio news anchors. Dietitians write books, appear on television cooking channels, and author corporate newsletters on nutrition and wellness. They also work as sales representatives for food manufacturing companies that provide nutritional supplements and tube feeding supplies.
## Consultant dietitians
Consultant dietitians work under private practice. They contract independently to provide nutrition services and educational programs to individuals, nursing homes, and in health care facilities. As recent studies have shown the importance of diet in both preventing and managing disease, many US states have moved towards covering medical nutrition therapy under the Medicaid/Medicare making consulting a much more lucrative option for dietitians due to insurance reimbursement.
# Other nutrition workers
These designations apply principally to the US although the generic classifications are likely to be applicable elsewhere.
## Dietetic Technicians
Dietetic Technicians or diet tech are a registered and licensed support professional responsible for assisting and carry out medical nutrition therapy under the direct supervision of a registerd dietitian. Most are employed with hospitals or long term care facilities.
## Dietary assistants
Dietary assistants or dietary aides are responsible for assisting and carrying out the medical nutrition therapy prescribed by the Dietitians and to ensure that food for the patients as instructed by the Dietitians are carried out correctly by checking menus against recent diet orders before tray assembly begins and being physically present in the kitchen plating-lines at meal hours. Dietary aides in some countries might also carry out a simple initial health screening for newly admitted patients and only inform the Dietitians if any screened patients requires a dietitian's expertise for further assessments or interventions.
## Dietary clerks
Dietary clerks perform clerical tasks such as entry and maintenance of dietary requirements to a database. They also track financial information, such as the number of meals served each day.
## Dietary managers
Dietary managers are responsible for retail, catering and tray lines. If an operation is large, there may be one or more managers to help in directing the dietary workers.
## Dietary workers
Dietary workers prepare the food and meal trays in the kitchen. They check for accuracy and completeness. They also maintain the storage area for food supplies and ensure practice of sanitary procedures. Dietary workers are trained on the job and can work in any commercial kitchen.
## Dietary hosts
Dietary hosts or hostesses deliver and bring back the meal trays to patients. They distribute and collect menus and help the patients to make complete selections.
## USA
A dietitian's education in health science involves significant scientific based knowledge in anatomy, chemistry, biochemistry, biology, physiology, nutrition, medical science. It is these strong foundations in advanced scientific knowledge and a internship that equipped with counseling skills and aspects of psychology enable a Registered Dietitian to assess, analyze, intervene, and educate a patient in relation to the diet and disease.
It can be said that in an interdisciplinary team (consisting of the physician, dietitian, speech therapist, physiotherapist, occupational therapist, social worker, and nurses), the physician and the dietitian are the two health professionals with the most well-rounded knowledge on human biochemistry and physiology.
There are a few different academic routes to becoming a fully qualified registrable dietitian:
- A professional bachelor degree in Dietetics which requires four years of studies
or
- A bachelor of science degree and a postgraduate diploma in Dietetics
or
- A bachelor of science degree and a master's degree in Dietetics
Besides academic education, registered dietitians must complete up to a year long dietetic internship of at least 900 hours through and accredited program before they can sit for the registration examination. The dietetic internship requires the intern to complete several areas of competency including rotations in clinical, community, long-term care nutrition as well as food service, public health and a variety of other worksites.
Once the degree is earned, the internship completed, and registration examination passed, the individual can now use the nationally recognized legal term, Registered Dietitian and is able to work in a variety of professional settings. Most states require additional licensure to work in most settings. To maintain, the RD credential, professionals must participate in and earn continuing education units 75 hours every 5 years.
# Professional associations
## USA & Canada
In the United States and Canada, the Dietitian, Registered Dietitian (RD), etc. are similarly protected titles. The professional association in Canada is the Dietitians of Canada. The US equivalent of it is The American Dietetic Association.
# Australia
In Australia, the qualified dietitian is called Accredited Practising Dietitian (APD)
# External links
- Ask the Dietitian
- International Confederation of Dietetic Associations
- The American Dietetic Association
- The British Dietetic Association
- Dietitians Association of Australia
- List of articles on "nutritionist" at Quackwatch, demonstrating the unregulated use of the word
it:Dietetica
no:Klinisk ernæringsfysiolog
fi:Ravitsemusterapeutti
sv:Dietist
Template:Jb1
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dietetics | |
e1c7553eb6a6dcb107d415b34d1d4889fa69799a | wikidoc | Difenoxin | Difenoxin
# Overview
Difenoxin (Motofen, R-15403) is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine) and more distantly related to alphaprodine and piritramide, and it is an active metabolite of the anti-diarrhoea drug diphenoxylate. Difenoxin et al. have a high peripheral/central actions ratio, working primarily on various opioid receptors in the intestines. Difenoxin was developed in 1970 in Belgium at Janssen Pharmaceutica.
# Related compounds
Loperamide (Imodium) is also closely related to difenoxin in chemical structure but does not cross the blood–brain barrier as does difenoxin, and the combination drug diphenoxylate hydrochloride with atropine sulfate (Lomotil) is the prototype of this four-member subfamily of the synthetic opioid receptor agonists and sub-category of opioid anti-diarrhoeals. Pethidine was serendipitously discovered in research during the 1930s on gastrointestinal drugs to serve as alternatives to belladonna and opium derivatives, but the anti-diarrhoeal effects of pethidine are less than those of this subclass and equivalent constipating doses of pethidine have prominent central actions. Therefore, with difenoxin and related drugs, the ratio of GI effects to central narcotic effects is particularly high, which makes it an attractive alternative in the minds of many to the other opioids used for diarrhoea, viz. codeine, morphine, dihydrocodeine, paregoric, laudanum and opium . The parent of the three above-mentioned pethidine-related anti-diarrhoeals is diphenoxylic acid, which can also be manufactured and used pharmaceutically.
# Legal status
Difenoxin is a Schedule I drug by itself (Lyspafen) in the USA. It has been approved for use in the late 1990s in the form of Motofen (difenoxin HCl and atropine tablets and elixir) which like Lomotil is a less-restrictive category Schedule IV on account of the adulterant; one difference is that the diphenoxylate and atropine formulation is Schedule V. Atropine is present in each dosage unit in the amount of 25 µg, or 1/40 of the therapeutic dose. Many other countries have been using this combination product for many years as a second-line centrally-acting and/or opioid-agonist anti-diarrhoeal, betwixt loperamide and paregoric. The combination of difenoxin and atropine, in Schedule IV, has the DEA ACSCN of 9167 and being in Schedule IV is not assigned an aggregate annual manufacturing quota. Pure difenoxin, in Schedule I, has a quota of 50 grammes, and an ACSCN of 9168.
# Side effects
Diarrhoea resulting from cyclic or diarrhoea-predominant IBS may not be optimally treated with diphenoxylate or difenoxin, and may not respond to a meaningful degree to loperamide; thus, diarrhoea and cramping which does not respond to belladonna derivatives and non-centrally-acting soothing and/or stool-desiccating agents are often treated with conservative doses of codeine, especially where paregoric and/or laudanum are not currently in general use.
Difenoxin also has some sedative and analgesic effects as with other opioids, but diphenoxylate itself is a relatively weak analgesic, and difenoxin has similarly limited analgesic effects, although it is a potent anti-diarrheal drug. Research suggests that additional non-opioid mechanisms may also be involved in the action of difenoxin, explaining its strong anti-diarrheal effects despite only limited opioid action. | Difenoxin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Difenoxin (Motofen, R-15403) is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine) and more distantly related to alphaprodine and piritramide, and it is an active metabolite of the anti-diarrhoea drug diphenoxylate. Difenoxin et al. have a high peripheral/central actions ratio, working primarily on various opioid receptors in the intestines.[1] Difenoxin was developed in 1970 in Belgium at Janssen Pharmaceutica.
# Related compounds
Loperamide (Imodium) is also closely related to difenoxin in chemical structure but does not cross the blood–brain barrier as does difenoxin, and the combination drug diphenoxylate hydrochloride with atropine sulfate (Lomotil) is the prototype of this four-member subfamily of the synthetic opioid receptor agonists and sub-category of opioid anti-diarrhoeals. Pethidine was serendipitously discovered in research during the 1930s on gastrointestinal drugs to serve as alternatives to belladonna and opium derivatives, but the anti-diarrhoeal effects of pethidine are less than those of this subclass and equivalent constipating doses of pethidine have prominent central actions. Therefore, with difenoxin and related drugs, the ratio of GI effects to central narcotic effects is particularly high, which makes it an attractive alternative in the minds of many to the other opioids used for diarrhoea, viz. codeine, morphine, dihydrocodeine, paregoric, laudanum and opium . The parent of the three above-mentioned pethidine-related anti-diarrhoeals is diphenoxylic acid, which can also be manufactured and used pharmaceutically.
# Legal status
Difenoxin is a Schedule I drug by itself (Lyspafen) in the USA.[2] It has been approved for use in the late 1990s in the form of Motofen (difenoxin HCl and atropine tablets and elixir) which like Lomotil is a less-restrictive category Schedule IV on account of the adulterant; one difference is that the diphenoxylate and atropine formulation is Schedule V. Atropine is present in each dosage unit in the amount of 25 µg, or 1/40 of the therapeutic dose. Many other countries have been using this combination product for many years as a second-line centrally-acting and/or opioid-agonist anti-diarrhoeal, betwixt loperamide and paregoric.[3] The combination of difenoxin and atropine, in Schedule IV, has the DEA ACSCN of 9167 and being in Schedule IV is not assigned an aggregate annual manufacturing quota. Pure difenoxin, in Schedule I, has a quota of 50 grammes, and an ACSCN of 9168.
# Side effects
Diarrhoea resulting from cyclic or diarrhoea-predominant IBS may not be optimally treated with diphenoxylate or difenoxin, and may not respond to a meaningful degree to loperamide; thus, diarrhoea and cramping which does not respond to belladonna derivatives and non-centrally-acting soothing and/or stool-desiccating agents are often treated with conservative doses of codeine, especially where paregoric and/or laudanum are not currently in general use.
Difenoxin also has some sedative and analgesic effects as with other opioids, but diphenoxylate itself is a relatively weak analgesic, and difenoxin has similarly limited analgesic effects, although it is a potent anti-diarrheal drug. Research suggests that additional non-opioid mechanisms may also be involved in the action of difenoxin, explaining its strong anti-diarrheal effects despite only limited opioid action.[4] | https://www.wikidoc.org/index.php/Difenoxin | |
ef1f40bca76f065a71b3216f5218b923d20c93c0 | wikidoc | Digitoxin | Digitoxin
# Overview
Digitoxin is a cardiac glycoside. It has similar structure and effects to digoxin (though the effects are longer-lasting). Unlike digoxin (which is eliminated from the body via the kidneys), it is eliminated via the liver, so could be used in patients with poor or erratic kidney function. However, it is now rarely used in current Western medical practice. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.
# Toxicity
Digitoxin exhibits similar toxic effects to the more commonly used digoxin, namely: anorexia, nausea, vomiting, diarrhea, confusion, visual disturbances, and cardiac arrhythmias. Antidigoxin antibody fragments, the specific treatment for digoxin poisoning, are also effective in serious digitoxin toxicity.
# History
The first description of the use of foxglove dates back to 1775. For quite some time, the active compound was not isolated. Oswald Schmiedeberg was able to obtain a pure sample in 1875. The modern therapeutic use of this molecule was made possible by the works of the pharmacist and the French chemist Claude-Adolphe Nativelle (1812-1889). The first structural analysis was done by Adolf Otto Reinhold Windaus in 1925, but the full structure with an exact determination of the sugar groups was not accomplished until 1962. | Digitoxin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Digitoxin is a cardiac glycoside. It has similar structure and effects to digoxin (though the effects are longer-lasting). Unlike digoxin (which is eliminated from the body via the kidneys), it is eliminated via the liver, so could be used in patients with poor or erratic kidney function. However, it is now rarely used in current Western medical practice. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.[1]
# Toxicity
Digitoxin exhibits similar toxic effects to the more commonly used digoxin, namely: anorexia, nausea, vomiting, diarrhea, confusion, visual disturbances, and cardiac arrhythmias. Antidigoxin antibody fragments, the specific treatment for digoxin poisoning, are also effective in serious digitoxin toxicity.[2]
# History
The first description of the use of foxglove dates back to 1775.[3] For quite some time, the active compound was not isolated. Oswald Schmiedeberg was able to obtain a pure sample in 1875. The modern therapeutic use of this molecule was made possible by the works of the pharmacist and the French chemist Claude-Adolphe Nativelle (1812-1889). The first structural analysis was done by Adolf Otto Reinhold Windaus in 1925, but the full structure with an exact determination of the sugar groups was not accomplished until 1962.[4][5] | https://www.wikidoc.org/index.php/Digitoxin | |
0640879afda13aa633f861f729a09642ed1e3ad2 | wikidoc | Dimension | Dimension
In mathematics the dimension of a space is roughly defined as the mimimum number of coordinates needed to specify every point within it. Dimensions can be thought of as the axes in a Cartesian coordinate system, which in a three-dimensional system run left-right, up-down and forward-backward. A set of three co-ordinates on these axes, or any other three-dimensional coordinate system, specifies the position of a particular point in space. In the physical world, according to the theory of relativity the fourth dimension is time, which runs before-after. An event’s position in space and time is therefore specified if four co-ordinates are given.
On surfaces such as a plane or the surface of a sphere, a point can be specified using just two numbers and so this space is said to be two-dimensional. Similarly a line is one-dimensional because only one co-ordinate is needed, whereas a point has no dimensions. In mathematics, spaces with more than three dimensions are used to describe other manifolds. In these n-dimensional spaces a point is located by n co-ordinates (x1, x2, … xn). Some theories, such as those used in fractal geometry, make use of non-integer and negative dimensions.
Another meaning of the term "dimension" in physics relates to the nature of a measurable quantity. In general, physical measurements that must be expressed in units of measurement, and quantities obtained by such measurements are dimensionful. An example of a dimension is length, abbreviated L, which is the dimension for measurements expressed in units of length, be they meters, nautical miles, or lightyears. Another example is time, abbreviated T, whether the measurement is expressed in seconds or in hours. Speed, which is the distance (length) travelled in a certain amount of time, is a dimensionful quantity that has the dimension LT −1 (meaning L/T). Acceleration, the change in speed per time unit, has dimension LT −2.
# In mathematics
In mathematics, no definition of dimension adequately captures the concept in all situations where we would like to make use of it. Consequently, mathematicians have devised numerous definitions of dimension for different types of spaces. All, however, are ultimately based on the concept of the dimension of Euclidean n-space E n. The point E 0 is 0-dimensional. The line E 1 is 1-dimensional. The plane E 2 is 2-dimensional. In general, E n is n-dimensional.
A tesseract is an example of a four-dimensional object.
Whereas outside of mathematics the use of the term "dimension" is as in: "A tesseract has four dimensions," mathematicians usually express this as: "The tesseract has dimension 4," or: "The dimension of the tesseract is 4."
Historically, the notion of higher dimensions in mathematics was introduced by Bernhard Riemann, in his 1854 Habilitationsschrift, where he considered a point to be any n numbers (x_1,\dots,x_n), abstractly, without any geometric picture needed nor implied.
The rest of this section examines some of the more important mathematical definitions of dimension.
## Hamel dimension
For vector spaces, there is a natural concept of dimension, namely the cardinality of a basis.
## Manifolds
A connected topological manifold is locally homeomorphic to Euclidean n-space, and the number n is called the manifold's dimension. One can show that this yields a uniquely defined dimension for every connected topological manifold.
The theory of manifolds, in the field of geometric topology, is characterized by the way dimensions 1 and 2 are relatively elementary, the high-dimensional cases n > 4 are simplified by having extra space in which to 'work'; and the cases n = 3 and 4 are in some senses the most difficult. This state of affairs was highly marked in the various cases of the Poincaré conjecture, where four different proof methods are applied.
## Lebesgue covering dimension
For any normal topological space X, the Lebesgue covering dimension of X is defined to be n if n is the smallest integer for which the following holds: any open cover has an open refinement (a second open cover where each element is a subset of an element in the first cover) such that no point is included in more than n + 1 elements. In this case we write dim X = n. For X a manifold, this coincides with the dimension mentioned above. If no such integer n exists, then the dimension of X is said to be infinite, and we write dim X = ∞. Note also that we say X has dimension -1, i.e. dim X = -1 if and only if X is empty.This definition of covering dimension can be extended from the class of normal spaces to all Tychonoff spaces merely by replacing the term "open" in the definition by the term "functionally open".
## Inductive dimension
The inductive dimension of a topological space may refer to the small inductive dimension or the large inductive dimension, and is based on the analogy that n+1-dimensional balls have n dimensional boundaries, permitting an inductive definition based on the dimension of the boundaries of open sets.
## Hausdorff dimension
For sets which are of a complicated structure, especially fractals, the Hausdorff dimension is useful. The Hausdorff dimension is defined for all metric spaces and, unlike the Hamel dimension, can also attain non-integer real values. The box dimension or Minkowski dimension is a variant of the same idea. In general, there exist more definitions of fractal dimensions that work for highly irregular sets and attain non-integer positive real values.
## Hilbert spaces
Every Hilbert space admits an orthonormal basis, and any two such bases for a particular space have the same cardinality. This cardinality is called the dimension of the Hilbert space. This dimension is finite if and only if the space's Hamel dimension is finite, and in this case the two dimensions coincide.
## Krull dimension of commutative rings
The Krull dimension of a commutative ring, named after Wolfgang Krull (1899–1971), is defined to be the maximal number of strict inclusions in an increasing chain of prime ideals in the ring.
## Negative dimension
The negative (fractal) dimension is introduced by Benoit Mandelbrot, in which, when it is positive gives the known definition, and when it is negative measures the degree of "emptiness" of empty sets.
# In physics
## Spatial dimensions
Classical physics theories describe three physical dimensions: from a particular point in space, the basic directions in which we can move are up/down, left/right, and forward/backward. Movement in any other direction can be expressed in terms of just these three. Moving down is the same as moving up a negative amount. Moving diagonally upward and forward is just as the name of the direction implies; i.e., moving in a linear combination of up and forward. In its simplest form: a line describes one dimension, a plane describes two dimensions, and a cube describes three dimensions. (See Space and Cartesian coordinate system.)
## Time
Time is often referred to as the "fourth dimension". It is one way to measure physical change. It is perceived differently from the three spatial dimensions in that there is only one of it, that movement in time occurs at the fixed rate of one second per second, and that we cannot move freely in time but subjectively move in one direction.
The equations used in physics to model reality do not treat time in the same way that humans perceive it. The equations of classical mechanics are symmetric with respect to time, and equations of quantum mechanics are typically symmetric if both time and other quantities (such as charge and parity) are reversed. In these models, the perception of time flowing in one direction is an artifact of the laws of thermodynamics (we perceive time as flowing in the direction of increasing entropy).
The best-known treatment of time as a dimension is Poincaré and Einstein's special relativity (and extended to general relativity), which treats perceived space and time as components of a four-dimensional manifold, known as spacetime, and in the special, flat case as Minkowski space.
## Additional dimensions
Theories such as string theory and M-theory predict that physical space in general has in fact 10 and 11 dimensions, respectively. The extra dimensions are spacelike. We perceive only three spatial dimensions, and no physical experiments have confirmed the reality of additional dimensions. A possible explanation that has been suggested is that space is as it were "curled up" in the extra dimensions on a very small, subatomic scale, possibly at the quark/string level of scale or below.
## Penrose's singularity theorem
In his book The Road to Reality: A Complete Guide to the Laws of the Universe, scientist Sir Roger Penrose explained his singularity theorem. It asserts that all theories that attribute more than three spatial dimensions and one temporal dimension to the world of experience are unstable. The instabilities that exist in systems of such extra dimensions would result in their rapid collapse into a singularity. For that reason, Penrose wrote, the unification of gravitation with other forces through extra dimensions cannot occur.
## Dimensionful quantities
In the physical sciences and in engineering, the dimension of a physical quantity is the expression of the class of physical unit that such a quantity is measured against. The dimension of speed, for example, is LT−1, that is, length divided by time. The units in which the quantity is expressed, such as ms−1 (meters per second) or mph (miles per hour), has to conform to the dimension.
# Science fiction
Science fiction texts often mention the concept of dimension, when really referring to parallel universes, alternate universes, or other planes of existence. This usage is derived from the idea that in order to travel to parallel/alternate universes/planes of existence one must travel in a spatial direction/dimension besides the standard ones. In effect, the other universes/planes are just a small distance away from our own, but the distance is in a fourth (or higher) spatial dimension, not the standard ones.
One of the most heralded science fiction novellas regarding true geometric dimensionality, and often recommended as a starting point for those just starting to investigate such matters, is the 1884 novel Flatland by Edwin A. Abbott. Isaac Asimov, in his foreword to the Signet Classics 1984 edition, described Flatland as "The best introduction one can find into the manner of perceiving dimensions."
# More dimensions
- Dimension of an algebraic variety
- Lebesgue covering dimension
- Isoperimetric dimension
- Poset dimension
- Metric dimension
- Pointwise dimension
- Lyapunov dimension
- Kaplan-Yorke dimension
- Exterior dimension
- Hurst exponent
- q-dimension; especially:
Information dimension (corresponding to q = 1)
Correlation dimension (corresponding to q = 2)
- Information dimension (corresponding to q = 1)
- Correlation dimension (corresponding to q = 2) | Dimension
In mathematics the dimension of a space is roughly defined as the mimimum number of coordinates needed to specify every point within it[1][2]. Dimensions can be thought of as the axes in a Cartesian coordinate system, which in a three-dimensional system run left-right, up-down and forward-backward. A set of three co-ordinates on these axes, or any other three-dimensional coordinate system, specifies the position of a particular point in space[3]. In the physical world, according to the theory of relativity the fourth dimension is time, which runs before-after. An event’s position in space and time is therefore specified if four co-ordinates are given.
On surfaces such as a plane or the surface of a sphere, a point can be specified using just two numbers and so this space is said to be two-dimensional. Similarly a line is one-dimensional because only one co-ordinate is needed, whereas a point has no dimensions. In mathematics, spaces with more than three dimensions are used to describe other manifolds. In these n-dimensional spaces a point is located by n co-ordinates (x1, x2, … xn). Some theories, such as those used in fractal geometry, make use of non-integer and negative dimensions.
Another meaning of the term "dimension" in physics relates to the nature of a measurable quantity. In general, physical measurements that must be expressed in units of measurement, and quantities obtained by such measurements are dimensionful. An example of a dimension is length, abbreviated L, which is the dimension for measurements expressed in units of length, be they meters, nautical miles, or lightyears. Another example is time, abbreviated T, whether the measurement is expressed in seconds or in hours. Speed, which is the distance (length) travelled in a certain amount of time, is a dimensionful quantity that has the dimension LT −1 (meaning L/T). Acceleration, the change in speed per time unit, has dimension LT −2.
# In mathematics
In mathematics, no definition of dimension adequately captures the concept in all situations where we would like to make use of it. Consequently, mathematicians have devised numerous definitions of dimension for different types of spaces. All, however, are ultimately based on the concept of the dimension of Euclidean n-space E n. The point E 0 is 0-dimensional. The line E 1 is 1-dimensional. The plane E 2 is 2-dimensional. In general, E n is n-dimensional.
A tesseract is an example of a four-dimensional object.
Whereas outside of mathematics the use of the term "dimension" is as in: "A tesseract has four dimensions," mathematicians usually express this as: "The tesseract has dimension 4," or: "The dimension of the tesseract is 4."
Historically, the notion of higher dimensions in mathematics was introduced by Bernhard Riemann, in his 1854 Habilitationsschrift, where he considered a point to be any n numbers <math>(x_1,\dots,x_n)</math>, abstractly, without any geometric picture needed nor implied.
The rest of this section examines some of the more important mathematical definitions of dimension.
## Hamel dimension
For vector spaces, there is a natural concept of dimension, namely the cardinality of a basis.
## Manifolds
A connected topological manifold is locally homeomorphic to Euclidean n-space, and the number n is called the manifold's dimension. One can show that this yields a uniquely defined dimension for every connected topological manifold.
The theory of manifolds, in the field of geometric topology, is characterized by the way dimensions 1 and 2 are relatively elementary, the high-dimensional cases n > 4 are simplified by having extra space in which to 'work'; and the cases n = 3 and 4 are in some senses the most difficult. This state of affairs was highly marked in the various cases of the Poincaré conjecture, where four different proof methods are applied.
## Lebesgue covering dimension
For any normal topological space X, the Lebesgue covering dimension of X is defined to be n if n is the smallest integer for which the following holds: any open cover has an open refinement (a second open cover where each element is a subset of an element in the first cover) such that no point is included in more than n + 1 elements. In this case we write dim X = n. For X a manifold, this coincides with the dimension mentioned above. If no such integer n exists, then the dimension of X is said to be infinite, and we write dim X = ∞. Note also that we say X has dimension -1, i.e. dim X = -1 if and only if X is empty.This definition of covering dimension can be extended from the class of normal spaces to all Tychonoff spaces merely by replacing the term "open" in the definition by the term "functionally open".
## Inductive dimension
The inductive dimension of a topological space may refer to the small inductive dimension or the large inductive dimension, and is based on the analogy that n+1-dimensional balls have n dimensional boundaries, permitting an inductive definition based on the dimension of the boundaries of open sets.
## Hausdorff dimension
For sets which are of a complicated structure, especially fractals, the Hausdorff dimension is useful. The Hausdorff dimension is defined for all metric spaces and, unlike the Hamel dimension, can also attain non-integer real values.[4] The box dimension or Minkowski dimension is a variant of the same idea. In general, there exist more definitions of fractal dimensions that work for highly irregular sets and attain non-integer positive real values.
## Hilbert spaces
Every Hilbert space admits an orthonormal basis, and any two such bases for a particular space have the same cardinality. This cardinality is called the dimension of the Hilbert space. This dimension is finite if and only if the space's Hamel dimension is finite, and in this case the two dimensions coincide.
## Krull dimension of commutative rings
The Krull dimension of a commutative ring, named after Wolfgang Krull (1899–1971), is defined to be the maximal number of strict inclusions in an increasing chain of prime ideals in the ring.
## Negative dimension
The negative (fractal) dimension is introduced by Benoit Mandelbrot, in which, when it is positive gives the known definition, and when it is negative measures the degree of "emptiness" of empty sets.[5]
# In physics
## Spatial dimensions
Classical physics theories describe three physical dimensions: from a particular point in space, the basic directions in which we can move are up/down, left/right, and forward/backward. Movement in any other direction can be expressed in terms of just these three. Moving down is the same as moving up a negative amount. Moving diagonally upward and forward is just as the name of the direction implies; i.e., moving in a linear combination of up and forward. In its simplest form: a line describes one dimension, a plane describes two dimensions, and a cube describes three dimensions. (See Space and Cartesian coordinate system.)
## Time
Time is often referred to as the "fourth dimension". It is one way to measure physical change. It is perceived differently from the three spatial dimensions in that there is only one of it, that movement in time occurs at the fixed rate of one second per second, and that we cannot move freely in time but subjectively move in one direction.
The equations used in physics to model reality do not treat time in the same way that humans perceive it. The equations of classical mechanics are symmetric with respect to time, and equations of quantum mechanics are typically symmetric if both time and other quantities (such as charge and parity) are reversed. In these models, the perception of time flowing in one direction is an artifact of the laws of thermodynamics (we perceive time as flowing in the direction of increasing entropy).
The best-known treatment of time as a dimension is Poincaré and Einstein's special relativity (and extended to general relativity), which treats perceived space and time as components of a four-dimensional manifold, known as spacetime, and in the special, flat case as Minkowski space.
## Additional dimensions
Theories such as string theory and M-theory predict that physical space in general has in fact 10 and 11 dimensions, respectively. The extra dimensions are spacelike. We perceive only three spatial dimensions, and no physical experiments have confirmed the reality of additional dimensions. A possible explanation that has been suggested is that space is as it were "curled up" in the extra dimensions on a very small, subatomic scale, possibly at the quark/string level of scale or below.
## Penrose's singularity theorem
In his book The Road to Reality: A Complete Guide to the Laws of the Universe, scientist Sir Roger Penrose explained his singularity theorem. It asserts that all theories that attribute more than three spatial dimensions and one temporal dimension to the world of experience are unstable. The instabilities that exist in systems of such extra dimensions would result in their rapid collapse into a singularity. For that reason, Penrose wrote, the unification of gravitation with other forces through extra dimensions cannot occur.
## Dimensionful quantities
In the physical sciences and in engineering, the dimension of a physical quantity is the expression of the class of physical unit that such a quantity is measured against. The dimension of speed, for example, is LT−1, that is, length divided by time. The units in which the quantity is expressed, such as ms−1 (meters per second) or mph (miles per hour), has to conform to the dimension.
# Science fiction
Science fiction texts often mention the concept of dimension, when really referring to parallel universes, alternate universes, or other planes of existence. This usage is derived from the idea that in order to travel to parallel/alternate universes/planes of existence one must travel in a spatial direction/dimension besides the standard ones. In effect, the other universes/planes are just a small distance away from our own, but the distance is in a fourth (or higher) spatial dimension, not the standard ones.
One of the most heralded science fiction novellas regarding true geometric dimensionality, and often recommended as a starting point for those just starting to investigate such matters, is the 1884 novel Flatland by Edwin A. Abbott. Isaac Asimov, in his foreword to the Signet Classics 1984 edition, described Flatland as "The best introduction one can find into the manner of perceiving dimensions."
# More dimensions
- Dimension of an algebraic variety
- Lebesgue covering dimension
- Isoperimetric dimension
- Poset dimension
- Metric dimension
- Pointwise dimension
- Lyapunov dimension
- Kaplan-Yorke dimension
- Exterior dimension
- Hurst exponent
- q-dimension; especially:
Information dimension (corresponding to q = 1)
Correlation dimension (corresponding to q = 2)
- Information dimension (corresponding to q = 1)
- Correlation dimension (corresponding to q = 2) | https://www.wikidoc.org/index.php/Dimension | |
c822d9094cbb3158f852266b6b42c2fb721d3549 | wikidoc | Valsartan | Valsartan
- When pregnancy is detected, discontinue valsartan as soon as possible.
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
## Hypertension
- Dosing information
- Recommended starting dosage: 80 mg or 160 mg PO qd when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose.
- Dosage range: 80 mg to 320 mg PO qd
- The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks.
- Maximum: 320 mg
- Addition of a diuretic has a greater effect than dose increases beyond ‘’‘80 mg’‘’.
- No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency. Care should be exercised with dosing of valsartan tablets in patients with hepatic or severe renal impairment.
- Valsartan tablets may be administered with other antihypertensive agents.
- Valsartan tablets may be administered with or without food.
## Heart Failure
- Dosing information
- Recommended starting dose 40 mg PO bid.
- Uptitration to 80 mg -160 mg PO bid should be done to the highest dose, as tolerated by the patient.
- Consideration should be given to reducing the dose of concomitant diuretics.
- Maximum dosage: 320 mg/day
## Prophylaxis of Diabetes mellitus type 2
- Dosing information
- Initial dosage: 80 mg PO qd with an increase to 160 mg PO qd after 2 weeks.
## Diabetic nephropathy
- Dosing information
- 40 mg/day
- 80 mg/day
## Erectile dysfunction
- Dosing information
- 80- 160 mg PO qd
## Impaired cognition
- Dosing information
- 160 PO qd
## Left ventricular hypertrophy
- Dosing information
- 40 mg PO qd
- 80 mg/day
## Prophylaxis of Newly detected atrial fibrillation
- Dosing information
- 80 mg/day
## Prophylaxis of Restenotic lesion of coronary artery
- Dosing information
- 80 mg/day
## Hypertension
- Dosing information
- For children who can swallow tablets
- Recommended starting dosage: ’‘’1.3 mg/kg PO qd (up to 40 mg total)‘’‘.
- The dosage should be adjusted according to blood pressure response.
- Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old.
- For children who can't swallow tablets,or children for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths of valsartan, the use of a suspension is recommended.
- The dosage should be adjusted according to blood pressure response.
- Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old.
- Do not coadminister aliskiren with Diovan in patients with diabetes
Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diovan as soon as possible.
# Hypotension
- Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Diovan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of Diovan, or the treatment should start under close medical supervision.
- Caution should be observed when initiating therapy in patients with heart failure or post-myocardial infarction patients. Patients with heart failure or post-myocardial infarction patients given Diovan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.
- If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
# Impaired Renal Function
- Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g. patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Diovan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Diovan.
# Hyperkalemia
- Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of Diovan may be required.
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
## Adult Hypertension
- Diovan (valsartan) has been evaluated for safety in more than 4,000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with Diovan was similar to placebo.
- The overall frequency of adverse reactions was neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was required in 2.3% of valsartan patients and 2.0% of placebo patients. The most common reasons for discontinuation of therapy with Diovan were headache and dizziness.
- The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Diovan and at a higher incidence in valsartan (n=2,316) than placebo (n=888) patients included viral infection (3% vs. 2%), fatigue (2% vs. 1%), and abdominal pain (2% vs. 1%).
- Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia occurred at a more than 1% rate but at about the same incidence in placebo and valsartan patients.
- In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE-inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p <0.001).
- Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness was observed in patients treated with Diovan 320 mg (8%) compared to 10 to 160 mg (2% to 4%).
- Diovan has been used concomitantly with hydrochlorothiazide without evidence of clinically important adverse interactions.
- Other adverse reactions that occurred in controlled clinical trials of patients treated with Diovan (>0.2% of valsartan patients) are listed below. It cannot be determined whether these events were causally related to Diovan.
Body as a Whole: Allergic reaction and asthenia
Cardiovascular: Palpitations
Dermatologic: Pruritus and rash
Digestive: Constipation, dry mouth, dyspepsia, and flatulence
Musculoskeletal: Back pain, muscle cramps, and myalgia
Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence
Respiratory: Dyspnea
Special Senses: Vertigo
Urogenital: Impotence
- Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema.
## Pediatric Hypertension
- Diovan has been evaluated for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were identified between the adverse experience profile for pediatric patients aged 6-16 years and that previously reported for adult patients. Headache and hyperkalemia were the most common adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively. Hyperkalemia was mainly observed in children with underlying renal disease. Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years revealed no overall clinically relevant adverse impact after treatment with Diovan for up to 1 year.
- Diovan is not recommended for pediatric patients under 6 years of age. In a study (n=90) of pediatric patients (1-5 years), two deaths and three cases of on-treatment transaminase elevations were seen in the one-year open-label extension phase. These 5 events occurred in a study population in which patients frequently had significant co-morbidities. A causal relationship to Diovan has not been established. In a second study in which 75 children aged 1 to 6 years were randomized, no deaths and one case of marked liver transaminase elevations occurred during a 1 year open-label extension.
## Heart Failure
- The adverse experience profile of Diovan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the Valsartan Heart Failure Trial, comparing valsartan in total daily doses up to 320 mg (n=2,506) to placebo (n=2,494), 10% of valsartan patients discontinued for adverse reactions vs. 7% of placebo patients.
- The table shows adverse reactions in double-blind short-term heart failure trials, including the first 4 months of the Valsartan Heart Failure Trial, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients. All patients received standard drug therapy for heart failure, frequently as multiple medications, which could include diuretics, digitalis, beta-blockers. About 93% of patients received concomitant ACE inhibitors.
- Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium.
- Other adverse reactions with an incidence greater than 1% and greater than placebo included headache NOS, nausea, renal impairment NOS, syncope, blurred vision, upper abdominal pain and vertigo. (NOS = not otherwise specified).
- From the long-term data in the Valsartan Heart Failure Trial, there did not appear to be any significant adverse reactions not previously identified.
## Post-Myocardial Infarction
- The safety profile of Diovan was consistent with the pharmacology of the drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated in the post-myocardial infarction setting. The table shows the percent of patients discontinued in the valsartan and captopril-treated groups in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) with a rate of at least 0.5% in either of the treatment groups.
- Discontinuations due to renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients.
- Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedemawith other drugs including ACE inhibitors. Diovan should not be re-administered to patients who have had angioedema.
Digestive: Elevated liver enzymes and very rare reports of hepatitis
Renal: Impaired renal function, renal failure
Clinical Laboratory Tests: Hyperkalemia
Dermatologic: Alopecia
Blood and Lymphatic: There are very rare reports of thrombocytopenia
Vascular: Vasculitis
- Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
- 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.
- Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin,cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics(e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.
- Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.
- The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
- Dual Blockade of the renin-angiotensin system (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Diovan and other agents that affect the RAS.
- Do not coadminister aliskiren with Diovan in patients with diabetes. Avoid use of aliskiren with Diovan in patients with renal impairment (GFR <60 mL/min).
# Clinical Laboratory Test Findings
- In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Diovan.
Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking Diovan and 0.6% given placebo in controlled clinical trials of hypertensive patients. In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of Diovan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.
Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of Diovan patients, compared with 0.1% and 0.1% in placebo-treated patients. One valsartan patient discontinued treatment for microcytic anemia.
Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan-treated patients. Three patients (< 0.1%) treated with valsartan discontinued treatment for elevated liver chemistries.
Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo.
Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of Diovan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of Diovan-treated patients compared to 5.1% of placebo-treated patients.
Blood Urea Nitrogen (BUN): In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of Diovan-treated patients compared to 6.3% of placebo-treated patients.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramniosis observed, discontinue Diovan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramniosmay not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Diovan for hypotension, oliguria, and hyperkalemia.
- In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated.
- Diovan is not recommended for pediatric patients under 6 years of age due to safety findings for which a relationship to treatment could not be excluded.
- No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m2.
- There is limited clinical experience with Diovan in pediatric patients with mild to moderate hepatic impairment.
- Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10% of the maximum recommended pediatric dose on a mg/m2 basis) from postnatal day 7 to postnatal day 70 produced persistent, irreversible kidney damage. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life. Since this period coincides with up to 44 weeks after conception in humans, it is not considered to point toward an increased safety concern in 6 to 16 year old children.
- If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
- Of the 2,511 patients with heart failure randomized to valsartan in the Valsartan Heart Failure Trial, 45% (1,141) were 65 years of age or older. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), 53% (2,596) of the 4,909 patients treated with valsartan and 51% (2,515) of the 4,885 patients treated with valsartan + captopril were 65 years of age or older. There were no notable differences in efficacy or safety between older and younger patients in either trial.
- There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself.
- Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
- Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensinII on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
- Valsartan is chemically described as N-(1-oxopentyl)-N--4-yl]methyl]-L-valine. Its empirical formula is C24H29N5O3, its molecular weight is 435.5, and its structural formula is
- Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water.
- Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.
- In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.
- In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.
Metabolism and Elimination: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
- Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).
Distribution: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
## Special Populations
Pediatric: In a study of pediatric hypertensive patients (n=26, 1-16 years of age) given single doses of a suspension of Diovan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation.
Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary.
Gender: Pharmacokinetics of valsartan does not differ significantly between males and females.
Heart Failure: The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to those observed in healthy volunteers. AUC and Cmax values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients.
Renal Insufficiency: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan.
Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease
- There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
- Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.
- Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
# Animal Toxicology and/or Pharmacology
## Reproductive Toxicology Studies
- No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m2 basis. Calculations assume an oral dose of 320 mg/day and a 60-kg patient.
## Adult Hypertension
- The antihypertensive effects of Diovan (valsartan) were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.
- Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.
- In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of Diovan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.
- Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.
- The blood pressure lowering effect of valsartan and thiazide-type diuretics are approximately additive.
- The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80-160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone.
- Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups.
- In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg.
- There are no trials of Diovan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.
- There was essentially no change in heart rate in valsartan-treated patients in controlled trials.
## Pediatric Hypertension
- The antihypertensive effects of Diovan were evaluated in two randomized, double-blind clinical studies.
- In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses). Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by -8, -10, -12 mm Hg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mm Hg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.
- In a clinical study involving 90 hypertensive pediatric patients 1 to 5 years of age with a similar study design, there was some evidence of effectiveness, but safety findings for which a relationship to treatment could not be excluded mitigate against recommending use in this age group.
# Heart Failure
- The Valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF <40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years. Although Val-HeFT’s primary goal was to examine the effect of valsartan when added to an ACE inhibitor, about 7% were not receiving an ACE inhibitor. Other background therapy included diuretics (86%), digoxin (67%), and beta-blockers (36%). The population studied was 80% male, 46% 65 years or older and 89% Caucasian. At the end of the trial, patients in the valsartan group had a blood pressure that was 4 mmHg systolic and 2 mmHg diastolic lower than the placebo group. There were two primary end points, both assessed as time to first event: all-cause mortality and heart failure morbidity, the latter defined as all-cause mortality, sudden death with resuscitation, hospitalization for heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours. These results are summarized in the table below.
- Although the overall morbidity result favored valsartan, this result was largely driven by the 7% of patients not receiving an ACE inhibitor, as shown in the following table.
- The modest favorable trend in the group receiving an ACE inhibitor was largely driven by the patients receiving less than the recommended dose of ACE inhibitor. Thus, there is little evidence of further clinical benefit when valsartan is added to an adequate dose of ACE inhibitor.
- Secondary end points in the subgroup not receiving ACE inhibitors were as follows.
- In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD).
- Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor. The number of black patients was small and does not permit a meaningful assessment in this subset of patients.
# Post-Myocardial Infarction
- The VALsartan In Acute myocardial infarction trial (VALIANT) was a randomized, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and either heart failure (signs, symptoms or radiological evidence) or left ventricular systolic dysfunction (ejection fraction ≤40% by radionuclide ventriculography or ≤35% by echocardiography or ventricular contrast angiography). Patients were randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan (titrated from 20 or 40 mg twice daily to the highest tolerated dose up to a maximum of 160 mg twice daily), the ACE inhibitor, captopril (titrated from 6.25 mg three times daily to the highest tolerated dose up to a maximum of 50 mg three times daily), or the combination of valsartan plus captopril. In the combination group, the dose of valsartan was titrated from 20 mg twice daily to the highest tolerated dose up to a maximum of 80 mg twice daily; the dose of captopril was the same as for monotherapy. The population studied was 69% male, 94% Caucasian, and 53% were 65 years of age or older. Baseline therapy included aspirin (91%), beta-blockers (70%), ACE inhibitors (40%), thrombolytics (35%) and statins (34%). The mean treatment duration was 2 years. The mean daily dose of Diovan in the monotherapy group was 217 mg.
- The primary endpoint was time to all-cause mortality. Secondary endpoints included (1) time to cardiovascular (CV) mortality, and (2) time to the first event of cardiovascular mortality, reinfarction, or hospitalization for heart failure. The results are summarized in the table below:
- There was no difference in overall mortality among the three treatment groups. There was thus no evidence that combining the ACE inhibitor captopril and the angiotensin II blocker valsartan was of value.
- The data were assessed to see whether the effectiveness of valsartan could be demonstrated by showing in a non-inferiority analysis that it preserved a fraction of the effect of captopril, a drug with a demonstrated survival effect in this setting. A conservative estimate of the effect of captopril(based on a pooled analysis of 3 post-infarction studies of captopril and 2 other ACE inhibitors) was a 14-16% reduction in mortality compared to placebo. Valsartan would be considered effective if it preserved a meaningful fraction of that effect and unequivocally preserved some of that effect. As shown in the table, the upper bound of the CI for the hazard ratio (valsartan/captopril) for overall or CV mortality is 1.09-1.11, a difference of about 9-11%, thus making it unlikely that valsartan has less than about half of the estimated effect of captopril and clearly demonstrating an effect of valsartan. The other secondary endpoints were consistent with this conclusion.
40 mg tablets are yellow colored, film-coated, oval-shaped tablets debossed with ' RX121' on one side and break line on the other side
NDC 51660-140-03 Bottles of 10
NDC 51660-140-30 Bottles of 30
NDC 51660-140-05 Bottles of 500
80 mg tablets are yellowish brown colored, film-coated, oval-shaped tablets debossed with ' RX124' on one side and plain on the other side
NDC 51660-141-03 Bottles of 10
NDC 51660-141-90 Bottles of 90
NDC 51660-141-05 Bottles of 500
160 mg tablets are pink colored, film-coated, oval-shaped tablets debossed with ' RX125' on one side and plain on the other side
NDC 51660-142-03 Bottles of 10
NDC 51660-142-90 Bottles of 90
NDC 51660-142-05 Bottles of 500
320 mg tablets are brown colored, film-coated, oval-shaped tablets debossed with ' RX126' on one side and plain on the other side
NDC 51660-143-03 Bottles of 10
NDC 51660-143-90 Bottles of 90
NDC 51660-143-05 Bottles of 500
Protect from moisture.
Dispense in tight container (USP).
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Distributed by:
Ohm Laboratories Inc.
North Brunswick, NJ 08902 USA
March 2014 FDA-02
CROSPOVIDONE
HYPROMELLOSES
MAGNESIUM STEARATE
CELLULOSE, MICROCRYSTALLINE
STARCH, CORN
TALC
TITANIUM DIOXIDE
POLYETHYLENE GLYCOLS
FERRIC OXIDE YELLOW|+sep=;
CROSPOVIDONE
HYPROMELLOSES
MAGNESIUM STEARATE
CELLULOSE, MICROCRYSTALLINE
STARCH, CORN
TALC
TITANIUM DIOXIDE
POLYETHYLENE GLYCOLS
FERRIC OXIDE YELLOW|+sep=;
CROSPOVIDONE
HYPROMELLOSES
MAGNESIUM STEARATE
CELLULOSE, MICROCRYSTALLINE
STARCH, CORN
TALC
TITANIUM DIOXIDE
POLYETHYLENE GLYCOLS
FERRIC OXIDE YELLOW|+sep=;
CROSPOVIDONE
HYPROMELLOSES
MAGNESIUM STEARATE
CELLULOSE, MICROCRYSTALLINE
STARCH, CORN
TALC
TITANIUM DIOXIDE
POLYETHYLENE GLYCOLS
FERRIC OXIDE YELLOW|+sep=;
- ↑ NAVIGATOR Study Group. McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B; et al. (2010). "Effect of valsartan on the incidence of diabetes and cardiovascular events". N Engl J Med. 362 (16): 1477–90. doi:10.1056/NEJMoa1001121. PMID 20228403.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .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} Review in: Ann Intern Med. 2010 Jun 15;152(12):JC6-9 Review in: Evid Based Med. 2011 Aug;16(4):122-3
- ↑ Suzuki K, Souda S, Ikarashi T, Kaneko S, Nakagawa O, Aizawa Y (2002). "Renoprotective effects of low-dose valsartan in type 2 diabetic patients with diabetic nephropathy". Diabetes Res Clin Pract. 57 (3): 179–83. PMID 12126767.CS1 maint: Multiple names: authors list (link)
- ↑ Jacobsen P, Andersen S, Jensen BR, Parving HH (2003). "Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy". J Am Soc Nephrol. 14 (4): 992–9. PMID 12660333.CS1 maint: Multiple names: authors list (link)
- ↑ Düsing R (2003). "Effect of the angiotensin II antagonist valsartan on sexual function in hypertensive men". Blood Press Suppl. 2: 29–34. PMID 14761074.
- ↑ Fogari R, Mugellini A, Zoppi A, Marasi G, Pasotti C, Poletti L; et al. (2004). "Effects of valsartan compared with enalapril on blood pressure and cognitive function in elderly patients with essential hypertension". Eur J Clin Pharmacol. 59 (12): 863–8. doi:10.1007/s00228-003-0717-9. PMID 14747881.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Suzuki K, Kato K, Soda S, Kamimura T, Aizawa Y (2004). "The effect of valsartan on regression of left ventricular hypertrophy in type 2 diabetic patients". Diabetes Obes Metab. 6 (3): 195–9. doi:10.1111/j.1462-8902.2004.00331.x. PMID 15056127.CS1 maint: Multiple names: authors list (link)
- ↑ Mutlu H, Ozhan H, Okçün B, Okuyan E, Yigit Z, Erbaş C; et al. (2002). "The efficacy of valsartan in essential hypertension and its effects on left ventricular hypertrophy". Blood Press. 11 (1): 53–5. PMID 11926352.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Schmieder RE, Kjeldsen SE, Julius S, McInnes GT, Zanchetti A, Hua TA; et al. (2008). "Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial". J Hypertens. 26 (3): 403–11. doi:10.1097/HJH.0b013e3282f35c67. PMID 18300848.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Peters S, Götting B, Trümmel M, Rust H, Brattström A (2001). "Valsartan for prevention of restenosis after stenting of type B2/C lesions: the VAL-PREST trial". J Invasive Cardiol. 13 (2): 93–7. PMID 11176015.CS1 maint: Multiple names: authors list (link) | Valsartan
- When pregnancy is detected, discontinue valsartan as soon as possible.
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
### Hypertension
- Dosing information
- Recommended starting dosage: 80 mg or 160 mg PO qd when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose.
- Dosage range: 80 mg to 320 mg PO qd
- The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks.
- Maximum: 320 mg
- Addition of a diuretic has a greater effect than dose increases beyond ‘’‘80 mg’‘’.
- No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency. Care should be exercised with dosing of valsartan tablets in patients with hepatic or severe renal impairment.
- Valsartan tablets may be administered with other antihypertensive agents.
- Valsartan tablets may be administered with or without food.
### Heart Failure
- Dosing information
- Recommended starting dose 40 mg PO bid.
- Uptitration to 80 mg -160 mg PO bid should be done to the highest dose, as tolerated by the patient.
- Consideration should be given to reducing the dose of concomitant diuretics.
- Maximum dosage: 320 mg/day
### Prophylaxis of Diabetes mellitus type 2
- Dosing information
- Initial dosage: 80 mg PO qd with an increase to 160 mg PO qd after 2 weeks.[1]
### Diabetic nephropathy
- Dosing information
- 40 mg/day[2]
- 80 mg/day[3]
### Erectile dysfunction
- Dosing information
- 80- 160 mg PO qd[4]
### Impaired cognition
- Dosing information
- 160 PO qd[5]
### Left ventricular hypertrophy
- Dosing information
- 40 mg PO qd [6]
- 80 mg/day [7]
### Prophylaxis of Newly detected atrial fibrillation
- Dosing information
- 80 mg/day[8]
### Prophylaxis of Restenotic lesion of coronary artery
- Dosing information
- 80 mg/day[9]
### Hypertension
- Dosing information
- For children who can swallow tablets
- Recommended starting dosage: ’‘’1.3 mg/kg PO qd (up to 40 mg total)‘’‘.
- The dosage should be adjusted according to blood pressure response.
- Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old.
- For children who can't swallow tablets,or children for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths of valsartan, the use of a suspension is recommended.
- The dosage should be adjusted according to blood pressure response.
- Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old.
- Do not coadminister aliskiren with Diovan in patients with diabetes
Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Diovan as soon as possible.
## Hypotension
- Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with Diovan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of Diovan, or the treatment should start under close medical supervision.
- Caution should be observed when initiating therapy in patients with heart failure or post-myocardial infarction patients. Patients with heart failure or post-myocardial infarction patients given Diovan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.
- If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
## Impaired Renal Function
- Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g. patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Diovan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Diovan.
## Hyperkalemia
- Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of Diovan may be required.
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
### Adult Hypertension
- Diovan (valsartan) has been evaluated for safety in more than 4,000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with Diovan was similar to placebo.
- The overall frequency of adverse reactions was neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was required in 2.3% of valsartan patients and 2.0% of placebo patients. The most common reasons for discontinuation of therapy with Diovan were headache and dizziness.
- The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with Diovan and at a higher incidence in valsartan (n=2,316) than placebo (n=888) patients included viral infection (3% vs. 2%), fatigue (2% vs. 1%), and abdominal pain (2% vs. 1%).
- Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia occurred at a more than 1% rate but at about the same incidence in placebo and valsartan patients.
- In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE-inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p <0.001).
- Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness was observed in patients treated with Diovan 320 mg (8%) compared to 10 to 160 mg (2% to 4%).
- Diovan has been used concomitantly with hydrochlorothiazide without evidence of clinically important adverse interactions.
- Other adverse reactions that occurred in controlled clinical trials of patients treated with Diovan (>0.2% of valsartan patients) are listed below. It cannot be determined whether these events were causally related to Diovan.
Body as a Whole: Allergic reaction and asthenia
Cardiovascular: Palpitations
Dermatologic: Pruritus and rash
Digestive: Constipation, dry mouth, dyspepsia, and flatulence
Musculoskeletal: Back pain, muscle cramps, and myalgia
Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence
Respiratory: Dyspnea
Special Senses: Vertigo
Urogenital: Impotence
- Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema.
### Pediatric Hypertension
- Diovan has been evaluated for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were identified between the adverse experience profile for pediatric patients aged 6-16 years and that previously reported for adult patients. Headache and hyperkalemia were the most common adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively. Hyperkalemia was mainly observed in children with underlying renal disease. Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years revealed no overall clinically relevant adverse impact after treatment with Diovan for up to 1 year.
- Diovan is not recommended for pediatric patients under 6 years of age. In a study (n=90) of pediatric patients (1-5 years), two deaths and three cases of on-treatment transaminase elevations were seen in the one-year open-label extension phase. These 5 events occurred in a study population in which patients frequently had significant co-morbidities. A causal relationship to Diovan has not been established. In a second study in which 75 children aged 1 to 6 years were randomized, no deaths and one case of marked liver transaminase elevations occurred during a 1 year open-label extension.
### Heart Failure
- The adverse experience profile of Diovan in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the Valsartan Heart Failure Trial, comparing valsartan in total daily doses up to 320 mg (n=2,506) to placebo (n=2,494), 10% of valsartan patients discontinued for adverse reactions vs. 7% of placebo patients.
- The table shows adverse reactions in double-blind short-term heart failure trials, including the first 4 months of the Valsartan Heart Failure Trial, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients. All patients received standard drug therapy for heart failure, frequently as multiple medications, which could include diuretics, digitalis, beta-blockers. About 93% of patients received concomitant ACE inhibitors.
- Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium.
- Other adverse reactions with an incidence greater than 1% and greater than placebo included headache NOS, nausea, renal impairment NOS, syncope, blurred vision, upper abdominal pain and vertigo. (NOS = not otherwise specified).
- From the long-term data in the Valsartan Heart Failure Trial, there did not appear to be any significant adverse reactions not previously identified.
### Post-Myocardial Infarction
- The safety profile of Diovan was consistent with the pharmacology of the drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated in the post-myocardial infarction setting. The table shows the percent of patients discontinued in the valsartan and captopril-treated groups in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) with a rate of at least 0.5% in either of the treatment groups.
- Discontinuations due to renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients.
- Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedemawith other drugs including ACE inhibitors. Diovan should not be re-administered to patients who have had angioedema.
Digestive: Elevated liver enzymes and very rare reports of hepatitis
Renal: Impaired renal function, renal failure
Clinical Laboratory Tests: Hyperkalemia
Dermatologic: Alopecia
Blood and Lymphatic: There are very rare reports of thrombocytopenia
Vascular: Vasculitis
- Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
- 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.
- Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
CYP 450 Interactions: In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Coadministration of inhibitors of the uptake transporter (rifampin,cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics(e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.
- Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.
- The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
- Dual Blockade of the renin-angiotensin system (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Diovan and other agents that affect the RAS.
- Do not coadminister aliskiren with Diovan in patients with diabetes. Avoid use of aliskiren with Diovan in patients with renal impairment (GFR <60 mL/min).
## Clinical Laboratory Test Findings
- In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Diovan.
Creatinine: Minor elevations in creatinine occurred in 0.8% of patients taking Diovan and 0.6% given placebo in controlled clinical trials of hypertensive patients. In heart failure trials, greater than 50% increases in creatinine were observed in 3.9% of Diovan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.
Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in 0.4% and 0.8%, respectively, of Diovan patients, compared with 0.1% and 0.1% in placebo-treated patients. One valsartan patient discontinued treatment for microcytic anemia.
Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan-treated patients. Three patients (< 0.1%) treated with valsartan discontinued treatment for elevated liver chemistries.
Neutropenia: Neutropenia was observed in 1.9% of patients treated with Diovan and 0.8% of patients treated with placebo.
Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of Diovan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10.0% of Diovan-treated patients compared to 5.1% of placebo-treated patients.
Blood Urea Nitrogen (BUN): In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of Diovan-treated patients compared to 6.3% of placebo-treated patients.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramniosis observed, discontinue Diovan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramniosmay not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Diovan for hypotension, oliguria, and hyperkalemia.
- In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated.
- Diovan is not recommended for pediatric patients under 6 years of age due to safety findings for which a relationship to treatment could not be excluded.
- No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m2.
- There is limited clinical experience with Diovan in pediatric patients with mild to moderate hepatic impairment.
- Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10% of the maximum recommended pediatric dose on a mg/m2 basis) from postnatal day 7 to postnatal day 70 produced persistent, irreversible kidney damage. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life. Since this period coincides with up to 44 weeks after conception in humans, it is not considered to point toward an increased safety concern in 6 to 16 year old children.
- If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
- Of the 2,511 patients with heart failure randomized to valsartan in the Valsartan Heart Failure Trial, 45% (1,141) were 65 years of age or older. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), 53% (2,596) of the 4,909 patients treated with valsartan and 51% (2,515) of the 4,885 patients treated with valsartan + captopril were 65 years of age or older. There were no notable differences in efficacy or safety between older and younger patients in either trial.
- There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one-200th that of valsartan itself.
- Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
- Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensinII on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
- Valsartan is chemically described as N-(1-oxopentyl)-N-[ [2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4-yl]methyl]-L-valine. Its empirical formula is C24H29N5O3, its molecular weight is 435.5, and its structural formula is
- Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water.
- Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.
- In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.
- In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.
Metabolism and Elimination: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism.
- Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).
Distribution: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
### Special Populations
Pediatric: In a study of pediatric hypertensive patients (n=26, 1-16 years of age) given single doses of a suspension of Diovan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was similar to that of adults receiving the same formulation.
Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary.
Gender: Pharmacokinetics of valsartan does not differ significantly between males and females.
Heart Failure: The average time to peak concentration and elimination half-life of valsartan in heart failure patients are similar to those observed in healthy volunteers. AUC and Cmax values of valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients.
Renal Insufficiency: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan.
Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease
- There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
- Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.
- Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
## Animal Toxicology and/or Pharmacology
### Reproductive Toxicology Studies
- No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m2 basis. Calculations assume an oral dose of 320 mg/day and a 60-kg patient.
### Adult Hypertension
- The antihypertensive effects of Diovan (valsartan) were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.
- Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.
- In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of Diovan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.
- Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.
- The blood pressure lowering effect of valsartan and thiazide-type diuretics are approximately additive.
- The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80-160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone.
- Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups.
- In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg.
- There are no trials of Diovan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.
- There was essentially no change in heart rate in valsartan-treated patients in controlled trials.
### Pediatric Hypertension
- The antihypertensive effects of Diovan were evaluated in two randomized, double-blind clinical studies.
- In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses). Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by -8, -10, -12 mm Hg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mm Hg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.
- In a clinical study involving 90 hypertensive pediatric patients 1 to 5 years of age with a similar study design, there was some evidence of effectiveness, but safety findings for which a relationship to treatment could not be excluded mitigate against recommending use in this age group.
## Heart Failure
- The Valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF <40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years. Although Val-HeFT’s primary goal was to examine the effect of valsartan when added to an ACE inhibitor, about 7% were not receiving an ACE inhibitor. Other background therapy included diuretics (86%), digoxin (67%), and beta-blockers (36%). The population studied was 80% male, 46% 65 years or older and 89% Caucasian. At the end of the trial, patients in the valsartan group had a blood pressure that was 4 mmHg systolic and 2 mmHg diastolic lower than the placebo group. There were two primary end points, both assessed as time to first event: all-cause mortality and heart failure morbidity, the latter defined as all-cause mortality, sudden death with resuscitation, hospitalization for heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours. These results are summarized in the table below.
- Although the overall morbidity result favored valsartan, this result was largely driven by the 7% of patients not receiving an ACE inhibitor, as shown in the following table.
- The modest favorable trend in the group receiving an ACE inhibitor was largely driven by the patients receiving less than the recommended dose of ACE inhibitor. Thus, there is little evidence of further clinical benefit when valsartan is added to an adequate dose of ACE inhibitor.
- Secondary end points in the subgroup not receiving ACE inhibitors were as follows.
- In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD).
- Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor. The number of black patients was small and does not permit a meaningful assessment in this subset of patients.
## Post-Myocardial Infarction
- The VALsartan In Acute myocardial infarction trial (VALIANT) was a randomized, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and either heart failure (signs, symptoms or radiological evidence) or left ventricular systolic dysfunction (ejection fraction ≤40% by radionuclide ventriculography or ≤35% by echocardiography or ventricular contrast angiography). Patients were randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan (titrated from 20 or 40 mg twice daily to the highest tolerated dose up to a maximum of 160 mg twice daily), the ACE inhibitor, captopril (titrated from 6.25 mg three times daily to the highest tolerated dose up to a maximum of 50 mg three times daily), or the combination of valsartan plus captopril. In the combination group, the dose of valsartan was titrated from 20 mg twice daily to the highest tolerated dose up to a maximum of 80 mg twice daily; the dose of captopril was the same as for monotherapy. The population studied was 69% male, 94% Caucasian, and 53% were 65 years of age or older. Baseline therapy included aspirin (91%), beta-blockers (70%), ACE inhibitors (40%), thrombolytics (35%) and statins (34%). The mean treatment duration was 2 years. The mean daily dose of Diovan in the monotherapy group was 217 mg.
- The primary endpoint was time to all-cause mortality. Secondary endpoints included (1) time to cardiovascular (CV) mortality, and (2) time to the first event of cardiovascular mortality, reinfarction, or hospitalization for heart failure. The results are summarized in the table below:
- There was no difference in overall mortality among the three treatment groups. There was thus no evidence that combining the ACE inhibitor captopril and the angiotensin II blocker valsartan was of value.
- The data were assessed to see whether the effectiveness of valsartan could be demonstrated by showing in a non-inferiority analysis that it preserved a fraction of the effect of captopril, a drug with a demonstrated survival effect in this setting. A conservative estimate of the effect of captopril(based on a pooled analysis of 3 post-infarction studies of captopril and 2 other ACE inhibitors) was a 14-16% reduction in mortality compared to placebo. Valsartan would be considered effective if it preserved a meaningful fraction of that effect and unequivocally preserved some of that effect. As shown in the table, the upper bound of the CI for the hazard ratio (valsartan/captopril) for overall or CV mortality is 1.09-1.11, a difference of about 9-11%, thus making it unlikely that valsartan has less than about half of the estimated effect of captopril and clearly demonstrating an effect of valsartan. The other secondary endpoints were consistent with this conclusion.
40 mg tablets are yellow colored, film-coated, oval-shaped tablets debossed with ' RX121' on one side and break line on the other side
NDC 51660-140-03 Bottles of 10
NDC 51660-140-30 Bottles of 30
NDC 51660-140-05 Bottles of 500
80 mg tablets are yellowish brown colored, film-coated, oval-shaped tablets debossed with ' RX124' on one side and plain on the other side
NDC 51660-141-03 Bottles of 10
NDC 51660-141-90 Bottles of 90
NDC 51660-141-05 Bottles of 500
160 mg tablets are pink colored, film-coated, oval-shaped tablets debossed with ' RX125' on one side and plain on the other side
NDC 51660-142-03 Bottles of 10
NDC 51660-142-90 Bottles of 90
NDC 51660-142-05 Bottles of 500
320 mg tablets are brown colored, film-coated, oval-shaped tablets debossed with ' RX126' on one side and plain on the other side
NDC 51660-143-03 Bottles of 10
NDC 51660-143-90 Bottles of 90
NDC 51660-143-05 Bottles of 500
Protect from moisture.
Dispense in tight container (USP).
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Distributed by:
Ohm Laboratories Inc.
North Brunswick, NJ 08902 USA
March 2014 FDA-02
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- ↑ NAVIGATOR Study Group. McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B; et al. (2010). "Effect of valsartan on the incidence of diabetes and cardiovascular events". N Engl J Med. 362 (16): 1477–90. doi:10.1056/NEJMoa1001121. PMID 20228403.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .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} Review in: Ann Intern Med. 2010 Jun 15;152(12):JC6-9 Review in: Evid Based Med. 2011 Aug;16(4):122-3
- ↑ Suzuki K, Souda S, Ikarashi T, Kaneko S, Nakagawa O, Aizawa Y (2002). "Renoprotective effects of low-dose valsartan in type 2 diabetic patients with diabetic nephropathy". Diabetes Res Clin Pract. 57 (3): 179–83. PMID 12126767.CS1 maint: Multiple names: authors list (link)
- ↑ Jacobsen P, Andersen S, Jensen BR, Parving HH (2003). "Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy". J Am Soc Nephrol. 14 (4): 992–9. PMID 12660333.CS1 maint: Multiple names: authors list (link)
- ↑ Düsing R (2003). "Effect of the angiotensin II antagonist valsartan on sexual function in hypertensive men". Blood Press Suppl. 2: 29–34. PMID 14761074.
- ↑ Fogari R, Mugellini A, Zoppi A, Marasi G, Pasotti C, Poletti L; et al. (2004). "Effects of valsartan compared with enalapril on blood pressure and cognitive function in elderly patients with essential hypertension". Eur J Clin Pharmacol. 59 (12): 863–8. doi:10.1007/s00228-003-0717-9. PMID 14747881.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Suzuki K, Kato K, Soda S, Kamimura T, Aizawa Y (2004). "The effect of valsartan on regression of left ventricular hypertrophy in type 2 diabetic patients". Diabetes Obes Metab. 6 (3): 195–9. doi:10.1111/j.1462-8902.2004.00331.x. PMID 15056127.CS1 maint: Multiple names: authors list (link)
- ↑ Mutlu H, Ozhan H, Okçün B, Okuyan E, Yigit Z, Erbaş C; et al. (2002). "The efficacy of valsartan in essential hypertension and its effects on left ventricular hypertrophy". Blood Press. 11 (1): 53–5. PMID 11926352.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Schmieder RE, Kjeldsen SE, Julius S, McInnes GT, Zanchetti A, Hua TA; et al. (2008). "Reduced incidence of new-onset atrial fibrillation with angiotensin II receptor blockade: the VALUE trial". J Hypertens. 26 (3): 403–11. doi:10.1097/HJH.0b013e3282f35c67. PMID 18300848.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Peters S, Götting B, Trümmel M, Rust H, Brattström A (2001). "Valsartan for prevention of restenosis after stenting of type B2/C lesions: the VAL-PREST trial". J Invasive Cardiol. 13 (2): 93–7. PMID 11176015.CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Diovan | |
1b7857c1e274c0f4573a23a67eed605b50517a29 | wikidoc | Diphallia | Diphallia
Steven C. Campbell, M.D., Ph.D.
# Overview
Diphallia, penile duplication (PD), diphallic terata, or diphallasparatus, is a medical condition in which a male infant is born with two penises. This is an extremely rare disorder with only approximately 100 cases of diphallia recorded since the first case reported by Johannes Jacob Wecker in 1609. Its occurrence is one in 5.5 million men in the United States.
When diphallia is present, it is usually accompanied by other congenital anomalies such as renal, vertebral, hindgut or anorectal duplication. There is also a higher risk of spina bifida. Infants born with PD and its related conditions have a higher death rate from various infections associated with their more complex renal or colorectal systems.
It is thought diphallia occurs in the fetus between the 23rd and 25th days of gestation when an injury, chemical stress, or malfunctioning homeobox genes hamper proper function of the caudal cell mass of the fetal mesoderm as the urogenital sinus separates from the genital tubercle and rectum to form the penis.
# Characteristics
- Those in possession of a diphallus tend to be sterile, due to either congenital defects or difficulties in application.
- Urine may be passed by both penises, by only one, or through some other aperture in the perineum.
- A range of duplication types have been seen, ranging from organs that fissure into two, to the presence of two distinct penises positioned at some distance from each other.
- Most diphalluses lie side by side and are of equal size, but they can be seated atop one another, with one distinctly larger than the other.
This rare condition has been documented in pigs and other mammals. It is commonly mistaken that all sharks have this condition, but in reality they have a pair of "claspers" which serve a reproductive function.
Diphallia is a medical condition and should not be confused with genital bisection, which is an elective procedure which involves the splitting of the penis.
# Pathological Findings
Images shown below are courtesy of Geneva Foundation for Medical Education and Research and Marmara Medical Journal. | Diphallia
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
Diphallia, penile duplication (PD), diphallic terata, or diphallasparatus, is a medical condition in which a male infant is born with two penises. This is an extremely rare disorder with only approximately 100 cases of diphallia recorded since the first case reported by Johannes Jacob Wecker in 1609. Its occurrence is one in 5.5 million men in the United States.[1][2]
When diphallia is present, it is usually accompanied by other congenital anomalies such as renal, vertebral, hindgut or anorectal duplication. There is also a higher risk of spina bifida. Infants born with PD and its related conditions have a higher death rate from various infections associated with their more complex renal or colorectal systems.
It is thought diphallia occurs in the fetus between the 23rd and 25th days of gestation when an injury, chemical stress, or malfunctioning homeobox genes hamper proper function of the caudal cell mass of the fetal mesoderm as the urogenital sinus separates from the genital tubercle and rectum to form the penis.
# Characteristics
- Those in possession of a diphallus tend to be sterile, due to either congenital defects or difficulties in application.
- Urine may be passed by both penises, by only one, or through some other aperture in the perineum.
- A range of duplication types have been seen, ranging from organs that fissure into two, to the presence of two distinct penises positioned at some distance from each other.
- Most diphalluses lie side by side and are of equal size, but they can be seated atop one another, with one distinctly larger than the other.
This rare condition has been documented in pigs and other mammals. It is commonly mistaken that all sharks have this condition, but in reality they have a pair of "claspers" which serve a reproductive function.
Diphallia is a medical condition and should not be confused with genital bisection, which is an elective procedure which involves the splitting of the penis.
# Pathological Findings
Images shown below are courtesy of Geneva Foundation for Medical Education and Research and Marmara Medical Journal.
-
- | https://www.wikidoc.org/index.php/Diphallia | |
a7f05f42acd5f38787b4510b12d799b0845a7350 | wikidoc | Diprobase | Diprobase
Diprobase is an emollient, specifically targeted at eczema and dermatitis. It is an occlusive emollient, meaning that it restores the layer of oil on the surface of the skin to slow water loss. This gives its tendency to make the applied area sticky.
# Ingredients
Diprobase contains no 'active ingredients'. It is made from a combination of paraffins and water, as well as cetomacrogol and cetostearyl alcohol as emulsifying agents, chlorocresol as an antimicrobial preservative, phosphoric acid, and sodium dihydrogen phosphate.
# Effects
Dry skin results from lack of water in the outer layer of skin cells (the stratum corneum). When this layer becomes dehydrated it loses its flexibility and becomes cracked, scaly and sometimes itchy. The stratum corneum contains natural water-holding substances that retain water seeping up from the deeper layers of the skin, and water is also normally retained in the stratum corneum by a surface film of natural oil (sebum) and broken-down skin cells, which slow down evaporation of water from the skin surface. Diprobase works by increasing that layer of oil. | Diprobase
Diprobase is an emollient, specifically targeted at eczema and dermatitis. It is an occlusive emollient, meaning that it restores the layer of oil on the surface of the skin to slow water loss. This gives its tendency to make the applied area sticky.
# Ingredients
Diprobase contains no 'active ingredients'. It is made from a combination of paraffins and water, as well as cetomacrogol and cetostearyl alcohol as emulsifying agents, chlorocresol as an antimicrobial preservative, phosphoric acid, and sodium dihydrogen phosphate.
# Effects
Dry skin results from lack of water in the outer layer of skin cells (the stratum corneum). When this layer becomes dehydrated it loses its flexibility and becomes cracked, scaly and sometimes itchy. The stratum corneum contains natural water-holding substances that retain water seeping up from the deeper layers of the skin, and water is also normally retained in the stratum corneum by a surface film of natural oil (sebum) and broken-down skin cells, which slow down evaporation of water from the skin surface. Diprobase works by increasing that layer of oil.
# External links
- NetDoctor's article on Diprobase Cream
Template:Treatment-stub | https://www.wikidoc.org/index.php/Diprobase | |
4084729b3a8119ec0066d707b64877e90c1d322a | wikidoc | Diradical | Diradical
# Overview
A diradical in organic chemistry is a molecular species with two electrons occupying two degenerate molecular orbitals (MO) of the same energy . They are known by their higher reactivities and shorter lifetimes. In a broader definition diradicals are even-electron molecules that have one bond less than the number permitted by the standard rules of valence . The electrons can pair up with opposite spin in one MO leaving the other empty. This is called a singlet state. Alternatively each electron can occupy one MO with spins parallel to each other. This is called a triplet state. The related radical has just one free electron. The phrases singlet and triplet are derived from the appearance of diradicals in electron spin resonance: a singlet diradical displays a single peak in its spectrum and a triplet has its peak split into a central peak with two adjacent peaks.
The triplet state has total spin quantum number S = 1 and is paramagnetic . The singlet state has S = 0 and is diamagnetic. The degeneracy of each state can be found with Hund's rule of maximum multiplicity: 2S + 1.
In molecules the free electrons can reside on one atom or on different atoms. A molecule can have a singlet state or triplet state with different energy and both states can inter-convert by a process called intersystem crossing. Phosphorescence is based on this principle.
Discrete molecules with a diradical nature are singlet oxygen and triplet oxygen. Other important diradicals are carbenes and nitrenes. Lesser known diradicals are nitrenium ions and organic so-called non-Kekulé molecules in which the electrons reside on different carbon atoms. | Diradical
# Overview
A diradical in organic chemistry is a molecular species with two electrons occupying two degenerate molecular orbitals (MO) of the same energy [1] [2]. They are known by their higher reactivities and shorter lifetimes. In a broader definition diradicals are even-electron molecules that have one bond less than the number permitted by the standard rules of valence [3] [4]. The electrons can pair up with opposite spin in one MO leaving the other empty. This is called a singlet state. Alternatively each electron can occupy one MO with spins parallel to each other. This is called a triplet state. The related radical has just one free electron. The phrases singlet and triplet are derived from the appearance of diradicals in electron spin resonance: a singlet diradical displays a single peak in its spectrum and a triplet has its peak split into a central peak with two adjacent peaks.
The triplet state has total spin quantum number S = 1 and is paramagnetic [5]. The singlet state has S = 0 and is diamagnetic. The degeneracy of each state can be found with Hund's rule of maximum multiplicity: 2S + 1.
In molecules the free electrons can reside on one atom or on different atoms. A molecule can have a singlet state or triplet state with different energy and both states can inter-convert by a process called intersystem crossing. Phosphorescence is based on this principle.
Discrete molecules with a diradical nature are singlet oxygen and triplet oxygen. Other important diradicals are carbenes and nitrenes. Lesser known diradicals are nitrenium ions and organic so-called non-Kekulé molecules in which the electrons reside on different carbon atoms.
# External links
- Diradicals @ www.meta-synthesis.com Link | https://www.wikidoc.org/index.php/Diradical | |
1d5085862ececb3cd4ed34d13c0c446e7d3d347d | wikidoc | Disc slip | Disc slip
Ahmad Muneeb, MBBS
Synonyms and keywords: Intervertebral Disc Displacements; Disc Displacements, Intervertebral; Disc Displacement, Intervertebral; Intervertebral Disk Displacements; Disk Displacements, Intervertebral; Disk Displacement, Intervertebral; Intervertebral Disk Displacement; Disks, Prolapsed; Slipped Disk; Disk Prolapse; Discs, Slipped; Herniated Disks; Slipped Discs; Herniated Disc; Disks, Slipped; Disk, Prolapsed; Prolapsed Disk; Disc, Slipped; Prolapses, Disk; Slipped Disc; Discs, Prolapsed; Discs, Herniated; Prolapsed Discs; Disks, Herniated; Disk, Herniated; Herniated Disk; Prolapse, Disk; Disk Prolapses; Prolapsed Disc; Disc, Herniated; Disc, Prolapsed; Slipped Disks; Disk, Slipped; Herniated Discs; Prolapsed Disks
# Overview
Intervertebral disk slip consists of 2 main parts, nucleus pulposus the central part, and annulus fibrosus the peripheral part. Intervertebral disc slip occurs when nucleus pulposus protrudes through annulus fibrosus. Most commonly disc slip is caused by degenerative changes and traumatic insults to the spine. Although, disc herniation can occur in any part of the vertebral column but lumbar disc slips are far more common than disc herniations in other parts of the spine. Males, obese, smokers and heavy weight lifters are at increased risk of developing disk slip. Clinical features of the disk slip vary depending upon the location and presence or absence of nerve impingement. Common clinical features include back pain, pain radiating to upper or lower extremity, motor weakness, numbness or tingling, absent deep tendon reflexes. MRI and CT scan have excellent sensitivity in diagnosing intervertebral disc slip. Conservative management starts with lifestyle modifications and medical therapy. Most of the patients get pain relief with conservative management. For severe or persistent cases surgical management can be used.
# Historical Perspective
- Intervertebral disc slip was first described by Virchow, a german physician, in in his publication related to disc pathologies.
- In , the first laminectomy was done by William MacEwen and Victor Horsely to treat lumbar disc slip. The first discectomy was done by surgeon Fedor Krause in 1908.
# Classification
- Intervertebral disc slip may be classified according to the extent of displacement of nucleus pulposus into 4 subtypes:
- Bulging: Disc margins extend beyond vertebral endplate margins.
- Protrusion: Nucleus pulposus impinges on annulus fibrosus, posterior longitudinal ligament stays intact.
- Extrusion: Nucleus pulposus extrudes through the annulus fibrosus, posterior longitudinal ligament stays intact.
- Sequestration: Posterior longitudinal ligament is compromised. Nucleus pulposus extrudes through the annulus fibrosus and posterior longitudinal ligament into epidural space.
# Pathophysiology
- The pathogenesis of disc slip is characterized by bulging of nucleus pulposus of the disk through the annulus pulposus. Nucleus pulposus is the central part of the intervertebral disc that contains proteoglycans. Proteoglycans cause water retention, thus nucleus pulposus is responsible for providing cushioning effect to vertebrae. Annulus fibrosis is the peripheral ring surrounding nucleus pulposus that is responsible for keeping nucleus pulposus in the center of the disk. Displaced fragments of nucleus pulposus can then compress the nerve roots passing behind the intervertebral disk space. Disc degeneration is the most common preceding factor in the development of disk slip. Several underlying changes have been implicated in the development of slipped discs including decreased water content in nucleus pulposus, increased activity of degradative processes including inflammatory mediators, apoptosis, and matrix metalloproteinase enzyme leading to degeneration of intervertebral discs. Role of multiple genes has also been implicated in intervertebral disc degeneration and consequent herniation. It is also documented that axial overburdening of vertebral column may cause disc slip.
- Genes responsible for disc slip include genes coding for matrix metalloproteinases, structural proteins, Vitamin D receptor, apoptosis factors, growth factors, collagen type I and IX, interleukin 1, interleukin 6, asporin, aggrecan.
# Causes
Disc slip may be caused by age-related degenerative changes, systemic inflammatory processes, vertebral trauma, sudden vertebral strain, twisted movement of the spine, connective tissue disorders.
# Differentiating intervertebral disc slip from other Diseases
- Disc slip must be differentiated from other diseases that cause radicular pain, sensory deficits, and motor weakness, such as :
- Spinal tumors
- Spinal abscess
- Spinal fractures
- Spinal stenosis
- Arthritis
- Spinal cysts
- Epidural hematoma
# Epidemiology and Demographics
- The incidence of intervertebral disc slip is estimated to be cases per 1000 individuals annually. In case of lumbar disc slips, 95% of the herniations in patients aged between 25 to 55 occur at L4-L5 or L5-S1 level. In case of cervical spine, C6-C7 disc is most commonly herniated.
## Age
- Intervertebral disc slip is more commonly observed among patients aged 30 to 50 years old.
## Gender
- Males are more commonly affected with intervertebral disc slip than females.
## Race
- There is no racial predilection for intervertebral disc slip.
# Risk Factors
- Common risk factors in the development of intervertebral disc slip are male gender, excessive body weight, smoking, sedentary life style, abrupt increase in physical activity, heavy weight lifting, poor posture, poor nutrition.
# Natural History, Complications and Prognosis
- Two-third of patients with lumbar disc herniation improve within 6 months as herniated disk tends to regress over time. After 6 weeks, only around 10% of the patients have persistent pain to consider surgery.
- If left untreated, patients with intervertebral disc slip may develop chronic back pain, permanent nerve damage, persistent motor weakness, persistent sensory deficits, Cauda equina syndrome.
# Diagnosis
## Diagnostic Criteria
There are no specific diagnostic criteria for intervertebral disc slip.
## History and Symptoms
- Symptoms of Intervertebral disc slip depend upon the site and extent of the slipped disc and are present in the are supplied by the compressed nerve. They may include the following:
### Lumbar disc slip
- Lower back pain
- electric shock like or sharp pain radiating from buttock to leg(sciatica)
- numbness or tingling in one leg
- lower extremity weakness
- loss of bowel or bladder control
- pain aggravation with walking, standing or sitting
### Cervical or thoracic disc slip
- Neck pain
- pain between shoulder girdles
- pain radiating down the arm to the hand or fingers
- numbness/tingling in the forearm, arm or shoulder
- increase in pain with neck movements.
- weakness in the muscles of hand or forearm
## Physical Examination
- Physical examination findings depend upon the nerve root compressed and maybe remarkable for:
- C5 nerve: numbness in lateral arm, weakened shoulder abduction, external rotation, forearm supination and elbow flexion, abnormal biceps reflex and brachioradialis reflex.
- C6 nerve: numbness in thumb, index finger, lateral foream, weakened shoulder abduction, external rotation, forearm supination, forearm pronation and elbow flexion, abnormal biceps reflex and brachioradialis reflex.
- C7 nerve: numbness in palm, index and middle fingers, weakened wrist flexion, radial extension, and forearm pronation, abnormal triceps reflex.
- C8 nerve: numbness in medial forearm and hand, weakened distal finger flexion, extension, abduction, adduction, distal thumb flexion and wrist extension. Normal reflexes
- T1 nerve: numbness in anterior and medial forearm, weakened finger adduction, abduction, thumb abduction and distal thumb flexion. Normal deep tendon reflexes
- L1 nerve: altered sensation in inguinal region, weakened hip flexion.
- L2,L3,L4 nerves: altered sensation in medial leg and anterior thigh, weakened hip fexion, adduction, knee extension, abnormal patellar reflex.
- L5 nerve: altered sensation in lateral calf, dorsal for and space between 1st and 2nd toe, weakened hip abduction, knee flexion, foot dorsiflexion, toe flexion and extension, foot eversion and inversion. Abnormal semitendinosus or semimembranosus reflex.
- S1 nerve: altered sensation on posterior calf, lateral or plantar foot, weakened hip extension, knee flexion, foot plantar flexion, loss of bowel or bladder control, sexual dysfunction.
- S2-S4 nerves: altered sensation on medial side of buttock, perianal and perineal region, absence of wink and bulbocavernosus reflex.
- positive straight leg raise test in lumbar radiculopathy.
## Laboratory Findings
- There are no specific laboratory findings associated with intervertebral disc slip.
## Electrocardiogram
There are no ECG findings associated with intervertebral disc slip.
## X-ray
There are no x-ray findings associated with intervertebral disc slip. However, an x-ray may be helpful in detecting other etiologies causing similar symptoms like fractures, abscesses, tumors, bony spurs etc.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with intervertebral disc slip.
## CT scan
CT scan may be helpful in the diagnosis of intervertebral disc slip. Like MRI, CT scan also provides a detailed view of the spinal canal and its contents, thus it can detect disc slip along with its extent and location.Findings on CT scan suggestive of intervertebral disc slip include bulging of intervertebral disc, nerve root compression, and spinal cord compression.
## MRI
MRI may be helpful in the diagnosis of intervertebral disc slip, as it is considered the gold standard for the diagnosis of this disorder. MRI has an excellent capacity to visualize all the soft tissues including the spinal cord, and nerve roots thus it can easily detect bulging intervertebral disc and also if there is any compression of nerve root or spinal cord. MRI is also very helpful in ruling out other differentials.
## Other Imaging Findings
Myelogram may be helpful in the diagnosis of intervertebral disc slip. It is a modified x-ray technique in which the spinal canal is visualized after injection of a contrast material. It can show if a slipped disk is compressing a nerve root or spinal cord
## Other Diagnostic Studies
Electromyogram and nerve conduction studies may be helpful in the diagnosis of intervertebral disc slip. These tests assess the response of nerve or muscle to electric stimulation. They can reveal if there is any nerve damage or compression as a consequence of slipped disk.
# Treatment
Certain non-pharmacologic treatments and lifestyle modifications can be used before any pharmacologic treatment is done. They include maintenance of activity level that is painless, physiotherapy, avoidance of any activity that incites pain, avoidance from lifting heavy weights, weight control, use of spinal support, spinal massage, spinal manipulation, spinal traction, heat or ice application.
## Medical Therapy
- The medical treatment options for pain relief in intervertebral disc slip are analgesic medications like NSAIDS or acetaminophen, muscle relaxants, steroids and anti depressants. A steroid injection in the epidural space may also be administered to provide pain relief.
## Surgery
- Discectomy can be performed for patients with intervertebral disc slip who do not improve with medical management and lifestyle modifications. It can also be performed in patients with persistent or progressive neurologic deficit due to nerve compression. Discectomy is of 2 types. Microsurgical discectomy involves a small incision in the center of the back followed by microdissection to reach the herniated disk. Then the part of the disk impinging on the nerve root is removed. Microendoscopic discectomy involves an incision at the back. In order to reach the vertebra, dilators are used. Then an endoscope is used to access and remove the herniated disk. Microendoscopic discectomy causes lesser tissue damage than microsurgical discectomy. Other options like laser discectomy are also available but their efficacy is not fully proven. In selective cases, discectomy can be combined with laminectomy and spinal fusion
## Prevention
- Effective measures for the primary prevention of intervertebral disc slip include maintaining a normal body weight, regular exercise, smoking cessation and good posture. | Disc slip
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor(s)-in-Chief:
Ahmad Muneeb, MBBS[2]
Synonyms and keywords: Intervertebral Disc Displacements; Disc Displacements, Intervertebral; Disc Displacement, Intervertebral; Intervertebral Disk Displacements; Disk Displacements, Intervertebral; Disk Displacement, Intervertebral; Intervertebral Disk Displacement; Disks, Prolapsed; Slipped Disk; Disk Prolapse; Discs, Slipped; Herniated Disks; Slipped Discs; Herniated Disc; Disks, Slipped; Disk, Prolapsed; Prolapsed Disk; Disc, Slipped; Prolapses, Disk; Slipped Disc; Discs, Prolapsed; Discs, Herniated; Prolapsed Discs; Disks, Herniated; Disk, Herniated; Herniated Disk; Prolapse, Disk; Disk Prolapses; Prolapsed Disc; Disc, Herniated; Disc, Prolapsed; Slipped Disks; Disk, Slipped; Herniated Discs; Prolapsed Disks
# Overview
Intervertebral disk slip consists of 2 main parts, nucleus pulposus the central part, and annulus fibrosus the peripheral part. Intervertebral disc slip occurs when nucleus pulposus protrudes through annulus fibrosus. Most commonly disc slip is caused by degenerative changes and traumatic insults to the spine. Although, disc herniation can occur in any part of the vertebral column but lumbar disc slips are far more common than disc herniations in other parts of the spine. Males, obese, smokers and heavy weight lifters are at increased risk of developing disk slip. Clinical features of the disk slip vary depending upon the location and presence or absence of nerve impingement. Common clinical features include back pain, pain radiating to upper or lower extremity, motor weakness, numbness or tingling, absent deep tendon reflexes. MRI and CT scan have excellent sensitivity in diagnosing intervertebral disc slip. Conservative management starts with lifestyle modifications and medical therapy. Most of the patients get pain relief with conservative management. For severe or persistent cases surgical management can be used.
# Historical Perspective
- Intervertebral disc slip was first described by Virchow, a german physician, in [1857] in his publication related to disc pathologies. [1]
- In [1887], the first laminectomy was done by William MacEwen and Victor Horsely to treat lumbar disc slip. The first discectomy was done by surgeon Fedor Krause in 1908. [2] [3]
# Classification
- Intervertebral disc slip may be classified according to the extent of displacement of nucleus pulposus into 4 subtypes[4]:
- Bulging: Disc margins extend beyond vertebral endplate margins.
- Protrusion: Nucleus pulposus impinges on annulus fibrosus, posterior longitudinal ligament stays intact.
- Extrusion: Nucleus pulposus extrudes through the annulus fibrosus, posterior longitudinal ligament stays intact.
- Sequestration: Posterior longitudinal ligament is compromised. Nucleus pulposus extrudes through the annulus fibrosus and posterior longitudinal ligament into epidural space.
# Pathophysiology
- The pathogenesis of disc slip is characterized by bulging of nucleus pulposus of the disk through the annulus pulposus. Nucleus pulposus is the central part of the intervertebral disc that contains proteoglycans. Proteoglycans cause water retention, thus nucleus pulposus is responsible for providing cushioning effect to vertebrae. Annulus fibrosis is the peripheral ring surrounding nucleus pulposus that is responsible for keeping nucleus pulposus in the center of the disk. Displaced fragments of nucleus pulposus can then compress the nerve roots passing behind the intervertebral disk space. Disc degeneration is the most common preceding factor in the development of disk slip. Several underlying changes have been implicated in the development of slipped discs including decreased water content in nucleus pulposus, increased activity of degradative processes including inflammatory mediators, apoptosis, and matrix metalloproteinase enzyme leading to degeneration of intervertebral discs. Role of multiple genes has also been implicated in intervertebral disc degeneration and consequent herniation. It is also documented that axial overburdening of vertebral column may cause disc slip. [5][6][7]
- Genes responsible for disc slip include genes coding for matrix metalloproteinases, structural proteins, Vitamin D receptor, apoptosis factors, growth factors, collagen type I and IX, interleukin 1, interleukin 6, asporin, aggrecan. [8][6]
# Causes
Disc slip may be caused by age-related degenerative changes, systemic inflammatory processes, vertebral trauma, sudden vertebral strain, twisted movement of the spine, connective tissue disorders. [9] [10]
# Differentiating intervertebral disc slip from other Diseases
- Disc slip must be differentiated from other diseases that cause radicular pain, sensory deficits, and motor weakness, such as[10] [11]:
- Spinal tumors
- Spinal abscess
- Spinal fractures
- Spinal stenosis
- Arthritis
- Spinal cysts
- Epidural hematoma
# Epidemiology and Demographics
- The incidence of intervertebral disc slip is estimated to be [5-20] cases per 1000 individuals annually. In case of lumbar disc slips, 95% of the herniations in patients aged between 25 to 55 occur at L4-L5 or L5-S1 level. In case of cervical spine, C6-C7 disc is most commonly herniated.[12] [13]
## Age
- Intervertebral disc slip is more commonly observed among patients aged 30 to 50 years old.
## Gender
- Males are more commonly affected with intervertebral disc slip than females.[12]
## Race
- There is no racial predilection for intervertebral disc slip.
# Risk Factors
- Common risk factors in the development of intervertebral disc slip are male gender, excessive body weight, smoking, sedentary life style, abrupt increase in physical activity, heavy weight lifting, poor posture, poor nutrition. [9] [14]
# Natural History, Complications and Prognosis
- Two-third of patients with lumbar disc herniation improve within 6 months as herniated disk tends to regress over time. After 6 weeks, only around 10% of the patients have persistent pain to consider surgery. [15]
- If left untreated, patients with intervertebral disc slip may develop chronic back pain, permanent nerve damage, persistent motor weakness, persistent sensory deficits, Cauda equina syndrome. [14] [16]
# Diagnosis
## Diagnostic Criteria
There are no specific diagnostic criteria for intervertebral disc slip.
## History and Symptoms
- Symptoms of Intervertebral disc slip depend upon the site and extent of the slipped disc and are present in the are supplied by the compressed nerve. They may include the following[10][17]:
### Lumbar disc slip
- Lower back pain
- electric shock like or sharp pain radiating from buttock to leg(sciatica)
- numbness or tingling in one leg
- lower extremity weakness
- loss of bowel or bladder control
- pain aggravation with walking, standing or sitting
### Cervical or thoracic disc slip
- Neck pain
- pain between shoulder girdles
- pain radiating down the arm to the hand or fingers
- numbness/tingling in the forearm, arm or shoulder
- increase in pain with neck movements.
- weakness in the muscles of hand or forearm
## Physical Examination
- Physical examination findings depend upon the nerve root compressed and maybe remarkable for[11]:
- C5 nerve: numbness in lateral arm, weakened shoulder abduction, external rotation, forearm supination and elbow flexion, abnormal biceps reflex and brachioradialis reflex.
- C6 nerve: numbness in thumb, index finger, lateral foream, weakened shoulder abduction, external rotation, forearm supination, forearm pronation and elbow flexion, abnormal biceps reflex and brachioradialis reflex.
- C7 nerve: numbness in palm, index and middle fingers, weakened wrist flexion, radial extension, and forearm pronation, abnormal triceps reflex.
- C8 nerve: numbness in medial forearm and hand, weakened distal finger flexion, extension, abduction, adduction, distal thumb flexion and wrist extension. Normal reflexes
- T1 nerve: numbness in anterior and medial forearm, weakened finger adduction, abduction, thumb abduction and distal thumb flexion. Normal deep tendon reflexes
- L1 nerve: altered sensation in inguinal region, weakened hip flexion.
- L2,L3,L4 nerves: altered sensation in medial leg and anterior thigh, weakened hip fexion, adduction, knee extension, abnormal patellar reflex.
- L5 nerve: altered sensation in lateral calf, dorsal for and space between 1st and 2nd toe, weakened hip abduction, knee flexion, foot dorsiflexion, toe flexion and extension, foot eversion and inversion. Abnormal semitendinosus or semimembranosus reflex.
- S1 nerve: altered sensation on posterior calf, lateral or plantar foot, weakened hip extension, knee flexion, foot plantar flexion, loss of bowel or bladder control, sexual dysfunction.
- S2-S4 nerves: altered sensation on medial side of buttock, perianal and perineal region, absence of wink and bulbocavernosus reflex.
- positive straight leg raise test in lumbar radiculopathy.
## Laboratory Findings
- There are no specific laboratory findings associated with intervertebral disc slip.
## Electrocardiogram
There are no ECG findings associated with intervertebral disc slip.
## X-ray
There are no x-ray findings associated with intervertebral disc slip. However, an x-ray may be helpful in detecting other etiologies causing similar symptoms like fractures, abscesses, tumors, bony spurs etc.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with intervertebral disc slip.
## CT scan
CT scan may be helpful in the diagnosis of intervertebral disc slip. Like MRI, CT scan also provides a detailed view of the spinal canal and its contents, thus it can detect disc slip along with its extent and location.Findings on CT scan suggestive of intervertebral disc slip include bulging of intervertebral disc, nerve root compression, and spinal cord compression. [10] [18]
## MRI
MRI may be helpful in the diagnosis of intervertebral disc slip, as it is considered the gold standard for the diagnosis of this disorder. MRI has an excellent capacity to visualize all the soft tissues including the spinal cord, and nerve roots thus it can easily detect bulging intervertebral disc and also if there is any compression of nerve root or spinal cord. MRI is also very helpful in ruling out other differentials.[18][10]
## Other Imaging Findings
Myelogram may be helpful in the diagnosis of intervertebral disc slip. It is a modified x-ray technique in which the spinal canal is visualized after injection of a contrast material. It can show if a slipped disk is compressing a nerve root or spinal cord[10]
## Other Diagnostic Studies
Electromyogram and nerve conduction studies may be helpful in the diagnosis of intervertebral disc slip. These tests assess the response of nerve or muscle to electric stimulation. They can reveal if there is any nerve damage or compression as a consequence of slipped disk.[10][18]
# Treatment
Certain non-pharmacologic treatments and lifestyle modifications can be used before any pharmacologic treatment is done. They include maintenance of activity level that is painless, physiotherapy, avoidance of any activity that incites pain, avoidance from lifting heavy weights, weight control, use of spinal support, spinal massage, spinal manipulation, spinal traction, heat or ice application. [10][9]
## Medical Therapy
- The medical treatment options for pain relief in intervertebral disc slip are analgesic medications like NSAIDS or acetaminophen, muscle relaxants, steroids and anti depressants. A steroid injection in the epidural space may also be administered to provide pain relief. [10][9]
## Surgery
- Discectomy can be performed for patients with intervertebral disc slip who do not improve with medical management and lifestyle modifications. It can also be performed in patients with persistent or progressive neurologic deficit due to nerve compression. Discectomy is of 2 types. Microsurgical discectomy involves a small incision in the center of the back followed by microdissection to reach the herniated disk. Then the part of the disk impinging on the nerve root is removed. Microendoscopic discectomy involves an incision at the back. In order to reach the vertebra, dilators are used. Then an endoscope is used to access and remove the herniated disk. Microendoscopic discectomy causes lesser tissue damage than microsurgical discectomy. Other options like laser discectomy are also available but their efficacy is not fully proven. In selective cases, discectomy can be combined with laminectomy and spinal fusion[18] [16]
## Prevention
- Effective measures for the primary prevention of intervertebral disc slip include maintaining a normal body weight, regular exercise, smoking cessation and good posture. [14] | https://www.wikidoc.org/index.php/Disc_slip | |
5b0fd216361bebc0775c7efb1a656f48d19f8056 | wikidoc | Discharge | Discharge
# Overview
Discharge is an exudate draining from the wounds. It can be internal or external. It is formed from the serum.
# Classification
## Serous
(resembling serum)
- Clear or straw colored in appearance.
- Arises from protein and fluid in the tissue.
- Supports the healing process and contains protein, electrolytes, sugar and white cells.
- Occurs as a normal process of healing.
## Sanguinous
(contains blood cells)
- Red drainage from trauma to a blood vessel.
- This may occur with the cleaning of a wound or disturbance to a wound.
- The consistency appears thin and watery with sanguinous fluid.
- Discharge fluid contains red blood cells, which give it its red appearance.
## Serosanguinous
(consisting of serum and blood)
- Serosanguinous fluid appears pink due to a small number of blood cells mixing with serous drainage.
- Thin and water-like consistency.
- Serosanguinous fluid is a normal occurrence in the healing of wounds.
## Purulent
(containing pus)
- Purulent discharge is yellow, gray or green in color.
- It results when infection occurs.
- The discharge fluid has infectious microbes, white cells and other inflammatory cells.
- The volume of the exudate increases with prolonged infection.
## Mucopurulent
(containing mucus and pus)
- Mucopurulent discharge is pus with mucoid cells.
- It is a whitish-yellow or yellow substance produced during inflammatory responses of the body.
- It can be noticed in regions of pyogenic bacterial infections.
- It consists of a thin, protein-rich fluid, known as liquor puris, and dead neutrophils (white blood cells), which are part of the body's innate immune response.
## Hemorrhagic
(characterized by hemorrhage)
- Hemorrhagic discharge indicates a leaking blood vessel leaking blood.
- The consistency is thicker than sanguinous fluid.
- It may require surgical methods to control bleeding. | Discharge
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [2]
# Overview
Discharge is an exudate draining from the wounds. It can be internal or external. It is formed from the serum.
# Classification
## Serous
(resembling serum)
- Clear or straw colored in appearance.
- Arises from protein and fluid in the tissue.
- Supports the healing process and contains protein, electrolytes, sugar and white cells.
- Occurs as a normal process of healing.
## Sanguinous
(contains blood cells)
- Red drainage from trauma to a blood vessel.
- This may occur with the cleaning of a wound or disturbance to a wound.
- The consistency appears thin and watery with sanguinous fluid.
- Discharge fluid contains red blood cells, which give it its red appearance.
## Serosanguinous
(consisting of serum and blood)
- Serosanguinous fluid appears pink due to a small number of blood cells mixing with serous drainage.
- Thin and water-like consistency.
- Serosanguinous fluid is a normal occurrence in the healing of wounds.
## Purulent
(containing pus)
- Purulent discharge is yellow, gray or green in color.
- It results when infection occurs.
- The discharge fluid has infectious microbes, white cells and other inflammatory cells.
- The volume of the exudate increases with prolonged infection.
## Mucopurulent
(containing mucus and pus)
- Mucopurulent discharge is pus with mucoid cells.
- It is a whitish-yellow or yellow substance produced during inflammatory responses of the body.
- It can be noticed in regions of pyogenic bacterial infections.
- It consists of a thin, protein-rich fluid, known as liquor puris, and dead neutrophils (white blood cells), which are part of the body's innate immune response.
## Hemorrhagic
(characterized by hemorrhage)
- Hemorrhagic discharge indicates a leaking blood vessel leaking blood.
- The consistency is thicker than sanguinous fluid.
- It may require surgical methods to control bleeding. | https://www.wikidoc.org/index.php/Discharge | |
1bc1a0402fc424ffe43debd8d7e07da5bb57a3c8 | wikidoc | Distichia | Distichia
A distichia is an eyelash that arises from an abnormal spot on the eyelid of a dog. Distichiae usually exit from the duct of the meibomian gland at the eyelid margin. They are usually multiple and sometimes more than one arises from a duct. They can affect either the upper or lower eyelid and are usually bilateral. The lower eyelids of dogs usually have no eyelashes. Distichiae usually cause no symptoms because the lashes are soft, but they can irritate the eye and cause tearing, squinting, inflammation, and corneal ulcers and scarring. Treatment options include manual removal, electrolysis, electrocautery, cryotherapy, and surgery.
# Commonly affected breeds
In veterinary medicine, some canine breeds are affected by distichiasis more frequently than others:
- Cocker Spaniel
- Dachshund (especially the miniature longhaired Dachshund)
- Bulldog
- Pekingese
- Yorkshire Terrier
- Flat-Coated Retriever
- Shetland Sheepdog
- Poodle
- Elo (dog)
# Ectopic cilia
An ectopic cilia is a special type of distichia. It is usually found in younger dogs. Commonly affected breeds include Poodles, Golden Retrievers, and Shih Tzus. The eyelash exits through the conjunctiva, usually at the middle of the upper eyelid. It can cause intense pain and corneal ulcers. Treatment is surgery or cryotherapy. | Distichia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A distichia is an eyelash that arises from an abnormal spot on the eyelid of a dog. Distichiae usually exit from the duct of the meibomian gland at the eyelid margin. They are usually multiple and sometimes more than one arises from a duct. They can affect either the upper or lower eyelid and are usually bilateral. The lower eyelids of dogs usually have no eyelashes.[1] Distichiae usually cause no symptoms because the lashes are soft, but they can irritate the eye and cause tearing, squinting, inflammation, and corneal ulcers and scarring.[2] Treatment options include manual removal, electrolysis, electrocautery, cryotherapy, and surgery.
# Commonly affected breeds
In veterinary medicine, some canine breeds are affected by distichiasis more frequently than others:
- Cocker Spaniel
- Dachshund (especially the miniature longhaired Dachshund)
- Bulldog
- Pekingese
- Yorkshire Terrier
- Flat-Coated Retriever
- Shetland Sheepdog
- Poodle[3]
- Elo (dog)[4]
# Ectopic cilia
An ectopic cilia is a special type of distichia. It is usually found in younger dogs. Commonly affected breeds include Poodles, Golden Retrievers, and Shih Tzus.[5] The eyelash exits through the conjunctiva, usually at the middle of the upper eyelid. It can cause intense pain and corneal ulcers. Treatment is surgery or cryotherapy. | https://www.wikidoc.org/index.php/Distichia | |
0fd0176924dc82ecd56dbe1d3409034fee5a802b | wikidoc | Dithranol | Dithranol
# Overview
Dithranol (INN) or Anthralin (USAN and former BAN) is a Hydroxyanthrone, anthracene derivative, medicine applied to the skin of people with psoriasis. It is available as creams, ointment or pastes in 0.1 to 2% stengths (Dithrocream®, Micanol® and Psorlin®).
# Pharmacology
Dithranol accumulates in mitochondria where it interferes with the supply of energy to the cell, probably by the oxidation of dithranol releasing free radicals. This impedes DNA replication and so slows the excessive cell division that occurs in psoriatic plaques. In addition Dithranol may act by reducing the elevated levels of cGMP that occurs in psoriasis.
More dithranol penetrates into impaired skin in 30 minutes than into intact skin during about 16 hours. For this reason weaker 0.1-0.5% preparations are applied over night, but stronger 1-2% products are applied for between 30 minutes and one hour depending upon the formulation.
# Clinical considerations
Dithranol has a slower onset of action in controlling psoriasis, typically several weeks, compared to glucocorticoid steroids, but is without the potential for rebound reaction on withdrawal. It cannot be used on the face or genitalia.
# Side effects
It temporarily stains the skin a yellowy-brown and permanently stains clothing fabrics. It may cause a local burning sensation and irritation, this may be minimised by careful attention to the details of treatment and only gradually stepping up through the strengths of dithranol formulations. The surrounding skin can be protected using soft white paraffin and the treated area is covered with tube gauze. | Dithranol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dithranol (INN) or Anthralin (USAN and former BAN) is a Hydroxyanthrone, anthracene derivative, medicine applied to the skin of people with psoriasis. It is available as creams, ointment or pastes in 0.1 to 2% stengths (Dithrocream®, Micanol® and Psorlin®).
# Pharmacology
Dithranol accumulates in mitochondria where it interferes with the supply of energy to the cell, probably by the oxidation of dithranol releasing free radicals. This impedes DNA replication and so slows the excessive cell division that occurs in psoriatic plaques. In addition Dithranol may act by reducing the elevated levels of cGMP that occurs in psoriasis.
More dithranol penetrates into impaired skin in 30 minutes than into intact skin during about 16 hours. For this reason weaker 0.1-0.5% preparations are applied over night, but stronger 1-2% products are applied for between 30 minutes and one hour depending upon the formulation.
# Clinical considerations
Dithranol has a slower onset of action in controlling psoriasis, typically several weeks, compared to glucocorticoid steroids, but is without the potential for rebound reaction on withdrawal. It cannot be used on the face or genitalia.
# Side effects
It temporarily stains the skin a yellowy-brown and permanently stains clothing fabrics. It may cause a local burning sensation and irritation, this may be minimised by careful attention to the details of treatment and only gradually stepping up through the strengths of dithranol formulations. The surrounding skin can be protected using soft white paraffin and the treated area is covered with tube gauze. | https://www.wikidoc.org/index.php/Dithranol | |
bc5fa34359427595447d29c601b26b2fbeb6f284 | wikidoc | Docetaxel | Docetaxel
Docetaxel Injection should not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 x ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of Docetaxel Injection therapy. Docetaxel Injection therapy should not be given to patients with neutrophil counts of <1500 cells/mm3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving Docetaxel Injection.
Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received a 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and administration of appropriate therapy. Docetaxel Injection must not be given to patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80.
Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites)
- All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.
- For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the Docetaxel Injection infusion.
# Breast Cancer
- Locally advanced or metastatic breast cancer after failure of prior chemotherapy
- Dose of Docetaxel Injection is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.
- Adjuvant treatment of operable node-positive breast cancer
- Docetaxel Injection dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2
- Cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses.
# Non-Small Cell Lung Cancer
- Treatment after failure of prior platinum-based chemotherapy
- Dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks.
- For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin
- Dosage: Docetaxel Injection is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30-60 minutes every 3 weeks.
# Prostate Cancer
- For hormone-refractory metastatic prostate cancer
- Docetaxel Injection 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion.
- Prednisone 5 mg orally twice daily is administered continuously
# Gastric Adenocarcinoma
- Dosage: Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m 2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion.
- Treatment is repeated every three weeks.
- Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration.
# Head and Neck Cancer
- Docetaxel Injection in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
- Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the docetaxel containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.
- Induction chemotherapy followed by radiotherapy (TAX323)
For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.
- Induction chemotherapy followed by chemoradiotherapy (TAX324)
For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.
- Neoadjuvant treatment in combination with an anthracycline-containing regimen for breast cancer
- Carcinoma of bladder
- Carcinoma of esophagus
- Mobilization of harvesting of peripheral blood stem cells
- Head and neck cancer
- Previously treated advanced ovarian cancer
- First line in combination with carboplatin for ovarian cancer
- Small cell carcinoma of lung
- Docetaxel Injection should not be used in patients with neutrophil counts of <1500 cells/mm3.
- Docetaxel administered at 100 mg/m2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN).
- Among patients dosed at 60 mg/m2, mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function.
- Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.
- Docetaxel administered at a dose of 100 mg/m2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies).
- There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m2 dose in the randomized trials.
- Among patients who experienced treatment-related mortality at the 75 mg/m2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry.
# Hepatic Impairment
Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Docetaxel Injection.
# Hematologic Effects
- Perform frequent peripheral blood cell counts on all patients receiving Docetaxel Injection.
- Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophil recover to a level >1500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3.
- A 25% reduction in the dose of Docetaxel Injection is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Docetaxel Injection cycle.
- Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 100 mg/m2 of docetaxel and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2.
- Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Docetaxel Injection should not be administered to patients with neutrophils <1500 cells/mm3.
- Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was very uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related.
- Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia.
- In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not.
- Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection.
# Hypersensitivity Reactions
- Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions.
- Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids.
- Severe hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and aggressive therapy.
- Patients with a history of severe hypersensitivity reactions should not be rechallenged with Docetaxel Injection.
- Hypersensitivity reactions may occur within a few minutes following initiation of a Docetaxel Injection infusion.
- If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required.
- All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Docetaxel Injection.
# Fluid Retention
- Severe fluid retention has been reported following docetaxel therapy. *Patients should be premedicated with oral corticosteroids prior to each Docetaxel Injection administration to reduce the incidence and severity of fluid retention.
- Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.
- When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.
- Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%.
- The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2.
- Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention.
- The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m2.
- Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks).
- Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).
# Acute Myeloid Leukemia
- Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer.
- In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel, doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin and cyclophosphamide. In TAC-treated patients, the risk of delayed myelodysplasia or acute myeloid leukemia requires hematological follow-up.
# Cutaneous Reactions
- Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended.
- The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients.
- Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued docetaxel due to skin toxicity.
# Neurologic Reactions
- Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted.
- If symptoms persist, treatment should be discontinued. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks).
- Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).
# Asthenia
- Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.
- Toxic Deaths
- Hepatotoxicity
- Neutropenia
- Hypersensitivity
- Fluid Retention
The most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.
Adverse reactions are described according to indication. 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.
Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established.
- Body as a whole: diffuse pain, chest pain, radiation recall phenomenon.
- Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.
- Cutaneous: very rare cases of cutaneous lupus erythematosis and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema.
- In some cases multiple factors may have contributed to the development of these effects.
- Severe hand and foot syndrome has been reported.
- Gastrointestinal: abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.
- Hematologic: Bleeding episodes- Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.
- Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.
- Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.
- Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.
- Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion.
- Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.
- Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.
- Renal: renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of Docetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with Docetaxel Injection, close monitoring for toxicity and a Docetaxel Injection dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.
Docetaxel Injection can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m2 basis), administered during the period of organogenesis, have shown that docetaxel is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity.
# Non-Small Cell Lung Cancer
In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively).
When docetaxel was combined with carboplatin for the treatment of chemotherapy-naïve, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin.
# Prostate Cancer
Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the following treatment emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively.
# Breast Cancer
In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients.
# Gastric Cancer
Among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored.
# Head and Neck Cancer
Among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively.
These clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients.
- Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during Docetaxel Injection therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docetaxel Injection therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.
- Combination Therapy with Docetaxel Injection in the Adjuvant Treatment of Breast Cancer
- Docetaxel Injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their Docetaxel Injection dose reduced to 60 mg/ m2. Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection dose decreased to 60 mg/ m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have their dosage of Docetaxel Injection reduced from 75 to 60 mg/ m2. If the patient continues to experience these reactions at 60 mg/ m2, treatment should be discontinued.
# Non-Small Cell Lung Cancer
- Monotherapy with Docetaxel Injection for NSCLC treatment after failure of prior platinum-based chemotherapy
- Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Docetaxel Injection treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.
- Combination therapy with Docetaxel Injection for chemotherapy-naïve NSCLC
- For patients who are dosed initially at Docetaxel Injection 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the docetaxel injection dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.
# Prostate Cancer
- Combination therapy with Docetaxel Injection for hormone-refractory metastatic prostate cancer
- Docetaxel injection should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have the dosage of Docetaxel Injection reduced from 75 to 60 mg/ m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.
# Gastric or Head and Neck Cancer
- Docetaxel Injection in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer
- Patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist
# Liver dysfunction
- In case of AST/ALT >2.5 to ≤5 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 × ULN and AP >2.5 to ≤5 × ULN, Docetaxel Injection should be reduced by 20%.
- In case of AST/ALT >5 × ULN and/or AP >5 × ULN Docetaxel Injection should be stopped.
- The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:
Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:
- Grade 2: Reduce cisplatin dose by 20%.
- Grade 3: Discontinue treatment.
Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.
Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 × normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered
In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.
For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.
For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribing information.
Combination Therapy with Strong CYP3A4 inhibitors:
Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% Docetaxel Injection dose reduction if patients require co-administration of a strong CYP3A4 inhibitor.
- In two reports of overdose, one patient received 150 mg/m2 and the other received 200 mg/m2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.
- In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m2 on a mg/m2 basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m2 on a mg/m2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.
Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14, and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water.
Distribution: The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.
Metabolism: In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 .
Elimination: A study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.
Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m2 basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.
Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50th the recommended human dose on a mg/m2 basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended human dose on a mg/m2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.
The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens).
In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m2 every 3 weeks) or the combination of mitomycin (12 mg/m2 every 6 weeks) and vinblastine (6 mg/m2 every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results.
In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m2) or doxorubicin (75 mg/m2) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below.
In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m2 (n=151), 75 mg/m2 (n=188) or 100 mg/m2 (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with docetaxel dose: 19.9% for the 60 mg/m2 group compared to 22.3% for the 75 mg/m2 and 29.8% for the 100 mg/m2 group; pair-wise comparison between the 60 mg/m2 and 100 mg/m2 groups was statistically significant (p=0.037).
Docetaxel at a dose of 100 mg/m2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0-44.8) and the complete response rate was 2.1%.
Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m2, in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2-55.7), similar to the response rate in single arm studies of 100 mg/m2.
# Adjuvant Treatment of Breast Cancer
A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC.
Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients.
At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90). There will be further analysis at the time survival data mature.
The following table describes the results of subgroup analyses for DFS and OS:
# Non-Small Cell Lung Cancer (NSCLC)
The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve.
Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy
Two randomized, controlled trials established that a docetaxel dose of 75 mg/m2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m2, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used.
One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m2. A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m2 or best supportive care.
In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to docetaxel 75 mg/m2, docetaxel 100 mg/m2 and a treatment in which the investigator chose either vinorelbine 30 mg/m2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m2 days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the docetaxel 75 mg/m2 arm and the comparator arms are summarized in Table 15 and Figures 3 and 4 showing the survival curves for the two studies.
Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m2.
Patients treated with docetaxel at a dose of 75 mg/m2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.
In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m2 administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin.
The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 16.
The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 17).
# Hormone Refractory Prostate Cancer
The safety and efficacy of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups:
- Docetaxel 75 mg/m 2 every 3 weeks for 10 cycles.
- Docetaxel 30 mg/m 2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
- Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles.
All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.
In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 18 and Figure 5.
# Gastric Adenocarcinoma
A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either docetaxel (T) (75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and fluorouracil (1000 mg/m2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The demographic characteristics were balanced between the two treatment arms. The median age was 55 years, 71% were male, 71% were Caucasian, 24% were 65 years of age or older, 19% had a prior curative surgery and 12% had palliative surgery. The median number of cycles administered per patient was 6 (with a range of 1 to 16) for the TCF arm compared to 4 (with a range of 1 to 12) for the CF arm. Time to progression (TTP) was the primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization. The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19 to 1.83) with a significantly longer TTP (p=0.0004) in the TCF arm. Approximately 75% of patients had died at the time of this analysis. Overall survival was significantly longer (p=0.0201) in the TCF arm with a HR of 1.29 (95% CI: 1.04 to 1.61). Efficacy results are summarized in Table 19 and Figures 6 and 7.
# Head and Neck Cancer
The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 on Day 1, followed by fluorouracil (F) 750 mg/m2 per day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 on Day 1, followed by fluorouracil (F) 1000 mg/m2 /day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy to 2 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy.
The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively). Efficacy results are presented in Table 20 and Figures 8 and 9.
The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m2/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m2/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles.
All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT.
The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the docetaxel-containing regimen compared to PF . Overall survival results are presented in Table 21 and Figure 10.
- 20 mg/2 mL
- Carton of 1 x 2 mL Multiple Dose Vial
- 80 mg/8 mL
- Carton of 1 x 8 mL Multiple Dose Vial
- 160 mg/16 mL
- Carton of 1 x 16 mL Multiple Dose Vial
- Obtain detailed allergy and concomitant drug information from the patient prior to Docetaxel Injection administration.
- Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report if they were not compliant with oral corticosteroid regimen.
- Instruct patients to immediately report signs of a hypersensitivity reaction.
- Tell patients to watch for signs of fluid retention such as peripheral edema in the lower extremities, weight gain and dyspnea.
- Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.
- Instruct patients to report myalgia, cutaneous, or neurologic reactions.
- Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, fatigue, excessive tearing, infusion site reactions, and hair loss are associated with docetaxel administration.
- Docefrez
- ↑ "FDA LABEL: DOCETAXEL- docetaxel injection, solution"..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} | Docetaxel
Docetaxel Injection should not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death. Patients with isolated elevations of transaminase >1.5 x ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, AST or ALT, and alkaline phosphatase values should be obtained prior to each cycle of Docetaxel Injection therapy. Docetaxel Injection therapy should not be given to patients with neutrophil counts of <1500 cells/mm3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving Docetaxel Injection.
Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received a 3-day dexamethasone premedication. Hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and administration of appropriate therapy. Docetaxel Injection must not be given to patients who have a history of severe hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 80.
Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites)
- All patients should be premedicated with oral corticosteroids (see below for prostate cancer) such as dexamethasone 16 mg per day (e.g., 8 mg twice daily) for 3 days starting 1 day prior to Docetaxel Injection administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.
- For hormone-refractory metastatic prostate cancer, given the concurrent use of prednisone, the recommended premedication regimen is oral dexamethasone 8 mg, at 12 hours, 3 hours and 1 hour before the Docetaxel Injection infusion.
### Breast Cancer
- Locally advanced or metastatic breast cancer after failure of prior chemotherapy
- Dose of Docetaxel Injection is 60 mg/m2 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks.
- Adjuvant treatment of operable node-positive breast cancer
- Docetaxel Injection dose is 75 mg/m2 administered 1 hour after doxorubicin 50 mg/m2
- Cyclophosphamide 500 mg/m2 every 3 weeks for 6 courses.
### Non-Small Cell Lung Cancer
- Treatment after failure of prior platinum-based chemotherapy
- Dose is 75 mg/m 2 administered intravenously over 1 hour every 3 weeks.
- For chemotherapy-naïve patients, docetaxel was evaluated in combination with cisplatin
- Dosage: Docetaxel Injection is 75 mg/m2 administered intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30-60 minutes every 3 weeks.
### Prostate Cancer
- For hormone-refractory metastatic prostate cancer
- Docetaxel Injection 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion.
- Prednisone 5 mg orally twice daily is administered continuously
### Gastric Adenocarcinoma
- Dosage: Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m 2 per day given as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin infusion.
- Treatment is repeated every three weeks.
- Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration.
### Head and Neck Cancer
- Docetaxel Injection in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
- Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the docetaxel containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.
- Induction chemotherapy followed by radiotherapy (TAX323)
For the induction treatment of locally advanced inoperable SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion followed by cisplatin 75 mg/m2 intravenously over 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. Following chemotherapy, patients should receive radiotherapy.
- Induction chemotherapy followed by chemoradiotherapy (TAX324)
For the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN, the recommended dose of Docetaxel Injection is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.
- Neoadjuvant treatment in combination with an anthracycline-containing regimen for breast cancer
- Carcinoma of bladder
- Carcinoma of esophagus
- Mobilization of harvesting of peripheral blood stem cells
- Head and neck cancer
- Previously treated advanced ovarian cancer
- First line in combination with carboplatin for ovarian cancer
- Small cell carcinoma of lung
- Docetaxel Injection should not be used in patients with neutrophil counts of <1500 cells/mm3.
- Docetaxel administered at 100 mg/m2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN).
- Among patients dosed at 60 mg/m2, mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function.
- Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.
- Docetaxel administered at a dose of 100 mg/m2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies).
- There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m2 dose in the randomized trials.
- Among patients who experienced treatment-related mortality at the 75 mg/m2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry.
### Hepatic Impairment
Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Docetaxel Injection.
### Hematologic Effects
- Perform frequent peripheral blood cell counts on all patients receiving Docetaxel Injection.
- Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophil recover to a level >1500 cells/mm3 and platelets recover to a level > 100,000 cells/mm3.
- A 25% reduction in the dose of Docetaxel Injection is recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Docetaxel Injection cycle.
- Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 100 mg/m2 of docetaxel and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2.
- Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Docetaxel Injection should not be administered to patients with neutrophils <1500 cells/mm3.
- Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was very uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related.
- Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia.
- In gastric cancer patients treated with docetaxel in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not.
- Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection.
### Hypersensitivity Reactions
- Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions.
- Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids.
- Severe hypersensitivity reactions require immediate discontinuation of the Docetaxel Injection infusion and aggressive therapy.
- Patients with a history of severe hypersensitivity reactions should not be rechallenged with Docetaxel Injection.
- Hypersensitivity reactions may occur within a few minutes following initiation of a Docetaxel Injection infusion.
- If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required.
- All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Docetaxel Injection.
### Fluid Retention
- Severe fluid retention has been reported following docetaxel therapy. *Patients should be premedicated with oral corticosteroids prior to each Docetaxel Injection administration to reduce the incidence and severity of fluid retention.
- Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.
- When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.
- Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%.
- The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m2.
- Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention.
- The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m2.
- Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of docetaxel to resolution (range: 0 to 42+ weeks).
- Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).
### Acute Myeloid Leukemia
- Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer.
- In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel, doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin and cyclophosphamide. In TAC-treated patients, the risk of delayed myelodysplasia or acute myeloid leukemia requires hematological follow-up.
### Cutaneous Reactions
- Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended.
- The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients.
- Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued docetaxel due to skin toxicity.
### Neurologic Reactions
- Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted.
- If symptoms persist, treatment should be discontinued. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks).
- Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).
### Asthenia
- Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.
- Toxic Deaths
- Hepatotoxicity
- Neutropenia
- Hypersensitivity
- Fluid Retention
The most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.
Adverse reactions are described according to indication. 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.
Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy, and treatment-related side effects has not been established.
- Body as a whole: diffuse pain, chest pain, radiation recall phenomenon.
- Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.
- Cutaneous: very rare cases of cutaneous lupus erythematosis and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema.
- In some cases multiple factors may have contributed to the development of these effects.
- Severe hand and foot syndrome has been reported.
- Gastrointestinal: abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.
- Hematologic: Bleeding episodes- Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.
- Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.
- Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.
- Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.
- Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion.
- Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.
- Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.
- Renal: renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.
In vivo studies showed that the exposure of docetaxel increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of Docetaxel Injection and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients receiving treatment with Docetaxel Injection, close monitoring for toxicity and a Docetaxel Injection dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided.
Docetaxel Injection can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m2 basis), administered during the period of organogenesis, have shown that docetaxel is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity.
### Non-Small Cell Lung Cancer
In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients less than 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients less than the age of 65 administered the same treatment (43%, 31%, 31% and 21%, respectively).
When docetaxel was combined with carboplatin for the treatment of chemotherapy-naïve, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin.
### Prostate Cancer
Of the 333 patients treated with docetaxel every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with docetaxel every three weeks, the following treatment emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively.
### Breast Cancer
In the adjuvant breast cancer trial (TAX316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients.
### Gastric Cancer
Among the 221 patients treated with docetaxel in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored.
### Head and Neck Cancer
Among the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively.
These clinical studies of docetaxel in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients.
- Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, or severe or cumulative cutaneous reactions during Docetaxel Injection therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should either be decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m2 and who do not experience febrile neutropenia, neutrophils <500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during Docetaxel Injection therapy may tolerate higher doses. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.
- Combination Therapy with Docetaxel Injection in the Adjuvant Treatment of Breast Cancer
- Docetaxel Injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their Docetaxel Injection dose reduced to 60 mg/ m2. Patients who experience grade 3 or 4 stomatitis should have their Docetaxel Injection dose decreased to 60 mg/ m2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have their dosage of Docetaxel Injection reduced from 75 to 60 mg/ m2. If the patient continues to experience these reactions at 60 mg/ m2, treatment should be discontinued.
### Non-Small Cell Lung Cancer
- Monotherapy with Docetaxel Injection for NSCLC treatment after failure of prior platinum-based chemotherapy
- Patients who are dosed initially at 75 mg/m2 and who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Docetaxel Injection treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop ≥grade 3 peripheral neuropathy should have Docetaxel Injection treatment discontinued entirely.
- Combination therapy with Docetaxel Injection for chemotherapy-naïve NSCLC
- For patients who are dosed initially at Docetaxel Injection 75 mg/m2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the docetaxel injection dosage in subsequent cycles should be reduced to 65 mg/m2. In patients who require a further dose reduction, a dose of 50 mg/m2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.
### Prostate Cancer
- Combination therapy with Docetaxel Injection for hormone-refractory metastatic prostate cancer
- Docetaxel injection should be administered when the neutrophil count is ≥1,500 cells/mm3. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Docetaxel Injection therapy should have the dosage of Docetaxel Injection reduced from 75 to 60 mg/ m2. If the patient continues to experience these reactions at 60 mg/m2, the treatment should be discontinued.
### Gastric or Head and Neck Cancer
- Docetaxel Injection in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer
- Patients treated with Docetaxel Injection in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur the Docetaxel Injection dose should be reduced from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia the Docetaxel Injection dose should be reduced from 75 mg/m2 to 60 mg/m2. Patients should not be retreated with subsequent cycles of Docetaxel Injection until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. Discontinue treatment if these toxicities persist
### Liver dysfunction
- In case of AST/ALT >2.5 to ≤5 × ULN and AP ≤2.5 × ULN, or AST/ALT >1.5 to ≤5 × ULN and AP >2.5 to ≤5 × ULN, Docetaxel Injection should be reduced by 20%.
- In case of AST/ALT >5 × ULN and/or AP >5 × ULN Docetaxel Injection should be stopped.
- The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:
Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:
- Grade 2: Reduce cisplatin dose by 20%.
- Grade 3: Discontinue treatment.
Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.
Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 × normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered
In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.
For other greater than grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.
For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribing information.
Combination Therapy with Strong CYP3A4 inhibitors:
Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% Docetaxel Injection dose reduction if patients require co-administration of a strong CYP3A4 inhibitor.
- In two reports of overdose, one patient received 150 mg/m2 and the other received 200 mg/m2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.
- In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m2 on a mg/m2 basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m2 on a mg/m2 basis) and was associated with abnormal mitosis and necrosis of multiple organs.
Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14, and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water.
Distribution: The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.
Metabolism: In vitro drug interaction studies revealed that docetaxel is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 [see Drug Interactions (7)].
Elimination: A study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged drug.
Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg (about 1/60th to 1/15th the recommended human dose on a mg/m2 basis). Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays.
Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50th the recommended human dose on a mg/m2 basis), but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3rd and 1/15th the recommended human dose on a mg/m2 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.
The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens).
In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m2 every 3 weeks) or the combination of mitomycin (12 mg/m2 every 6 weeks) and vinblastine (6 mg/m2 every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results.
In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m2) or doxorubicin (75 mg/m2) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below.
In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m2 (n=151), 75 mg/m2 (n=188) or 100 mg/m2 (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with docetaxel dose: 19.9% for the 60 mg/m2 group compared to 22.3% for the 75 mg/m2 and 29.8% for the 100 mg/m2 group; pair-wise comparison between the 60 mg/m2 and 100 mg/m2 groups was statistically significant (p=0.037).
Docetaxel at a dose of 100 mg/m2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0-44.8) and the complete response rate was 2.1%.
Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m2, in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2-55.7), similar to the response rate in single arm studies of 100 mg/m2.
### Adjuvant Treatment of Breast Cancer
A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m2 administered 1-hour after doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (TAC arm), or doxorubicin 50 mg/m2 followed by fluorouracil 500 mg/m2 and cyclosphosphamide 500 mg/m2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC.
Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients.
At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90). There will be further analysis at the time survival data mature.
The following table describes the results of subgroup analyses for DFS and OS:
### Non-Small Cell Lung Cancer (NSCLC)
The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve.
Monotherapy with Docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy
Two randomized, controlled trials established that a docetaxel dose of 75 mg/m2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy (see below). Docetaxel at a dose of 100 mg/m2, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used.
One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m2. A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m2 or best supportive care.
In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to docetaxel 75 mg/m2, docetaxel 100 mg/m2 and a treatment in which the investigator chose either vinorelbine 30 mg/m2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m2 days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the docetaxel 75 mg/m2 arm and the comparator arms are summarized in Table 15 and Figures 3 and 4 showing the survival curves for the two studies.
Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m2.
Patients treated with docetaxel at a dose of 75 mg/m2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.
In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m2 administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m2 administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin.
The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin (see table below). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 16.
The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression (see Table 17).
### Hormone Refractory Prostate Cancer
The safety and efficacy of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups:
- Docetaxel 75 mg/m 2 every 3 weeks for 10 cycles.
- Docetaxel 30 mg/m 2 administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles.
- Mitoxantrone 12 mg/m 2 every 3 weeks for 10 cycles.
All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.
In the docetaxel every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the docetaxel every 3 week arm versus the control arm are summarized in Table 18 and Figure 5.
### Gastric Adenocarcinoma
A multicenter, open-label, randomized trial was conducted to evaluate the safety and efficacy of docetaxel for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not received prior chemotherapy for advanced disease. A total of 445 patients with KPS >70 were treated with either docetaxel (T) (75 mg/m2 on day 1) in combination with cisplatin (C) (75 mg/m2 on day 1) and fluorouracil (F) (750 mg/m2 per day for 5 days) or cisplatin (100 mg/m2 on day 1) and fluorouracil (1000 mg/m2 per day for 5 days). The length of a treatment cycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. The demographic characteristics were balanced between the two treatment arms. The median age was 55 years, 71% were male, 71% were Caucasian, 24% were 65 years of age or older, 19% had a prior curative surgery and 12% had palliative surgery. The median number of cycles administered per patient was 6 (with a range of 1 to 16) for the TCF arm compared to 4 (with a range of 1 to 12) for the CF arm. Time to progression (TTP) was the primary endpoint and was defined as time from randomization to disease progression or death from any cause within 12 weeks of the last evaluable tumor assessment or within 12 weeks of the first infusion of study drugs for patients with no evaluable tumor assessment after randomization. The hazard ratio (HR) for TTP was 1.47 (CF/TCF, 95% CI: 1.19 to 1.83) with a significantly longer TTP (p=0.0004) in the TCF arm. Approximately 75% of patients had died at the time of this analysis. Overall survival was significantly longer (p=0.0201) in the TCF arm with a HR of 1.29 (95% CI: 1.04 to 1.61). Efficacy results are summarized in Table 19 and Figures 6 and 7.
### Head and Neck Cancer
The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 followed by cisplatin (P) 75 mg/m2 on Day 1, followed by fluorouracil (F) 750 mg/m2 per day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m2 on Day 1, followed by fluorouracil (F) 1000 mg/m2 /day as a continuous infusion on Days 1 to 5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy to 2 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy.
The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively). Efficacy results are presented in Table 20 and Figures 8 and 9.
The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m2/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m2/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles.
All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT.
The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the docetaxel-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 to 0.90]. Overall survival results are presented in Table 21 and Figure 10.
- 20 mg/2 mL
- 66758-050-01
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- 66758-050-02
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- 160 mg/16 mL
- 66758-050-03
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- Obtain detailed allergy and concomitant drug information from the patient prior to Docetaxel Injection administration.
- Explain the significance of oral corticosteroids such as dexamethasone administration to the patient to help facilitate compliance. Instruct patients to report if they were not compliant with oral corticosteroid regimen.
- Instruct patients to immediately report signs of a hypersensitivity reaction.
- Tell patients to watch for signs of fluid retention such as peripheral edema in the lower extremities, weight gain and dyspnea.
- Explain the significance of routine blood cell counts. Instruct patients to monitor their temperature frequently and immediately report any occurrence of fever.
- Instruct patients to report myalgia, cutaneous, or neurologic reactions.
- Explain to patients that side effects such as nausea, vomiting, diarrhea, constipation, fatigue, excessive tearing, infusion site reactions, and hair loss are associated with docetaxel administration.
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74186b88a358413763ccbeb5ed9ef556a3be7d23 | wikidoc | Docosanol | Docosanol
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# Overview
Docosanol is an antiviral cream that is FDA approved for the treatment of cold sores, fever, blisters on the face or lips. Common adverse reactions include application site reaction.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Treats cold sores/fever, blisters on the face or lips
- Shortens healing time and duration of symptoms:
- Tingling, pain, burning, and/or itching
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Docosanol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Docosanol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Docosanol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Docosanol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Docosanol in pediatric patients.
# Contraindications
There is limited information regarding Docosanol Contraindications in the drug label.
# Warnings
For external use only
Do not use
- If you are allergic to any ingredient in this product
When using this product
Apply only to affected areas
- Do not use in or near the eyes
- Avoid applying directly inside your mouth
- Do not share this product with anyone. This may spread infection.
Stop use and ask a doctor if
- Your cold sore gets worse or the cold sore is not healed within 10 days
- Keep out of reach of children.
- If swallowed, get medical help or contact a poison control center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Docosanol in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Docosanol in the drug label.
# Drug Interactions
There is limited information regarding Docosanol Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Docosanol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Docosanol during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Docosanol with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Docosanol with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Docosanol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Docosanol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Docosanol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Docosanol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Docosanol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Docosanol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Docosanol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Docosanol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Docosanol in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Docosanol in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Docosanol Mechanism of Action in the drug label.
## Structure
There is limited information regarding Docosanol Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Docosanol in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Docosanol in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Docosanol in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Docosanol in the drug label.
# How Supplied
There is limited information regarding Docosanol How Supplied in the drug label.
## Storage
- Store at 20 o-25 oC (68 o-77 oF)
- Do not freeze
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Adults and children 12 years or over:
- Wash hands before and after applying cream
- Apply to affected area on face or lips at the first sign of cold sore/fever blister (tingle).
- Early treatment ensures the best results
- Rub in gently but completely
- Use 5 times a day until healed
Children under 12 years: ask a doctor
FREQUENTLY ASKED QUESTIONS:
How is ABREVA different from the over-the-counter cold sore remedies I have already been using?
- Abreva is the only FDA approved non-prescription cold sore medicine that can actually shorten healing time and the duration of symptoms. The sooner you start using ABREVA, the sooner you can begin healing your cold sore.
Who can use ABREVA?
- Adults and children 12 years and over can use ABREVA.
How often can I apply ABREVA?
- ABREVA should be used five times a day until the cold sore is healed. Apply it directly to the cold sore at the first sign of a tingle, redness, bump or itch for best results.
Can I apply cosmetics on top of ABREVA?
- Yes, cosmetics such as lipstick may be applied over ABREVA. However, use a separate applicator, like a cotton swab, to apply cosmetics over an unhealed cold sore to avoid spreading the infection. For best results, remove any cosmetics prior to applying ABREVA.
# Precautions with Alcohol
- Alcohol-Docosanol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
ABREVA
# Look-Alike Drug Names
There is limited information regarding Docosanol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Docosanol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, 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.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Docosanol is an antiviral cream that is FDA approved for the treatment of cold sores, fever, blisters on the face or lips. Common adverse reactions include application site reaction.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Treats cold sores/fever, blisters on the face or lips
- Shortens healing time and duration of symptoms:
- Tingling, pain, burning, and/or itching
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Docosanol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Docosanol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Docosanol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Docosanol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Docosanol in pediatric patients.
# Contraindications
There is limited information regarding Docosanol Contraindications in the drug label.
# Warnings
For external use only
Do not use
- If you are allergic to any ingredient in this product
When using this product
Apply only to affected areas
- Do not use in or near the eyes
- Avoid applying directly inside your mouth
- Do not share this product with anyone. This may spread infection.
Stop use and ask a doctor if
- Your cold sore gets worse or the cold sore is not healed within 10 days
- Keep out of reach of children.
- If swallowed, get medical help or contact a poison control center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Docosanol in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Docosanol in the drug label.
# Drug Interactions
There is limited information regarding Docosanol Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Docosanol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Docosanol during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Docosanol with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Docosanol with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Docosanol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Docosanol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Docosanol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Docosanol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Docosanol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Docosanol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Docosanol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Docosanol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Docosanol in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Docosanol in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Docosanol Mechanism of Action in the drug label.
## Structure
There is limited information regarding Docosanol Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Docosanol in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Docosanol in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Docosanol in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Docosanol in the drug label.
# How Supplied
There is limited information regarding Docosanol How Supplied in the drug label.
## Storage
- Store at 20 o-25 oC (68 o-77 oF)
- Do not freeze
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Adults and children 12 years or over:
- Wash hands before and after applying cream
- Apply to affected area on face or lips at the first sign of cold sore/fever blister (tingle).
- Early treatment ensures the best results
- Rub in gently but completely
- Use 5 times a day until healed
Children under 12 years: ask a doctor
FREQUENTLY ASKED QUESTIONS:
How is ABREVA different from the over-the-counter cold sore remedies I have already been using?
- Abreva is the only FDA approved non-prescription cold sore medicine that can actually shorten healing time and the duration of symptoms. The sooner you start using ABREVA, the sooner you can begin healing your cold sore.
Who can use ABREVA?
- Adults and children 12 years and over can use ABREVA.
How often can I apply ABREVA?
- ABREVA should be used five times a day until the cold sore is healed. Apply it directly to the cold sore at the first sign of a tingle, redness, bump or itch for best results.
Can I apply cosmetics on top of ABREVA?
- Yes, cosmetics such as lipstick may be applied over ABREVA. However, use a separate applicator, like a cotton swab, to apply cosmetics over an unhealed cold sore to avoid spreading the infection. For best results, remove any cosmetics prior to applying ABREVA.
# Precautions with Alcohol
- Alcohol-Docosanol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
ABREVA
# Look-Alike Drug Names
There is limited information regarding Docosanol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Docosanol | |
afdac58b04e024dc815debffdb6f78669b97dc0a | wikidoc | Doctorate | Doctorate
A doctorate is an academic degree that indicates a high, if not the highest, level of academic achievement. A terminal degree in most countries, some Central and Eastern European countries place the doctorate second only to the habilitation.
The term doctorate comes from the Latin docere, meaning "to teach", shortened from the full Latin title licentia docendi, meaning "license to teach." This was translated from the equivalent Arabic term ijazat attadris, which was a distinction granted to certain Islamic scholars, thus qualifying them to teach.
# Types of doctorate
Since the Middle Ages, there has been considerable evolution and proliferation in the number and types of doctorates awarded by universities throughout the world, and practices vary from one country to another. While a doctorate usually entitles one to be addressed as "doctor", usage of the title varies widely, depending on the type of doctorate earned and the doctor's occupation. See the main article for Doctor (title) for more information.
Broadly speaking, doctorates may be loosely classified into the following categories:
## Research doctorates
Research doctorates are awarded in recognition of both mastery of research methods (as evidenced in class grades and a comprehensive examination) and academic research that is ideally publishable in a peer-reviewed academic journal, but that will minimally be assessed by submission and defense of a thesis or dissertation. The best-known degree of this type is that of Doctor of Philosophy (PhD) awarded throughout the world; others include the U.S. degrees of Doctor of Engineering (DEng) and Doctor of Science (DSc or ScD), the UK Engineering Doctorate (EngD), and the German degree of Doctor rerum naturalium (Dr.rer.nat.).
The minimum time required to earn a doctorate varies by country, and can be a short as three years (excluding bachelor's and master's studies). However, some candidates can take anywhere from five to ten years to complete. The median number of years to completion of doctoral degrees for all fields in the US is seven years. Students are discouraged from taking unnecessarily long to graduate by having their financial support (stipends, research funds, etc.) relinquished. Furthermore, doctoral applicants were previously required have a master's degree, but many programs will now accept students straight out of undergraduate studies.
## Higher doctorates
In some countries, especially the United Kingdom, Ireland and some Scandinavian, Commonwealth nations or former USSR countries, there is a higher tier of
research doctorates, awarded on the basis of a formally submitted portfolio of published research of a very high standard. Examples include the Doctor of Science (DSc/ScD) and Doctor of Letters (DLitt/LittD) degrees found in the UK, Ireland and some Commonwealth countries, and the Danish doctorate (doktorgrad; e.g. dr.theol., doctor theologiæ, Latin for Doctor of Theology).
The German habilitation postdoctoral qualification is sometimes regarded as belonging to this category, even though, strictly speaking, the habilitation is not an academic degree, but rather a professional license to teach at a German university.
Higher doctorates are often also awarded honoris causa when a university wishes to formally recognize an individual's achievements and contributions to a particular field.
## Professional doctorates
Professional doctorates are awarded in certain fields where most holders of the degree are not engaged primarily in scholarly research, but rather in a profession, such as law, medicine, music or ministry. Examples include the U.S. degrees of Doctor of Medicine (MD) and Doctor of Jurisprudence (JD), the Dutch Professional Doctorate in Engineering (PDEng), and the Czech degrees of Doctor of Dental Medicine (MDDr.) and Doctor of Veterinary Medicine (MVDr.).
The term Professional Doctorate is also used to refer to research doctorates with a focus on applied research. Among others, these include the Doctor of Education (EdD), Doctor of Applied Linguistics (DAppLing), and Doctor of Business Administration (DBA).
## Honorary doctorates
When a university wishes to formally recognize an individual's contributions to a particular field or philanthropic efforts, it may choose to a doctoral degree honoris causa (i.e., "for the sake of the honor"), the university waiving the usual formal requirements for bestowal of the degree. Some universities (e.g., Cornell University, the University of Virginia) do not award honorary degrees, feeling the bestowal unethical.
# Country-specific practice
## Argentina
Similar to other countries, in Argentina the doctorate (doctorado) is the highest. The intention is that candidates produce true and original contributions in a specific field of knowledge within a frame of academic excellence. The doctoral candidate's work should be presented in a dissertation or thesis prepared under the supervision of a tutor or director, and reviewed by a Doctoral Committee. This Committee should be composed of examiners external to the program, and at least one of them should also be external to the institution. The academic degree of Doctor is received after a successful defense of the candidate’s dissertation. Currently, there are approximately 2,151 postgraduate careers in the country, of which 14% were doctoral degrees. Doctoral programs in Argentina are overseen by the Comisión Nacional de Evaluación y Acreditación Universitaria, which is a decentralized agency in Argentina’s Ministry of Education, Science and Technology.
## Germany
A research doctorate usually takes three to five years to complete. In Germany, most doctorates are awarded with specific designations for the field of research instead of a general "PhD" for all fields. The degree is written in front of the first name for addresses (within texts, the abbreviation "Dr." is common) and accompanies the person's name (unlike in German-speaking Switzerland).
There are no first degree doctorates but medical students can obtain a "Dr. med." after one semester of mostly undergraduate research or data evaluation. The "Dr. med." is not equivalent to a PhD but to a Masters degree. Medical Students going into research can obtain a research doctorate in some subjects, such as molecular medicine or human biology.
Upon the completion of the Habilitationsschrift a senior doctorate (habil.) is awarded. This senior doctorate is known as the habilitation. It is not a degree, but an additional qualification. It authorizes the owner to teach at (German) universities ("facultas docendi"), plus qualifies the holder of the "habil." to teacher in a certain subject ("venia legendi"). This or an equivalent professional experience is - traditionally - the necessary prerequisite for a position of Privatdozent and Professor. Now, with the Bachelor/Master model and the Juniorprofessoren to be introduced, this has already changed partially.
## Spain
Doctor Degrees are regulated by Royal Decree (R.D. 778/1998), Decreto Real (in Spanish). They are granted by the University on behalf of the King, and its Diploma has the force of a public document. The Ministry of Science keeps a National Registry of Theses called TESEO . According to the National Institute of Statistics (INE), less than 5% of M.Sc. degree holders are admitted to Ph.D. programs, and less than 10% of 1st year Ph.D. students are finally granted a Doctorate.
All doctoral programs are of research nature. A minimum of 5 years of study are required, divided into 2 stages:
1) A 3-year long period of studies, which concludes with a public dissertation presented to a panel of 3 Professors. If the projects receives approval from the university, he/she will receive a "Diploma de Estudios Avanzados" (part qualified doctor).
2) A 2-year (or longer) period of research. Extensions may be requested for up to 10 years. The student must write his thesis presenting a new discovery or original contribution to Science. If approved by his "thesis director", the study will be presented to a panel of 5 distinguished scholars. Any Doctor attending the public presentations is allowed to challenge the candidate with questions on his research. If approved, he will receive the doctorate. Four marks can be granted (Unsatisfactory, Pass, "Cum laude", and "Summa cum laude"). Those Doctors granted their degree "Summa Cum Laude" are allowed to apply for an "Extraordinary Award".
A Doctor Degree is required in order to apply to a teaching position at the University.
The social standing of Doctors in Spain is evidenced by the fact that only Doctors and Grandees/Dukes can take seat and cover their heads before the King. All Doctorate Degree holders are reciprocally recognized as equivalent in Germany and Spain ("Bonn Agreement of November 14th 1994").
## United Kingdom
All doctorates (except for those awarded honoris causa) granted by British universities are research doctorates in the sense described above, in that their main (and in many cases only) component is the submission of a thesis or portfolio of original research, examined by an expert panel appointed by the university.
Even the relatively new 'vocational doctorates' such as the EngD, EdD, DSocSci and DClinPsych require the submission of a body of original research of a similar length to a PhD thesis. In the case of the EngD, however, this might be in the form of a portfolio of technical reports on different research projects undertaken by the candidate as opposed to a single, long monographical thesis. Another important difference is that traditional PhD programs are mostly academic-oriented and normally require full-time study at the university, whereas, in an EngD program, the candidate typically works full-time for an industrial sponsor on application-oriented topics of direct interest to the partner company and is jointly supervised by university faculty members and company employees.
The PhD itself is a comparatively recent introduction to the UK, dating from 1917. It was originally introduced in order to provide a similar level of graduate research training as was available in several other countries, notably Germany and the USA. Previously, the only doctorates available were the higher doctorates, awarded in recognition of an illustrious research career.
The universities of Oxford and Sussex denote the degree of Doctor of Philosophy with the postnominal initials DPhil. The University of York also did this for some years, switching to the more conventional PhD quite recently.
### Higher doctorates in the United Kingdom
Higher doctorates are awarded in recognition of a substantial body of original research undertaken over the course of many years. Typically the candidate will submit a collection of work which has been previously published in a peer-refereed context. Most universities restrict candidacy to graduates or academic staff of several years' standing. The most common doctorates of this type are those in Divinity (DD), Medicine (MD or DM), Laws (LLD), Civil Law (DCL), Music (DMus or MusD), Letters (DLitt or LittD) and Science (DSc or ScD).
Of these, the DD historically ranked highest, theology being the senior faculty in the mediaeval universities. The degree of Doctor of Canon Law was next in the order of precedence, but (except for a brief revival during the reign of Mary Tudor) did not survive the Protestant reformation, a consequence of the fact that the teaching of canon law at Cambridge and Oxford was forbidden by Henry VIII, founder of the Church of England. The DMus was, historically, in an anomalous situation, since a candidate was not required to be a member of Convocation (that is, to be a Master of Arts). The DLitt and DSc are relatively recent innovations, dating from the latter part of the 19th century.
### Honorary doctorates in the United Kingdom
Most British universities award degrees honoris causa in order to recognise individuals who have made a substantial contribution to a particular field. Usually an appropriate higher doctorate is used in these circumstances, depending on the achievements of the candidate. However, some universities, in order to differentiate between honorary and substantive doctorates, have introduced the degree of Doctor of the University (DUniv) for these purposes, and reserve the higher doctorates for formal academic research.
## United States
### Research doctorate in the United States
The most common research doctorate is the Doctor of Philosophy (Ph.D.). This degree was first awarded in the U.S. at the 1861 Yale University commencement. The University of Pennsylvania followed shortly thereafter in 1870, while Harvard (1872) and Princeton (1879) also followed suit.
The requirements for obtaining Ph.D.s and other research doctorates in the U.S. typically entail successful completion of pertinent classes, passing of a comprehensive examination, and defense of a dissertation.
### Professional doctorates in the United States
In the United States, there are numerous degrees which incorporate the word "doctor" and are known as "professional doctorates." Such fields include audiology, chiropractic, dentistry, law, medicine, occupational therapy, optometry, osteopathic medicine, pharmacy, physical therapy, podiatry, practical theology, psychology, veterinary medicine, and many others that usually require such degress for licensure. Generally, these degrees are considered "first professional degrees."
The primary difference between a professional doctorate (such as in the fields of medicine and law) and a research doctorate is that the former are, with few exceptions, not a terminal degree - that is, it is not the highest level of academic achievement in that field. In addition, the professional degree usually does not focus primarily upon research, which is the central component of doctoral and most master's level research degrees. In addition, the research doctorate will require the creation of an original idea adding to the body of knowledge in the field, which is not a requirement of the professional doctorate. Some law schools and a small number of medical schools require that the candidate perform original research and write a formal research paper; all accredited law schools have a writing requirement, but some allow it to be satisfied by a professional, as opposed to an academic-research, writing. Even when not a requirement, most medical students still conduct some form of academic research before residency, often leading to publication. The typical minimum term for such a degree (M.D.) is 4 years past postsecondary education. In addition, in many academic fields (such as law) the professional degree is the norm for academic and research careers.
### Professional doctorates in Korea and Japan
As part of a reform plan adopted in 2004, South Korea is creating a system of American-style graduate law schools which will award a Juris Doctor (professional doctoral) degree. Only graduates of these law schools, scheduled to matriculate their first students in 2009, will be eligible to take the bar exam. In Japan, a similar reform was started in 2004 and the degree of Juris Doctor is awarded to graduates of three year graduate studies in law. | Doctorate
A doctorate is an academic degree that indicates a high, if not the highest, level of academic achievement. A terminal degree in most countries, some Central and Eastern European countries place the doctorate second only to the habilitation.
The term doctorate comes from the Latin docere, meaning "to teach", shortened from the full Latin title licentia docendi, meaning "license to teach." This was translated from the equivalent Arabic term ijazat attadris, which was a distinction granted to certain Islamic scholars, thus qualifying them to teach.[citation needed]
# Types of doctorate
Since the Middle Ages, there has been considerable evolution and proliferation in the number and types of doctorates awarded by universities throughout the world, and practices vary from one country to another. While a doctorate usually entitles one to be addressed as "doctor", usage of the title varies widely, depending on the type of doctorate earned and the doctor's occupation. See the main article for Doctor (title) for more information.
Broadly speaking, doctorates may be loosely classified into the following categories:
## Research doctorates
Research doctorates are awarded in recognition of both mastery of research methods (as evidenced in class grades and a comprehensive examination) and academic research that is ideally publishable in a peer-reviewed academic journal, but that will minimally be assessed by submission and defense of a thesis or dissertation.[1] The best-known degree of this type is that of Doctor of Philosophy (PhD) awarded throughout the world; others include the U.S. degrees of Doctor of Engineering (DEng) and Doctor of Science (DSc or ScD), the UK Engineering Doctorate (EngD), and the German degree of Doctor rerum naturalium (Dr.rer.nat.).
The minimum time required to earn a doctorate varies by country, and can be a short as three years (excluding bachelor's and master's studies). However, some candidates can take anywhere from five to ten years to complete. The median number of years to completion of doctoral degrees for all fields in the US is seven years.[2] Students are discouraged from taking unnecessarily long to graduate by having their financial support (stipends, research funds, etc.) relinquished. Furthermore, doctoral applicants were previously required have a master's degree, but many programs will now accept students straight out of undergraduate studies.[3][4]
## Higher doctorates
In some countries, especially the United Kingdom, Ireland and some Scandinavian, Commonwealth nations or former USSR countries, there is a higher tier of
research doctorates, awarded on the basis of a formally submitted portfolio of published research of a very high standard. Examples include the Doctor of Science (DSc/ScD) and Doctor of Letters (DLitt/LittD) degrees found in the UK, Ireland and some Commonwealth countries, and the Danish doctorate (doktorgrad; e.g. dr.theol., doctor theologiæ, Latin for Doctor of Theology).
The German habilitation postdoctoral qualification is sometimes regarded as belonging to this category, even though, strictly speaking, the habilitation is not an academic degree, but rather a professional license to teach at a German university.
Higher doctorates are often also awarded honoris causa when a university wishes to formally recognize an individual's achievements and contributions to a particular field.
## Professional doctorates
Professional doctorates are awarded in certain fields where most holders of the degree are not engaged primarily in scholarly research, but rather in a profession, such as law, medicine, music or ministry. Examples include the U.S. degrees of Doctor of Medicine (MD) and Doctor of Jurisprudence (JD), the Dutch Professional Doctorate in Engineering (PDEng), and the Czech degrees of Doctor of Dental Medicine (MDDr.) and Doctor of Veterinary Medicine (MVDr.).
The term Professional Doctorate is also used to refer to research doctorates with a focus on applied research. Among others, these include the Doctor of Education (EdD), Doctor of Applied Linguistics (DAppLing), and Doctor of Business Administration (DBA).[5]
## Honorary doctorates
When a university wishes to formally recognize an individual's contributions to a particular field or philanthropic efforts, it may choose to a doctoral degree honoris causa (i.e., "for the sake of the honor"), the university waiving the usual formal requirements for bestowal of the degree.[6][7] Some universities (e.g., Cornell University[8], the University of Virginia[9]) do not award honorary degrees, feeling the bestowal unethical.
# Country-specific practice
Template:Refimprovesect
## Argentina
Similar to other countries, in Argentina the doctorate (doctorado)[10] is the highest. The intention is that candidates produce true and original contributions in a specific field of knowledge within a frame of academic excellence.[11] The doctoral candidate's work should be presented in a dissertation or thesis prepared under the supervision of a tutor or director, and reviewed by a Doctoral Committee. This Committee should be composed of examiners external to the program, and at least one of them should also be external to the institution. The academic degree of Doctor is received after a successful defense of the candidate’s dissertation.[12] Currently, there are approximately 2,151 postgraduate careers in the country, of which 14% were doctoral degrees.[13] Doctoral programs in Argentina are overseen by the Comisión Nacional de Evaluación y Acreditación Universitaria, which is a decentralized agency in Argentina’s Ministry of Education, Science and Technology.[14]
## Germany
A research doctorate usually takes three to five years to complete. In Germany, most doctorates are awarded with specific designations for the field of research instead of a general "PhD" for all fields. The degree is written in front of the first name for addresses (within texts, the abbreviation "Dr." is common) and accompanies the person's name (unlike in German-speaking Switzerland).
There are no first degree doctorates but medical students can obtain a "Dr. med." after one semester of mostly undergraduate research or data evaluation. The "Dr. med." is not equivalent to a PhD but to a Masters degree. Medical Students going into research can obtain a research doctorate in some subjects, such as molecular medicine or human biology.
Upon the completion of the Habilitationsschrift a senior doctorate (habil.) is awarded. This senior doctorate is known as the habilitation. It is not a degree, but an additional qualification. It authorizes the owner to teach at (German) universities ("facultas docendi"), plus qualifies the holder of the "habil." to teacher in a certain subject ("venia legendi"). This or an equivalent professional experience is - traditionally - the necessary prerequisite for a position of Privatdozent and Professor. Now, with the Bachelor/Master model and the Juniorprofessoren to be introduced, this has already changed partially.
## Spain
Doctor Degrees are regulated by Royal Decree (R.D. 778/1998)[15], Decreto Real (in Spanish). They are granted by the University on behalf of the King, and its Diploma has the force of a public document. The Ministry of Science keeps a National Registry of Theses called TESEO [16]. According to the National Institute of Statistics (INE), less than 5% of M.Sc. degree holders are admitted to Ph.D. programs, and less than 10% of 1st year Ph.D. students are finally granted a Doctorate[17].
All doctoral programs are of research nature. A minimum of 5 years of study are required, divided into 2 stages:
1) A 3-year long period of studies, which concludes with a public dissertation presented to a panel of 3 Professors. If the projects receives approval from the university, he/she will receive a "Diploma de Estudios Avanzados" (part qualified doctor).
2) A 2-year (or longer) period of research. Extensions may be requested for up to 10 years. The student must write his thesis presenting a new discovery or original contribution to Science. If approved by his "thesis director", the study will be presented to a panel of 5 distinguished scholars. Any Doctor attending the public presentations is allowed to challenge the candidate with questions on his research. If approved, he will receive the doctorate. Four marks can be granted (Unsatisfactory, Pass, "Cum laude", and "Summa cum laude"). Those Doctors granted their degree "Summa Cum Laude" are allowed to apply for an "Extraordinary Award".
A Doctor Degree is required in order to apply to a teaching position at the University.
The social standing of Doctors in Spain is evidenced by the fact that only Doctors and Grandees/Dukes can take seat and cover their heads before the King[18]. All Doctorate Degree holders are reciprocally recognized as equivalent in Germany and Spain ("Bonn Agreement of November 14th 1994")[19].
## United Kingdom
All doctorates (except for those awarded honoris causa) granted by British universities are research doctorates in the sense described above, in that their main (and in many cases only) component is the submission of a thesis or portfolio of original research, examined by an expert panel appointed by the university.
Even the relatively new 'vocational doctorates' such as the EngD, EdD, DSocSci and DClinPsych require the submission of a body of original research of a similar length to a PhD thesis. In the case of the EngD, however, this might be in the form of a portfolio of technical reports on different research projects undertaken by the candidate as opposed to a single, long monographical thesis. Another important difference is that traditional PhD programs are mostly academic-oriented and normally require full-time study at the university, whereas, in an EngD program, the candidate typically works full-time for an industrial sponsor on application-oriented topics of direct interest to the partner company and is jointly supervised by university faculty members and company employees.
The PhD itself is a comparatively recent introduction to the UK, dating from 1917. It was originally introduced in order to provide a similar level of graduate research training as was available in several other countries, notably Germany and the USA. Previously, the only doctorates available were the higher doctorates, awarded in recognition of an illustrious research career.
The universities of Oxford and Sussex denote the degree of Doctor of Philosophy with the postnominal initials DPhil. The University of York also did this for some years, switching to the more conventional PhD quite recently.
### Higher doctorates in the United Kingdom
Higher doctorates are awarded in recognition of a substantial body of original research undertaken over the course of many years. Typically the candidate will submit a collection of work which has been previously published in a peer-refereed context. Most universities restrict candidacy to graduates or academic staff of several years' standing. The most common doctorates of this type are those in Divinity (DD), Medicine (MD or DM), Laws (LLD), Civil Law (DCL), Music (DMus or MusD), Letters (DLitt or LittD) and Science (DSc or ScD).
Of these, the DD historically ranked highest, theology being the senior faculty in the mediaeval universities. The degree of Doctor of Canon Law was next in the order of precedence, but (except for a brief revival during the reign of Mary Tudor) did not survive the Protestant reformation[20], a consequence of the fact that the teaching of canon law at Cambridge and Oxford was forbidden by Henry VIII, founder of the Church of England. The DMus was, historically, in an anomalous situation, since a candidate was not required to be a member of Convocation (that is, to be a Master of Arts). The DLitt and DSc are relatively recent innovations, dating from the latter part of the 19th century.
### Honorary doctorates in the United Kingdom
Most British universities award degrees honoris causa in order to recognise individuals who have made a substantial contribution to a particular field. Usually an appropriate higher doctorate is used in these circumstances, depending on the achievements of the candidate. However, some universities, in order to differentiate between honorary and substantive doctorates, have introduced the degree of Doctor of the University (DUniv) for these purposes, and reserve the higher doctorates for formal academic research.
## United States
### Research doctorate in the United States
The most common research doctorate is the Doctor of Philosophy (Ph.D.). This degree was first awarded in the U.S. at the 1861 Yale University commencement. The University of Pennsylvania followed shortly thereafter in 1870, while Harvard (1872) and Princeton (1879) also followed suit.[21]
The requirements for obtaining Ph.D.s and other research doctorates in the U.S. typically entail successful completion of pertinent classes, passing of a comprehensive examination, and defense of a dissertation.[22]
### Professional doctorates in the United States
In the United States, there are numerous degrees which incorporate the word "doctor" and are known as "professional doctorates." Such fields include audiology, chiropractic, dentistry, law, medicine, occupational therapy, optometry, osteopathic medicine, pharmacy, physical therapy, podiatry, practical theology, psychology, veterinary medicine, and many others that usually require such degress for licensure. Generally, these degrees are considered "first professional degrees."
The primary difference between a professional doctorate (such as in the fields of medicine and law) and a research doctorate is that the former are, with few exceptions, not a terminal degree - that is, it is not the highest level of academic achievement in that field. In addition, the professional degree usually does not focus primarily upon research, which is the central component of doctoral and most master's level research degrees. In addition, the research doctorate will require the creation of an original idea adding to the body of knowledge in the field, which is not a requirement of the professional doctorate. Some law schools and a small number of medical schools require that the candidate perform original research and write a formal research paper; all accredited law schools have a writing requirement, but some allow it to be satisfied by a professional, as opposed to an academic-research, writing.[23] Even when not a requirement, most medical students still conduct some form of academic research before residency, often leading to publication. The typical minimum term for such a degree (M.D.) is 4 years past postsecondary education. In addition, in many academic fields (such as law) the professional degree is the norm for academic and research careers.
### Professional doctorates in Korea and Japan
As part of a reform plan adopted in 2004, South Korea is creating a system of American-style graduate law schools which will award a Juris Doctor (professional doctoral) degree. Only graduates of these law schools, scheduled to matriculate their first students in 2009, will be eligible to take the bar exam.[24] In Japan, a similar reform was started in 2004 and the degree of Juris Doctor is awarded to graduates of three year graduate studies in law. | https://www.wikidoc.org/index.php/Doctorate | |
181059d194742ea1cd84873c4281f95092a7d2ad | wikidoc | Dominance | Dominance
Dominance may refer to several different concepts:
- Coercion
- Coronary artery dominance, a description of how many of the three major branches supplying the posterior and inferior wall of the left ventricle from the right coronary artery (RCA) and how many arise from the circumflex artery (CX)
- Dominance (biology), the state of having high social status relative to other individuals which causes them to react submissively, in biology and anthropology
- Domination and submission (BDSM), a form of human sexuality
- Dominance hierarchy
- Dominance relationship, a property of genes that determine whether offspring will inherit a characteristic from the father, the mother, or some blend of both
- Dominance (game theory), a property that makes one strategy a better choice than another
- Dominance (economics), a measure of firms' share distribution (of production, sales, capacity or reserves) in a market or industry
- Dominating decision rule, a decision rule that always achieves lower risk in decision theory
- Dominance can refer to the preference of a body part on one side to its counterpart on the other side of the body. Handedness refers to the dominance of a specific hand over another, while footedness is for feet and ocular dominance is for eyes.
- Power (sociology)
- State power
- Stochastic dominance, a situation in which one lottery (a probability distribution of outcomes) can be ranked as superior to another, with only limited knowledge of preferences
da:Dominans
de:Dominanz | Dominance
Dominance may refer to several different concepts:
- Coercion
- Coronary artery dominance, a description of how many of the three major branches supplying the posterior and inferior wall of the left ventricle from the right coronary artery (RCA) and how many arise from the circumflex artery (CX)
- Dominance (biology), the state of having high social status relative to other individuals which causes them to react submissively, in biology and anthropology
- Domination and submission (BDSM), a form of human sexuality
- Dominance hierarchy
- Dominance relationship, a property of genes that determine whether offspring will inherit a characteristic from the father, the mother, or some blend of both
- Dominance (game theory), a property that makes one strategy a better choice than another
- Dominance (economics), a measure of firms' share distribution (of production, sales, capacity or reserves) in a market or industry
- Dominating decision rule, a decision rule that always achieves lower risk in decision theory
- Dominance can refer to the preference of a body part on one side to its counterpart on the other side of the body. Handedness refers to the dominance of a specific hand over another, while footedness is for feet and ocular dominance is for eyes.
- Power (sociology)
- State power
- Stochastic dominance, a situation in which one lottery (a probability distribution of outcomes) can be ranked as superior to another, with only limited knowledge of preferences
Template:Disambig
da:Dominans
de:Dominanz | https://www.wikidoc.org/index.php/Dominance | |
8befc4480fc255d1dab76f559682b9d791fbaab2 | wikidoc | Doripenem | Doripenem
# 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
Doripenem is a beta-lactam that is FDA approved for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. Common adverse reactions include headache, nausea, diarrhea, rash and phlebitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomona aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.
- Dosage: 500 mg administered every 8 hours by intravenous infusion over one hour for 5-14 days
- Is indicated as a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomona aeruginosa, and Acinetobacter baumannii.
- Dosage: 500 mg administered every 8 hours by intravenous infusion over one hour for 10 days
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Doripenem in adult patients.
### Non–Guideline-Supported Use
- Bacteremia associated with intravascular line
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Doripenem in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Doripenem in pediatric patients.
# Contraindications
Doripenem is contraindicated in patients with known serious hypersensitivity to doripenem or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams.
# Warnings
In a clinical trial of patients with ventilator-associated pneumonia comparing doripenem to imipenem, more subjects receiving doripenem died 23% (31/135) compared to those receiving imipenem 16.7% (22/132) based on 28-day all-cause mortality in the intent-to-treat (ITT) population. Clinical response rates were also lower in the doripenem arm. Doripenem is not approved for the treatment of ventilator associated pneumonia.
Serious and occasionally fatal hypersensitivity (anaphylactic) and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before therapy with doripenem is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other carbapenems, cephalosporins, penicillins or other allergens. If this product is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross-reactivity among beta-lactam antibiotics has been clearly documented.
If an allergic reaction to doripenem occurs, discontinue the drug. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment, as clinically indicated.
Seizures have been reported during treatment with doripenem. In clinical trials, doripenem-treated patients with pre-existing central nervous system (CNS) disorders (e.g. stroke or history of seizures), patients with compromised renal function and patients given doses greater than 500 mg every 8 hours appear to be at greater risk for developing seizures.
Due to a drug interaction, patients with seizure disorders controlled with valproic acid or sodium valproate will be at an increased risk for breakthrough seizures when treated with doripenem concomitantly. Reduction in serum valproic acid concentrations to below the therapeutic concentration range (50 to 100 mcg/mL) was observed by 12 hours after the initiation of doripenem in healthy subjects co-administered both drugs. A similar drug interaction involving other carbapenem antibacterials and valproic acid has been described in published case reports. In some of these reports, increasing the dose of valproic acid or sodium valproate did not result in increased valproic acid serum concentrations. Alternative antibacterial therapies should be considered for patients receiving valproic acid or sodium valproate. If administration of doripenem is necessary, supplemental anti-convulsant therapy should be considered.
Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Prescribing doripenem in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
When doripenem has been used investigationally via inhalation, pneumonitis has occurred. doripenem should not be administered by this route.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.
During clinical investigations, 1338 adult patients were treated with doripenem (1076 patients received doripenem 500 mg administered over 1 hour every 8 hours and 262 patients received doripenem 500 mg administered over 4 hours every 8 hours); in some patients parenteral therapy was followed by a switch to an oral antimicrobial. The median age of patients treated with doripenem was 54 years (range 18–90) in the comparative complicated urinary tract infections (cUTI) study, 46 years (range 18–94) in the pooled comparative complicated intra-abdominal infections (cIAI) studies, and 56 years (range 18-94) in the other Phase 3 trials. There was a female predominance (62%) in the comparative cUTI study and a male predominance (63% and 75%) in the comparative cIAI and other Phase 3 trials, respectively. The patients treated with doripenem were predominantly Caucasian (79%) in the five comparator-controlled Phase 3 studies.
The most common adverse drug reactions (≥ 5%) observed in the five doripenem comparator-controlled Phase 3 clinical trials were anemia, headache, nausea, diarrhea, rash, phlebitis, and elevated hepatic enzymes. During clinical trials, adverse events led to discontinuation of doripenem in 4.1% (55 of 1338) of patients compared to 4.3% (58 of 1325) of comparator-treated patients.
Adverse reactions due to doripenem 500 mg every 8 hours that occurred at a rate ≥ 1 % are listed in Table 4. Hypersensitivity reactions related to intravenous study drug occurred at a rate of less than 1%.
In a Phase 1 study of healthy subjects receiving doripenem doses greater than the approved dose of 500 mg every 8 hours for 10 to 14 days, the incidence of rash was higher than that observed in subjects who received 500 mg every 8 hours. The rash resolved within 10 days after doripenem administration was discontinued.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of doripenem. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Anaphylaxis
- Leukopenia
- Neutropenia
- Seizure
- Thrombocytopenia
- Toxic epidermal necrolysis, Stevens-Johnson Syndrome
- Interstitial pneumonia
# Drug Interactions
Co-administration of doripenem with valproic acid causes the serum concentrations of valproic acid to fall below the therapeutic range, increasing the risk for breakthrough seizures. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that doripenem may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the plasma concentrations of valproic acid. This is consistent with case reports for other carbapenems, where serum concentrations of valproic acid were reduced upon co-administration with a carbapenem. If administration of doripenem is necessary, supplemental anti-convulsant therapy should be considered. The pharmacokinetics of doripenem were unaffected by the co-administration of valproic acid.
Probenecid interferes with the active tubular secretion of doripenem, resulting in increased plasma concentrations of doripenem. Coadministration of probenecid with doripenem is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Doripenem was not teratogenic and did not produce effects on ossification, developmental delays or fetal weight following intravenous administration during organogenesis at doses as high as 1 g/kg/day in rats and 50 mg/kg/day in rabbits (based on AUC, at least 2.4 and 0.8 times the exposure to humans dosed at 500 mg administered every 8 hours, respectively). 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 Doripenem in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Doripenem 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 doripenem is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Of the total number of subjects in clinical studies of doripenem, 28% were 65 and over, while 12% were 75 and over. Clinical cure rates in complicated intra-abdominal and complicated urinary tract infections were slightly lower in patients ≥ 65 years of age and also in the subgroup of patients ≥ 75 years of age versus patients < 65. These results were similar between doripenem and comparator treatment groups.
This drug is known to be excreted substantially by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function or pre-renal azotemia. Because elderly patients are more likely to have decreased renal function or pre-renal azotemia, care should be taken in dose selection, and it may be useful to monitor renal function.
Elderly subjects had greater doripenem plasma concentrations relative to non-elderly subjects; however, this increase in exposure was mainly attributed to age-related changes in renal function.
No overall differences in safety were observed between older and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male (n=12) and female (n=12) subjects. Doripenem Cmax and AUC were similar between males and females. No dose adjustment is recommended based on gender.
### Race
The effect of race on doripenem pharmacokinetics was examined using a population pharmacokinetic analysis of data from phase 1 and 2 studies. No significant difference in mean doripenem clearance was observed across race groups and therefore, no dosage adjustment is recommended based on race.
### Renal Impairment
Dosage adjustment is required in patients with moderately or severely impaired renal function. In such patients, renal function should be monitored.
### Hepatic Impairment
The pharmacokinetics of doripenem in patients with hepatic impairment have not been established. As doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of doripenem are not expected to be affected by hepatic impairment.
### Females of Reproductive Potential and Males
Intravenous injection of doripenem had no adverse effects on general fertility of treated male and female rats or on postnatal development and reproductive performance of the offspring at doses as high as 1 g/kg/day (based on AUC, greater than 1.5 times the exposure to humans at the dose of 500 mg administered every 8 hours).
### Immunocompromised Patients
There is no FDA guidance one the use of Doripenem in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Doripenem Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Doripenem and IV administrations.
# Overdosage
In the event of overdose, doripenem should be discontinued and general supportive treatment given.
Doripenem can be removed by hemodialysis. In subjects with end-stage renal disease administered doripenem 500 mg, the mean total recovery of doripenem and doripenem-M1 in the dialysate following a 4-hour hemodialysis session was 259 mg (52% of the dose). However, no information is available on the use of hemodialysis to treat overdosage.
# Pharmacology
## Mechanism of Action
Doripenem belongs to the carbapenem class of antimicrobials. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death. In E. coli and P. aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.
## Structure
Its molecular weight is 438.52, and its chemical structure is:
## Pharmacodynamics
Similar to other beta-lactam antimicrobial agents, the time that unbound plasma concentration of doripenem exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamic relationship for doripenem has not been evaluated in patients.
In a randomized, positive- and placebo-controlled crossover QT study, 60 healthy subjects were administered doripenem 500 mg IV every 8 hours × 4 doses and doripenem 1 g IV every 8 hours × 4 doses, placebo, and a single oral dose of positive control. At both the 500 mg and 1 g doripenem doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
## Pharmacokinetics
Mean plasma concentrations of doripenem following a single 1-hour intravenous infusion of a 500 mg dose of doripenem to 24 healthy subjects are shown below in Figure 1. The mean (SD) plasma Cmax and AUC0–∞ values were 23.0 (6.6) µg/mL and 36.3 (8.8) µghr/mL, respectively.
The pharmacokinetics of doripenem (Cmax and AUC) are linear over a dose range of 500 mg to 1 g when intravenously infused over 1 hour. There is no accumulation of doripenem following multiple intravenous infusions of either 500 mg or 1 g administered every 8 hours for 7 to 10 days in subjects with normal renal function.
The average binding of doripenem to plasma proteins is approximately 8.1% and is independent of plasma drug concentrations. The median (range) volume of distribution at steady state in healthy subjects is 16.8 L (8.09–55.5 L), similar to extracellular fluid volume (18.2 L).
Doripenem penetrates into several body fluids and tissues, including those at the site of infection for the approved indications. Doripenem concentrations in peritoneal and retroperitoneal fluid either match or exceed those required to inhibit most susceptible bacteria; however, the clinical relevance of this finding has not been established. Concentrations achieved in selected tissues and fluids following administration of doripenem are shown in Table 5:
Metabolism of doripenem to a microbiologically inactive ring-opened metabolite (doripenem-M1) occurs primarily via dehydropeptidase-I. The mean (SD) plasma doripenem-M1-to-doripenem AUC ratio following single 500 mg and 1 g doses in healthy subjects is 18% (7.2%).
In pooled human liver microsomes, no in vitro metabolism of doripenem could be detected, indicating that doripenem is not a substrate for hepatic CYP450 enzymes.
Doripenem is primarily eliminated unchanged by the kidneys. The mean plasma terminal elimination half-life of doripenem in healthy non-elderly adults is approximately 1 hour and mean (SD) plasma clearance is 15.9 (5.3) L/hour. Mean (SD) renal clearance is 10.3 (3.5) L/hour. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem with concomitant probenecid administration, suggests that doripenem undergoes both glomerular filtration and active tubular secretion. In healthy adults given a single 500 mg dose of doripenem, a mean of 71% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy adults, less than 1% of the total radioactivity was recovered in feces after one week.
## Nonclinical Toxicology
Bacterial resistance mechanisms that affect doripenem include drug inactivation by carbapenem-hydrolyzing enzymes, mutant or acquired PBPs, decreased outer membrane permeability and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria, with the exception of carbapenem hydrolyzing beta-lactamases. Although cross-resistance may occur, some isolates resistant to other carbapenems may be susceptible to doripenem.
Because of the short duration of treatment and intermittent clinical use, long-term carcinogenicity studies have not been conducted with doripenem.
Doripenem did not show evidence of mutagenic activity in standard tests that included bacterial reverse mutation assay, chromosomal aberration assay with Chinese hamster lung fibroblast cells, and mouse bone marrow micronucleus assay.
# Clinical Studies
A total of 946 adults with complicated intra-abdominal infections were randomized and received study medications in two identical multinational, multi-center, double-blind studies comparing doripenem (500 mg administered over 1 hour every 8 hours) to meropenem (1 g administered over 3–5 minutes every 8 hours). Both regimens allowed the option to switch to oral amoxicillin/clavulanate (875 mg/125 mg administered twice daily) after a minimum of 3 days of intravenous therapy for a total of 5–14 days of intravenous and oral treatment. Patients with complicated appendicitis, or other complicated intra-abdominal infections, including bowel perforation, cholecystitis, intra-abdominal or solid organ abscess and generalized peritonitis were enrolled.
Doripenem was non-inferior to meropenem with regard to clinical cure rates in microbiologically evaluable (ME) patients, i.e., in patients with susceptible pathogens isolated at baseline and no major protocol deviations at test of cure (TOC) visit, 25–45 days after completing therapy. Doripenem was also non-inferior to meropenem in microbiological modified intent-to-treat (mMITT) patients, i.e., patients with baseline pathogens isolated regardless of susceptibility. Clinical cure rates at TOC are displayed by patient populations in Table 8. Microbiological cure rates at TOC by pathogen in ME patients are presented in Table 9.
A total of 1171 adults with complicated urinary tract infections, including pyelonephritis (49 percent of microbiologically evaluable patients) were randomized and received study medications in two multi-center, multinational studies. Complicated pyelonephritis, i.e., pyelonephritis associated with predisposing anatomical or functional abnormality, comprised 17% of patients with pyelonephritis. One study was double-blind and compared doripenem (500 mg administered over 1 hour every 8 hours) to IV levofloxacin (250 mg administered every 24 hours). The second study was a non-comparative study but of otherwise similar design. Both studies permitted the option of switching to oral levofloxacin (250 mg administered every 24 hours) after a minimum of 3 days of IV therapy for a total of 10 days of treatment. Patients with confirmed concurrent bacteremia were allowed to receive 500 mg of IV levofloxacin (either IV or oral as appropriate) for a total of 10 to 14 days of treatment.
doripenem was non-inferior to levofloxacin with regard to the microbiological eradication rates in microbiologically evaluable (ME) patients, i.e., patients with baseline uropathogens isolated, no major protocol deviations and urine cultures at test of cure (TOC) visit 5-11 days after completing therapy. Doripenem was also non-inferior to levofloxacin in microbiological modified intent-to-treat (mMITT) patients, i.e., patients with pretreatment urine cultures. Overall microbiological eradication rates at TOC and the 95% CIs for the comparative study are displayed in Table 10. Microbiological eradication rates at TOC by pathogen in ME patients are presented in Table 11.
# How Supplied
- Doripenem 500 mg/vial
- Doripenem 250 mg/vial
## Storage
Doripenem should be stored at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should report any previous hypersensitivity reactions to doripenem, other carbapenems, beta-lactams or other allergens.
- Patients should be counseled that anti-bacterial drugs including doripenem should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doripenem 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 doripenem or other antibacterial drugs in the future.
- Patients should be counseled to inform their physician
- if they have central nervous system disorders such as stroke or history of seizures. Seizures have been reported during treatment with doripenem and with closely related antibiotics
- if they are taking valproic acid or sodium valproate. Valproic acid concentrations in the blood will drop below the therapeutic range upon co-administration with doripenem. If treatment with doripenem is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed.
- Keep out of the reach of children.
# Precautions with Alcohol
Alcohol-Doripenem interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Doribax
# Look-Alike Drug Names
There is limited information regarding Doripenem Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Doripenem
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
Doripenem is a beta-lactam that is FDA approved for the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. Common adverse reactions include headache, nausea, diarrhea, rash and phlebitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomona aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros.
- Dosage: 500 mg administered every 8 hours by intravenous infusion over one hour for 5-14 days
- Is indicated as a single agent for the treatment of complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomona aeruginosa, and Acinetobacter baumannii.
- Dosage: 500 mg administered every 8 hours by intravenous infusion over one hour for 10 days
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Doripenem in adult patients.
### Non–Guideline-Supported Use
- Bacteremia associated with intravascular line
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Doripenem in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Doripenem in pediatric patients.
# Contraindications
Doripenem is contraindicated in patients with known serious hypersensitivity to doripenem or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams.
# Warnings
In a clinical trial of patients with ventilator-associated pneumonia comparing doripenem to imipenem, more subjects receiving doripenem died 23% (31/135) compared to those receiving imipenem 16.7% (22/132) based on 28-day all-cause mortality in the intent-to-treat (ITT) population. Clinical response rates were also lower in the doripenem arm. Doripenem is not approved for the treatment of ventilator associated pneumonia.
Serious and occasionally fatal hypersensitivity (anaphylactic) and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. Before therapy with doripenem is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to other carbapenems, cephalosporins, penicillins or other allergens. If this product is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross-reactivity among beta-lactam antibiotics has been clearly documented.
If an allergic reaction to doripenem occurs, discontinue the drug. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment, as clinically indicated.
Seizures have been reported during treatment with doripenem. In clinical trials, doripenem-treated patients with pre-existing central nervous system (CNS) disorders (e.g. stroke or history of seizures), patients with compromised renal function and patients given doses greater than 500 mg every 8 hours appear to be at greater risk for developing seizures.
Due to a drug interaction, patients with seizure disorders controlled with valproic acid or sodium valproate will be at an increased risk for breakthrough seizures when treated with doripenem concomitantly. Reduction in serum valproic acid concentrations to below the therapeutic concentration range (50 to 100 mcg/mL) was observed by 12 hours after the initiation of doripenem in healthy subjects co-administered both drugs. A similar drug interaction involving other carbapenem antibacterials and valproic acid has been described in published case reports. In some of these reports, increasing the dose of valproic acid or sodium valproate did not result in increased valproic acid serum concentrations. Alternative antibacterial therapies should be considered for patients receiving valproic acid or sodium valproate. If administration of doripenem is necessary, supplemental anti-convulsant therapy should be considered.
Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Prescribing doripenem in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
When doripenem has been used investigationally via inhalation, pneumonitis has occurred. doripenem should not be administered by this route.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.
During clinical investigations, 1338 adult patients were treated with doripenem (1076 patients received doripenem 500 mg administered over 1 hour every 8 hours and 262 patients received doripenem 500 mg administered over 4 hours every 8 hours); in some patients parenteral therapy was followed by a switch to an oral antimicrobial. The median age of patients treated with doripenem was 54 years (range 18–90) in the comparative complicated urinary tract infections (cUTI) study, 46 years (range 18–94) in the pooled comparative complicated intra-abdominal infections (cIAI) studies, and 56 years (range 18-94) in the other Phase 3 trials. There was a female predominance (62%) in the comparative cUTI study and a male predominance (63% and 75%) in the comparative cIAI and other Phase 3 trials, respectively. The patients treated with doripenem were predominantly Caucasian (79%) in the five comparator-controlled Phase 3 studies.
The most common adverse drug reactions (≥ 5%) observed in the five doripenem comparator-controlled Phase 3 clinical trials were anemia, headache, nausea, diarrhea, rash, phlebitis, and elevated hepatic enzymes. During clinical trials, adverse events led to discontinuation of doripenem in 4.1% (55 of 1338) of patients compared to 4.3% (58 of 1325) of comparator-treated patients.
Adverse reactions due to doripenem 500 mg every 8 hours that occurred at a rate ≥ 1 % are listed in Table 4. Hypersensitivity reactions related to intravenous study drug occurred at a rate of less than 1%.
In a Phase 1 study of healthy subjects receiving doripenem doses greater than the approved dose of 500 mg every 8 hours for 10 to 14 days, the incidence of rash was higher than that observed in subjects who received 500 mg every 8 hours. The rash resolved within 10 days after doripenem administration was discontinued.
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of doripenem. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Anaphylaxis
- Leukopenia
- Neutropenia
- Seizure
- Thrombocytopenia
- Toxic epidermal necrolysis, Stevens-Johnson Syndrome
- Interstitial pneumonia
# Drug Interactions
Co-administration of doripenem with valproic acid causes the serum concentrations of valproic acid to fall below the therapeutic range, increasing the risk for breakthrough seizures. Although the mechanism of this interaction is not fully understood, data from in vitro and animal studies suggest that doripenem may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the plasma concentrations of valproic acid. This is consistent with case reports for other carbapenems, where serum concentrations of valproic acid were reduced upon co-administration with a carbapenem. If administration of doripenem is necessary, supplemental anti-convulsant therapy should be considered. The pharmacokinetics of doripenem were unaffected by the co-administration of valproic acid.
Probenecid interferes with the active tubular secretion of doripenem, resulting in increased plasma concentrations of doripenem. Coadministration of probenecid with doripenem is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Doripenem was not teratogenic and did not produce effects on ossification, developmental delays or fetal weight following intravenous administration during organogenesis at doses as high as 1 g/kg/day in rats and 50 mg/kg/day in rabbits (based on AUC, at least 2.4 and 0.8 times the exposure to humans dosed at 500 mg administered every 8 hours, respectively). 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 Doripenem in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Doripenem 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 doripenem is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Of the total number of subjects in clinical studies of doripenem, 28% were 65 and over, while 12% were 75 and over. Clinical cure rates in complicated intra-abdominal and complicated urinary tract infections were slightly lower in patients ≥ 65 years of age and also in the subgroup of patients ≥ 75 years of age versus patients < 65. These results were similar between doripenem and comparator treatment groups.
This drug is known to be excreted substantially by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function or pre-renal azotemia. Because elderly patients are more likely to have decreased renal function or pre-renal azotemia, care should be taken in dose selection, and it may be useful to monitor renal function.
Elderly subjects had greater doripenem plasma concentrations relative to non-elderly subjects; however, this increase in exposure was mainly attributed to age-related changes in renal function.
No overall differences in safety were observed between older and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
The effect of gender on the pharmacokinetics of doripenem was evaluated in healthy male (n=12) and female (n=12) subjects. Doripenem Cmax and AUC were similar between males and females. No dose adjustment is recommended based on gender.
### Race
The effect of race on doripenem pharmacokinetics was examined using a population pharmacokinetic analysis of data from phase 1 and 2 studies. No significant difference in mean doripenem clearance was observed across race groups and therefore, no dosage adjustment is recommended based on race.
### Renal Impairment
Dosage adjustment is required in patients with moderately or severely impaired renal function. In such patients, renal function should be monitored.
### Hepatic Impairment
The pharmacokinetics of doripenem in patients with hepatic impairment have not been established. As doripenem does not appear to undergo hepatic metabolism, the pharmacokinetics of doripenem are not expected to be affected by hepatic impairment.
### Females of Reproductive Potential and Males
Intravenous injection of doripenem had no adverse effects on general fertility of treated male and female rats or on postnatal development and reproductive performance of the offspring at doses as high as 1 g/kg/day (based on AUC, greater than 1.5 times the exposure to humans at the dose of 500 mg administered every 8 hours).
### Immunocompromised Patients
There is no FDA guidance one the use of Doripenem in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Doripenem Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Doripenem and IV administrations.
# Overdosage
In the event of overdose, doripenem should be discontinued and general supportive treatment given.
Doripenem can be removed by hemodialysis. In subjects with end-stage renal disease administered doripenem 500 mg, the mean total recovery of doripenem and doripenem-M1 in the dialysate following a 4-hour hemodialysis session was 259 mg (52% of the dose). However, no information is available on the use of hemodialysis to treat overdosage.
# Pharmacology
## Mechanism of Action
Doripenem belongs to the carbapenem class of antimicrobials. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. Doripenem inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death. In E. coli and P. aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.
## Structure
Its molecular weight is 438.52, and its chemical structure is:
## Pharmacodynamics
Similar to other beta-lactam antimicrobial agents, the time that unbound plasma concentration of doripenem exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamic relationship for doripenem has not been evaluated in patients.
In a randomized, positive- and placebo-controlled crossover QT study, 60 healthy subjects were administered doripenem 500 mg IV every 8 hours × 4 doses and doripenem 1 g IV every 8 hours × 4 doses, placebo, and a single oral dose of positive control. At both the 500 mg and 1 g doripenem doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
## Pharmacokinetics
Mean plasma concentrations of doripenem following a single 1-hour intravenous infusion of a 500 mg dose of doripenem to 24 healthy subjects are shown below in Figure 1. The mean (SD) plasma Cmax and AUC0–∞ values were 23.0 (6.6) µg/mL and 36.3 (8.8) µg•hr/mL, respectively.
The pharmacokinetics of doripenem (Cmax and AUC) are linear over a dose range of 500 mg to 1 g when intravenously infused over 1 hour. There is no accumulation of doripenem following multiple intravenous infusions of either 500 mg or 1 g administered every 8 hours for 7 to 10 days in subjects with normal renal function.
The average binding of doripenem to plasma proteins is approximately 8.1% and is independent of plasma drug concentrations. The median (range) volume of distribution at steady state in healthy subjects is 16.8 L (8.09–55.5 L), similar to extracellular fluid volume (18.2 L).
Doripenem penetrates into several body fluids and tissues, including those at the site of infection for the approved indications. Doripenem concentrations in peritoneal and retroperitoneal fluid either match or exceed those required to inhibit most susceptible bacteria; however, the clinical relevance of this finding has not been established. Concentrations achieved in selected tissues and fluids following administration of doripenem are shown in Table 5:
Metabolism of doripenem to a microbiologically inactive ring-opened metabolite (doripenem-M1) occurs primarily via dehydropeptidase-I. The mean (SD) plasma doripenem-M1-to-doripenem AUC ratio following single 500 mg and 1 g doses in healthy subjects is 18% (7.2%).
In pooled human liver microsomes, no in vitro metabolism of doripenem could be detected, indicating that doripenem is not a substrate for hepatic CYP450 enzymes.
Doripenem is primarily eliminated unchanged by the kidneys. The mean plasma terminal elimination half-life of doripenem in healthy non-elderly adults is approximately 1 hour and mean (SD) plasma clearance is 15.9 (5.3) L/hour. Mean (SD) renal clearance is 10.3 (3.5) L/hour. The magnitude of this value, coupled with the significant decrease in the elimination of doripenem with concomitant probenecid administration, suggests that doripenem undergoes both glomerular filtration and active tubular secretion. In healthy adults given a single 500 mg dose of doripenem, a mean of 71% and 15% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours. Following the administration of a single 500 mg dose of radiolabeled doripenem to healthy adults, less than 1% of the total radioactivity was recovered in feces after one week.
## Nonclinical Toxicology
Bacterial resistance mechanisms that affect doripenem include drug inactivation by carbapenem-hydrolyzing enzymes, mutant or acquired PBPs, decreased outer membrane permeability and active efflux. Doripenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria, with the exception of carbapenem hydrolyzing beta-lactamases. Although cross-resistance may occur, some isolates resistant to other carbapenems may be susceptible to doripenem.
Because of the short duration of treatment and intermittent clinical use, long-term carcinogenicity studies have not been conducted with doripenem.
Doripenem did not show evidence of mutagenic activity in standard tests that included bacterial reverse mutation assay, chromosomal aberration assay with Chinese hamster lung fibroblast cells, and mouse bone marrow micronucleus assay.
# Clinical Studies
A total of 946 adults with complicated intra-abdominal infections were randomized and received study medications in two identical multinational, multi-center, double-blind studies comparing doripenem (500 mg administered over 1 hour every 8 hours) to meropenem (1 g administered over 3–5 minutes every 8 hours). Both regimens allowed the option to switch to oral amoxicillin/clavulanate (875 mg/125 mg administered twice daily) after a minimum of 3 days of intravenous therapy for a total of 5–14 days of intravenous and oral treatment. Patients with complicated appendicitis, or other complicated intra-abdominal infections, including bowel perforation, cholecystitis, intra-abdominal or solid organ abscess and generalized peritonitis were enrolled.
Doripenem was non-inferior to meropenem with regard to clinical cure rates in microbiologically evaluable (ME) patients, i.e., in patients with susceptible pathogens isolated at baseline and no major protocol deviations at test of cure (TOC) visit, 25–45 days after completing therapy. Doripenem was also non-inferior to meropenem in microbiological modified intent-to-treat (mMITT) patients, i.e., patients with baseline pathogens isolated regardless of susceptibility. Clinical cure rates at TOC are displayed by patient populations in Table 8. Microbiological cure rates at TOC by pathogen in ME patients are presented in Table 9.
A total of 1171 adults with complicated urinary tract infections, including pyelonephritis (49 percent of microbiologically evaluable patients) were randomized and received study medications in two multi-center, multinational studies. Complicated pyelonephritis, i.e., pyelonephritis associated with predisposing anatomical or functional abnormality, comprised 17% of patients with pyelonephritis. One study was double-blind and compared doripenem (500 mg administered over 1 hour every 8 hours) to IV levofloxacin (250 mg administered every 24 hours). The second study was a non-comparative study but of otherwise similar design. Both studies permitted the option of switching to oral levofloxacin (250 mg administered every 24 hours) after a minimum of 3 days of IV therapy for a total of 10 days of treatment. Patients with confirmed concurrent bacteremia were allowed to receive 500 mg of IV levofloxacin (either IV or oral as appropriate) for a total of 10 to 14 days of treatment.
doripenem was non-inferior to levofloxacin with regard to the microbiological eradication rates in microbiologically evaluable (ME) patients, i.e., patients with baseline uropathogens isolated, no major protocol deviations and urine cultures at test of cure (TOC) visit 5-11 days after completing therapy. Doripenem was also non-inferior to levofloxacin in microbiological modified intent-to-treat (mMITT) patients, i.e., patients with pretreatment urine cultures. Overall microbiological eradication rates at TOC and the 95% CIs for the comparative study are displayed in Table 10. Microbiological eradication rates at TOC by pathogen in ME patients are presented in Table 11.
# How Supplied
- Doripenem 500 mg/vial
- Doripenem 250 mg/vial
## Storage
Doripenem should be stored at 25°C (77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should report any previous hypersensitivity reactions to doripenem, other carbapenems, beta-lactams or other allergens.
- Patients should be counseled that anti-bacterial drugs including doripenem should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doripenem 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 doripenem or other antibacterial drugs in the future.
- Patients should be counseled to inform their physician
- if they have central nervous system disorders such as stroke or history of seizures. Seizures have been reported during treatment with doripenem and with closely related antibiotics
- if they are taking valproic acid or sodium valproate. Valproic acid concentrations in the blood will drop below the therapeutic range upon co-administration with doripenem. If treatment with doripenem is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed.
- Keep out of the reach of children.
# Precautions with Alcohol
Alcohol-Doripenem interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Doribax [1]
# Look-Alike Drug Names
There is limited information regarding Doripenem Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Doribax | |
b84939950ea6e8e4a6b87cee0fd2399260bfd7aa | wikidoc | Dosimetry | Dosimetry
# Overview
Radiation dosimetry is the calculation of absorbed dose in matter and tissue resulting from the exposure to ionizing radiation. It is a scientific subspecialty in the fields of health physics and medical physics that is focused on the calculation of internal and external doses from ionizing radiation.
Dose is reported in gray (Gy) for the matter or sieverts (Sv) for biological tissue, where 1 Gy or 1 Sv is equal to 1 joule per kilogram. Non-SI units are still prevalent as well, where dose is often reported in rads and dose equivalent in rems. By definition, 1 Gy = 100 rad and 1 Sv = 100 rem.
# Radiation effects on living tissue
The distinction between absorbed dose (Gy) and dose equivalent (Sv) is based upon the biological effects of the radiation in question and the tissue and organism irradiated. For different types of radiation, the same absorbed dose (measured in Gy) may have very different biological consequences. Therefore, a radiation weighting factor (denoted wr) and tissue/organ weighting factor (WT) have been established, which compare the relative biological effects of various types of radiation and the susceptibility of different organs.
## Organ Dose Weighting Factors
By definition, the weighting factor for the whole body is 1, such that 1 Gy of radiation delivered to the whole body (i.e. an evenly distributed 1 joule of energy deposited per kilogram of body) is equal to one Sievert (for photons with a radiation weighting factor of 1, see below). Therefore, the weighting factors for each organ must sum to 1 as the unit Gray is defined per kilogram and is therefore a local effect. As the table below shows, 1 Gray delivered to the gonads is equivalent to 0.25 Gy to the whole body - in this case, the actual energy deposited to the gonads, being small, would also be small.
## Radiation Weighting Factors
By definition, x-rays and gamma rays have a weighting factor of unity, such that 1 Gy = 1 Sv (for whole-body irradiation). Values of wr are as high as 20 for alpha particles and neutrons, i.e. for the same absorbed dose in Gy, alpha particles are 20 times as biologically potent as X or gamma rays.
# Dose versus activity
Radiation dose refers to the amount of energy deposited in matter and/or biological effects of radiation, and should not be confused with the unit of radioactive activity (becquerel, Bq). Exposure to a radioactive source will give a dose which is dependent on the activity, time of exposure, energy of the radiation emitted, distance from the source and shielding. The equivalent dose is then dependent upon the weighting factors above. Dose is a measure of deposited dose, and therefore can never go down - removal of a radioactive source can only reduce the rate of increase of absorbed dose, never the total absorbed dose.
The worldwide average background dose for a human being is about 3.5 mSv per year , mostly from cosmic radiation and natural isotopes in the earth. The largest single source of radiation exposure to the general public is naturally-occurring radon gas, which comprises approximately 55% of the annual background dose. It is estimated that radon is responsible for 10% of lung cancers in the United States.
# Measuring dose
There are several ways of measuring doses from ionizing radiation. Workers who come in contact with radioactive substances or may be exposed to radiation routinely carry personal dosimeters. In the United States, these dosimeters usually contain materials that can be used in thermoluminescent dosimetry (TLD) or optically stimulated luminescence (OSL). Outside the United States, the most widely-used type of personal dosimeter is the film badge dosimeter, which uses photographic emulsions that are sensitive to ionizing radiation. The equipment used in radiotherapy (linear particle accelerator in external beam therapy) is routinely calibrated using ionization chambers.
## Dose standards
Because the human body is approximately 70% water and has an overall density close to 1 g/cm3, dose measurement is usually calculated and calibrated as dose to water.
National standards laboratories such as the NPL provide calibration factors for ionization chambers and other measurement devices to convert from the instrument's readout to absorbed dose. The standards laboratories operate a Primary Standard, which is normally calibrated by absolute calorimetry, the warming of substances when they absorb energy. A user sends their Secondary Standard to the laboratory, where it is exposed to a known amount of radiation (derived from the Primary Standard) and a factor is issued to convert the instrument's reading to that dose. The user may then use their Secondary Standard to derive calibration factors for other instruments they use, which then become Tertiary Standards, or field instruments.
The NPL in the UK operates a graphite-calorimeter for absolute photon dosimetry. Graphite is used instead of water as its specific heat capacity is one-sixth that of water and therefore the temperature rises in graphite are 6 times more than the equivalent in water and measurements are more accurate. Significant problems exist in insulating the graphite from the laboratory in order to measure the tiny temperature changes. A lethal dose of radiation to a human is approximately 10-20 Gy. This is 10-20 joules per kg. A 1 cm3 piece of graphite weighing 2 grams would therefore absorb around 20-40 mJ. With a specific heat capacity of around 700 Jkg-1K-1, this equates to a temperature rise of just 20 mK.
sl:dozimetrija | Dosimetry
# Overview
Radiation dosimetry is the calculation of absorbed dose in matter and tissue resulting from the exposure to ionizing radiation. It is a scientific subspecialty in the fields of health physics and medical physics that is focused on the calculation of internal and external doses from ionizing radiation.
Dose is reported in gray (Gy) for the matter or sieverts (Sv) for biological tissue, where 1 Gy or 1 Sv is equal to 1 joule per kilogram. Non-SI units are still prevalent as well, where dose is often reported in rads and dose equivalent in rems. By definition, 1 Gy = 100 rad and 1 Sv = 100 rem.
# Radiation effects on living tissue
The distinction between absorbed dose (Gy) and dose equivalent (Sv) is based upon the biological effects of the radiation in question and the tissue and organism irradiated. For different types of radiation, the same absorbed dose (measured in Gy) may have very different biological consequences. Therefore, a radiation weighting factor (denoted wr) and tissue/organ weighting factor (WT) have been established, which compare the relative biological effects of various types of radiation and the susceptibility of different organs.
## Organ Dose Weighting Factors
By definition, the weighting factor for the whole body is 1, such that 1 Gy of radiation delivered to the whole body (i.e. an evenly distributed 1 joule of energy deposited per kilogram of body) is equal to one Sievert (for photons with a radiation weighting factor of 1, see below). Therefore, the weighting factors for each organ must sum to 1 as the unit Gray is defined per kilogram and is therefore a local effect. As the table below shows, 1 Gray delivered to the gonads is equivalent to 0.25 Gy to the whole body - in this case, the actual energy deposited to the gonads, being small, would also be small.
## Radiation Weighting Factors
By definition, x-rays and gamma rays have a weighting factor of unity, such that 1 Gy = 1 Sv (for whole-body irradiation). Values of wr are as high as 20 for alpha particles and neutrons, i.e. for the same absorbed dose in Gy, alpha particles are 20 times as biologically potent as X or gamma rays.
# Dose versus activity
Radiation dose refers to the amount of energy deposited in matter and/or biological effects of radiation, and should not be confused with the unit of radioactive activity (becquerel, Bq). Exposure to a radioactive source will give a dose which is dependent on the activity, time of exposure, energy of the radiation emitted, distance from the source and shielding. The equivalent dose is then dependent upon the weighting factors above. Dose is a measure of deposited dose, and therefore can never go down - removal of a radioactive source can only reduce the rate of increase of absorbed dose, never the total absorbed dose.
The worldwide average background dose for a human being is about 3.5 mSv per year [1], mostly from cosmic radiation and natural isotopes in the earth. The largest single source of radiation exposure to the general public is naturally-occurring radon gas, which comprises approximately 55% of the annual background dose. It is estimated that radon is responsible for 10% of lung cancers in the United States.
# Measuring dose
There are several ways of measuring doses from ionizing radiation. Workers who come in contact with radioactive substances or may be exposed to radiation routinely carry personal dosimeters. In the United States, these dosimeters usually contain materials that can be used in thermoluminescent dosimetry (TLD) or optically stimulated luminescence (OSL). Outside the United States, the most widely-used type of personal dosimeter is the film badge dosimeter, which uses photographic emulsions that are sensitive to ionizing radiation. The equipment used in radiotherapy (linear particle accelerator in external beam therapy) is routinely calibrated using ionization chambers.
## Dose standards
Because the human body is approximately 70% water and has an overall density close to 1 g/cm3, dose measurement is usually calculated and calibrated as dose to water.
National standards laboratories such as the NPL provide calibration factors for ionization chambers and other measurement devices to convert from the instrument's readout to absorbed dose. The standards laboratories operate a Primary Standard, which is normally calibrated by absolute calorimetry, the warming of substances when they absorb energy. A user sends their Secondary Standard to the laboratory, where it is exposed to a known amount of radiation (derived from the Primary Standard) and a factor is issued to convert the instrument's reading to that dose. The user may then use their Secondary Standard to derive calibration factors for other instruments they use, which then become Tertiary Standards, or field instruments.
The NPL in the UK operates a graphite-calorimeter for absolute photon dosimetry. Graphite is used instead of water as its specific heat capacity is one-sixth that of water and therefore the temperature rises in graphite are 6 times more than the equivalent in water and measurements are more accurate. Significant problems exist in insulating the graphite from the laboratory in order to measure the tiny temperature changes. A lethal dose of radiation to a human is approximately 10-20 Gy. This is 10-20 joules per kg. A 1 cm3 piece of graphite weighing 2 grams would therefore absorb around 20-40 mJ. With a specific heat capacity of around 700 Jkg-1K-1, this equates to a temperature rise of just 20 mK.
sl:dozimetrija
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Dosimetry | |
97a42c03428b024c7b16f1e804ac5a9ee5823747 | wikidoc | Dosulepin | Dosulepin
# Overview
Dosulepin (INN, BAN) formerly known as dothiepin (USAN), and marketed under the brand names Prothiaden, Dothep, Thaden, and Dopress, is a tricyclic antidepressant that is used in several European and South Asian countries, as well as Australia, South Africa, and New Zealand. It is not used in the United States.
# Medical uses
Dosulepin is used for the treatment of major depressive disorder and neuropathic pain. Dosulepin is only TGA- and MHRA-approved for the treatment of major depressive disorder. There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.
# Adverse effects
Common adverse effects:
- Drowsiness
- Extrapyramidal symptoms
- Tremor
- Confusion
- Disorientation
- Dizziness
- Paresthesias
- Alterations to ECG patterns
- Dry mouth
- Sweating
- Urinary retention
- Hypotension
- Postural hypotension
- Tachycardia
- Palpitations
- Arrhythmias
- Conduction defects
- Increased or decreased libido
- Nausea
- Vomiting
- Constipation
- Blurred vision
Less common adverse effects:
- Disturbed concentration
- Delusions
- Hallucinations
- Anxiety
- Fatigue
- Headaches
- Restlessness
- Excitement
- Insomnia
- Hypomania
- Nightmares
- Peripheral neuropathy
- Ataxia
- Incoordination
- Seizures
- Paralytic ileus
- Hypertension
- Heart block
- Myocardial infarction
- Stroke
- Gynecomastia (swelling of breast tissue in males)
- Testicular swelling
- Impotence
- Epigastric distress
- Abdominal cramps
- Parotid swellings
- Diarrhea
- Stomatitis (swelling of the mouth)
- Black tongue
- Peculiar taste sensations
- Cholestatic jaundice
- Altered liver function
- Hepatitis (swelling of the liver)
- Skin rash
- Urticaria (hives)
- Photosensitisation
- Skin blisters
- Angioneurotic edema
- Weight loss
- Urinary frequency
- Mydriasis
- Weight gain
- Hyponatremia (low blood sodium)
- Movement disorders
- Dyspepsia (indigestion)
- Increased intraocular pressure
- Changes in blood sugar levels
- Thrombocytopenia (an abnormally low number of platelets in the blood. This makes one more susceptible to bleeds)
- Eosinophilia (an abnormally high amount of eosinophils in the blood)
- Agranulocytosis (a dangerously low number of white blood cells in the blood leaving one open to potentially life-threatening infections)
- Galactorrhea (lactation that is unassociated with breastfeeding and lactation)
## Contraindications
Contraindications include:
- Epilepsy as it can lower the seizure threshold
- TCAs should not be used concomitantly or within 14 days of treatment with monoamine oxidase inhibitors due to the risk for serotonin syndrome
- Acute recovery phase following myocardial infarction as TCAs may produce conduction defects and arrhythmias
- Liver failure
- Hypersensitivity to dothiepin
## Drug interactions
Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination. TCAs potentiate the sedative effects of barbiturates, tranquillisers and CNS depressants. Guanethidine and other adrenergic neurone blocking drugs can have their antihypertensive effects blocked by dosulepin. Sympathomimetics may potentiate the sympathomimetic effects of dosulepin. Due to the anticholinergic and antihistamine effects of dosulepin anticholinergic and antihistamine medications may have their effects potentiated by dosulepin and hence these combinations are advised against. Dosulepin may have its postural hypotensive effects potentiated by diuretics. Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.
## Overdose
The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants. Dosulepin may be particularly toxic in overdose compared to other TCAs. The onset of toxic effects is around 4–6 hours after dosulepin is ingested. In order to minimise the risk of overdose it is advised that patients only receive a limited number of tablets at a time so as to limit their risk of overdosing. It is also advised that patients are not prescribed any medications that are known to increase the risk of toxicity in those receiving dosulepin due to the potential for mixed overdoses. The medication should also be kept out of reach of children.
# Mechanism of action
Dosulepin is a serotonin-norepinephrine reuptake inhibitor (SNRI) with anticholinergic, antihistamine, and antiadrenergic effects.
# Pharmacokinetics
Dothiepin is readily absorbed from the small intestine and is extensively metabolised on first-pass through the liver into its chief active metabolite, northiaden (desmethyldosulepin). Peak plasma concentrations of between 30.4 ng/mL to 278.8 ng/mL occur within 2–3 hours of oral administration. It is distributed in breast milk and crosses the placenta and blood-brain barrier. It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.
# Chemistry
Dosulepin is also the dibenzothiepine analogue of doxepin, from which it differs by the replacement of the oxygen position with that of sulfur.
File:Dothiepin Synthesis.png
The synthesis of this agent is quite similar to that used for its oxygen analogue, doxepin (), though with a reversed functionality. The sequence in the present case starts with the alkylation of thiosalicylic acid () with benzyl chloride () to give the thioether (). The product is then cyclized by means of polyphosphoric acid to give the ketone (). Condensation with the
familiar dimethylpropylamine Grignard reagent serves to introduce the side chain (). Dehydration of the tertiary alcohol then affords dothiepin () as a mixture of isomers. | Dosulepin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dosulepin (INN, BAN) formerly known as dothiepin (USAN), and marketed under the brand names Prothiaden, Dothep, Thaden, and Dopress, is a tricyclic antidepressant that is used in several European and South Asian countries, as well as Australia, South Africa, and New Zealand. It is not used in the United States.[7]
# Medical uses
Dosulepin is used for the treatment of major depressive disorder and neuropathic pain.[2] Dosulepin is only TGA- and MHRA-approved for the treatment of major depressive disorder.[8][9] There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year.[10]
# Adverse effects
Common adverse effects:[1]
- Drowsiness
- Extrapyramidal symptoms
- Tremor
- Confusion
- Disorientation
- Dizziness
- Paresthesias
- Alterations to ECG patterns
- Dry mouth
- Sweating
- Urinary retention
- Hypotension
- Postural hypotension
- Tachycardia
- Palpitations
- Arrhythmias
- Conduction defects
- Increased or decreased libido
- Nausea
- Vomiting
- Constipation
- Blurred vision
Less common adverse effects:[1]
- Disturbed concentration
- Delusions
- Hallucinations
- Anxiety
- Fatigue
- Headaches
- Restlessness
- Excitement
- Insomnia
- Hypomania
- Nightmares
- Peripheral neuropathy
- Ataxia
- Incoordination
- Seizures
- Paralytic ileus
- Hypertension
- Heart block
- Myocardial infarction
- Stroke
- Gynecomastia (swelling of breast tissue in males)
- Testicular swelling
- Impotence
- Epigastric distress
- Abdominal cramps
- Parotid swellings
- Diarrhea
- Stomatitis (swelling of the mouth)
- Black tongue
- Peculiar taste sensations
- Cholestatic jaundice
- Altered liver function
- Hepatitis (swelling of the liver)
- Skin rash
- Urticaria (hives)
- Photosensitisation
- Skin blisters
- Angioneurotic edema
- Weight loss
- Urinary frequency
- Mydriasis
- Weight gain
- Hyponatremia (low blood sodium)
- Movement disorders
- Dyspepsia (indigestion)
- Increased intraocular pressure
- Changes in blood sugar levels
- Thrombocytopenia (an abnormally low number of platelets in the blood. This makes one more susceptible to bleeds)
- Eosinophilia (an abnormally high amount of eosinophils in the blood)
- Agranulocytosis (a dangerously low number of white blood cells in the blood leaving one open to potentially life-threatening infections)
- Galactorrhea (lactation that is unassociated with breastfeeding and lactation)
## Contraindications
Contraindications include:[1]
- Epilepsy as it can lower the seizure threshold
- TCAs should not be used concomitantly or within 14 days of treatment with monoamine oxidase inhibitors due to the risk for serotonin syndrome
- Acute recovery phase following myocardial infarction as TCAs may produce conduction defects and arrhythmias
- Liver failure
- Hypersensitivity to dothiepin
## Drug interactions
Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination.[1] TCAs potentiate the sedative effects of barbiturates, tranquillisers and CNS depressants.[1] Guanethidine and other adrenergic neurone blocking drugs can have their antihypertensive effects blocked by dosulepin.[1] Sympathomimetics may potentiate the sympathomimetic effects of dosulepin.[1] Due to the anticholinergic and antihistamine effects of dosulepin anticholinergic and antihistamine medications may have their effects potentiated by dosulepin and hence these combinations are advised against.[1] Dosulepin may have its postural hypotensive effects potentiated by diuretics.[1] Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold.[1]
## Overdose
The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.[8] Dosulepin may be particularly toxic in overdose compared to other TCAs.[8] The onset of toxic effects is around 4–6 hours after dosulepin is ingested.[1] In order to minimise the risk of overdose it is advised that patients only receive a limited number of tablets at a time so as to limit their risk of overdosing.[1] It is also advised that patients are not prescribed any medications that are known to increase the risk of toxicity in those receiving dosulepin due to the potential for mixed overdoses.[1] The medication should also be kept out of reach of children.[1]
# Mechanism of action
Dosulepin is a serotonin-norepinephrine reuptake inhibitor (SNRI) with anticholinergic, antihistamine, and antiadrenergic effects.[11]
# Pharmacokinetics
Dothiepin is readily absorbed from the small intestine and is extensively metabolised on first-pass through the liver into its chief active metabolite, northiaden (desmethyldosulepin).[1] Peak plasma concentrations of between 30.4 ng/mL to 278.8 ng/mL occur within 2–3 hours of oral administration.[1] It is distributed in breast milk and crosses the placenta and blood-brain barrier.[1] It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours.[1]
# Chemistry
Dosulepin is also the dibenzothiepine analogue of doxepin, from which it differs by the replacement of the oxygen position with that of sulfur.
File:Dothiepin Synthesis.png
The synthesis of this agent is quite similar to that used for its oxygen analogue, doxepin (), though with a reversed functionality. The sequence in the present case starts with the alkylation of thiosalicylic acid () with benzyl chloride () to give the thioether (). The product is then cyclized by means of polyphosphoric acid to give the ketone (). Condensation with the
familiar dimethylpropylamine Grignard reagent serves to introduce the side chain (). Dehydration of the tertiary alcohol then affords dothiepin () as a mixture of isomers.[13] | https://www.wikidoc.org/index.php/Dosulepin | |
c5219be7268f05204a76f67190d49744afd49a96 | wikidoc | Dr Pepper | Dr Pepper
Dr Pepper is a caramel-colored, carbonated soft drink marketed in North America by Cadbury Schweppes Americas Beverages (CSAB), a unit of Cadbury Schweppes. The headquarters of CSAB are situated in Plano, Texas, a suburb of Dallas. The ownership of the trademark varies in other countries, although most non-U.S. territories are controlled by Coca-Cola Company. There is also a no-calorie version, Diet Dr Pepper, as well as many other flavors.
# Overview and history
The drink was first sold in Waco, Texas, in 1885. It was introduced nationally in the United States at the 1904 Louisiana Purchase Exposition as a new kind of cola. Dr. Pepper is not a kind of root beer. The exact date of Dr Pepper's conception is unknown, but the U.S. Patent Office recognizes December 1, 1885 as the first time Dr Pepper was served.
It was formulated by German pharmacist Charles Alderton in Morrison's Old Corner Drug Store in Waco.To test his new drink, he first offered it to store owner Wade Morrison, who also found it to his liking. After repeated sample testing by the two, Alderton was ready to offer his new drink to some of the fountain customers. Other patrons at Morrison's soda fountain soon learned of Alderton's new drink and began ordering a "Waco". Alderton gave the formula to Morrison. A popular belief is that the drink was named after Morrison's former employer in Texas, but this has been disputed by the Dr Pepper company itself. They state that before moving to Texas, Morrison lived in Wythe County, Virginia near a Dr. Charles T. Pepper, and may have been close to Pepper's daughter at the time. The name is also reinforced by being an obvious play on "pep", i.e. providing quick energy to its consumer.
Unlike Coca-Cola and Pepsi, Dr Pepper is not marketed as a cola. Dr Pepper's flavor is allegedly derived from a mixture of soda fountain flavors popular when the drink was first devised. A partial list of these flavors can be seen at the bottling plant in Dublin, Texas, although the formula itself (with its twenty-three ingredients) is a closely guarded secret. There is a long-lived urban legend that Dr Pepper contains prune juice. However, according to the manufacturer, prune juice is not and never has been an ingredient of the drink.
There is also a Dr Pepper Museum in downtown Waco. It is located in the Artesian Manufacturing and Bottling Company building in downtown Waco, and opened to the public in 1991. The Artesian Manufacturing and Bottling Company building was the first building to be built specifically to bottle Dr Pepper. The building was completed in 1906 and Dr Pepper was bottled there until the 1960s. The museum has three floors of exhibits, a working old-fashioned soda fountain, and a gift store full of Dr Pepper memorabilia. (As the picture shows, the building has differing color bricks, since it was heavily damaged by the Waco Tornado.)
Dr Pepper almost became a Coca-Cola brand in the mid-to-late 1980s. Dr Pepper became insolvent in the early 1980s, prompting an investment group to take the company private. Several years later, Coca-Cola attempted to acquire Dr Pepper, but was blocked from doing so by the United States Federal Trade Commission (FTC). Around the same time, Seven Up was acquired from Phillip Morris by the same investment company that bailed out Dr Pepper. Upon the failure of the Coca-Cola merger, Dr Pepper and Seven Up merged (creating Dr Pepper/Seven Up, Inc., or DPSU), giving up international branding rights in the process. After the DPSU merger, Coca-Cola obtained most non-U.S. rights to the Dr Pepper name (with PepsiCo taking the Seven Up rights).
## Distribution
In the United States, Cadbury Schweppes Americas Beverages (CSAB) does not have a complete network of bottlers and distributors, so the drink is sometimes bottled under contract by Coca-Cola or Pepsi bottlers. Prior to the initial Cadbury Schweppes investment-turned-buyout, 30% of Dr Pepper/Seven Up products were produced and distributed by Pepsi bottlers, and another 30% by Coca-Cola bottlers. The remaining 40% was produced and distributed by independent bottlers (mainly consisting of pre-Dr Pepper/Seven Up-merger regional bottlers) and the Dr Pepper/Seven Up Bottling Group.
Presently, Dr Pepper is mostly reliant on the Cadbury Schweppes Bottling Group (known as Dr Pepper/Seven Up Bottling Group until June, 2006) to bottle and distribute its products in 30+ states. Coca-Cola and Pepsi have essentially stopped bottling and distributing CSAB products in favor of in-house alternatives, although regional exceptions can be found. It is notable that Pepsi bottlers have been dropping Dr Pepper without an equivalent replacement. Previously a Pepsi bottler without a Dr Pepper franchise would typically bottle Dr. Wells, and Coke bottlers would make Mr. Pibb.
In Canada and Poland, Cadbury-Schweppes has licensed distribution rights to PepsiCo. In Mexico, Germany, France, Italy, Sweden, The Netherlands, Slovakia, Finland, Austria, Czech Republic, Belgium, and Norway, Cadbury-Schweppes owns the trademark and distributes the product. In Spain, Turkey, and Greece it is almost impossible to find as it is usually imported from the United Kingdom in particular supermarkets. In almost all of the other countries of the world, The Coca-Cola Company purchased the trademark from Cadbury-Schweppes and distributes the product. This mixed worldwide ownership of the trademark is due to antitrust regulations which prevented Coca-Cola from purchasing the rights everywhere. Dr Pepper is also available in Japan, New Zealand and South Korea.
## Dr Pepper and high fructose corn syrup
Much of the soft drink industry in the United States stopped using sugar in the 1980s, in response to a series of price supports and import quotas introduced beginning in 1982 that increased the price of sugar above the global market price. As a result, most U.S. soft drinks, including Dr Pepper, now use high fructose corn syrup instead of sugar.
A handful of U.S. bottling plants still use sugar to sweeten Dr Pepper. Perhaps best known is the Dr Pepper bottling plant in Dublin, Texas, the product of which is known as Dublin Dr Pepper. In the 1980s, plant owner Bill Kloster (1918 – 1999) refused to convert the plant to high fructose corn syrup. Since 2003, Dublin Dr Pepper has expanded its distribution to most of Texas and the Internet. Other bottlers still using sugar include Temple Bottling Company, in Temple, Texas, Ab-Tex in Abilene, and West Jefferson Dr Pepper (WJDP) of West Jefferson, NC.
On March 25, 2007, Coca-Cola bottlers in the Dr Pepper Heartland commenced sales of 16 ounce cans of Dr Pepper made with cane sugar and featuring a logo with 'Old Doc' himself on them. This product is scheduled to be a limited time release.
# Name formatting
The period (fullstop) after "Dr" was discarded for stylistic and legibility reasons in the 1950s. Dr Pepper's logo was redesigned and the text in this new logo was slanted. The period made "Dr." look like "Di:". After some debate, the period was removed for good (it had been used off and on in previous logos), as it would also help remove any medical connotation with the product.
# Miscellany
Dr Pepper is the name of a poker variant, whereby in addition to jokers, the cards 10, 2, and 4 are wild cards (taken from a previous advertising slogan which encouraged customers to drink a Dr Pepper at 10, 2, and 4 o'clock).
The company sells more Dr Pepper in the Roanoke Valley area of Virginia than any other metropolitan area east of the Mississippi River. Roanoke is approximately 90 miles east of the hometown of Dr Charles T. Pepper, which is Rural Retreat, Virginia. In the past, the city has been named the "Dr Pepper Capital of the World," and broke world records for its mass consumption of Dr Pepper in the late 1950s. Dr Pepper donated a portion of its sales revenue in the Roanoke area to finance restoration of a circa-1950s neon Dr Pepper sign, which has the company's "10, 2, 4" logo from the time, in downtown Roanoke.
# Advertising and product placement
Arguably the most famous of Dr Pepper's advertising campaigns was their "Be a Pepper" series. These commercials referred to fans of Dr Pepper as "Peppers," and often featured crowd dance scenes with elaborate, over-the-top choreography. One popular ad included the jingle:
This became grist for a number of pop culture references and parodies. One of the first was a sketch on the program SCTV, in which an overly-excited injured man (Eugene Levy) extols the work of a "Dr. Shekter" (Rick Moranis) who's been treating him. Levy and a group of patients wearing casts and crutches engage in their own elaborate dancing and singing (Wouldn't you like to have my doctor, too?), all to the alarm of Shekter (These people should not be dancing!).
Perhaps the most familiar face of these "I'm a Pepper" commercials, David Naughton, later had his breakthrough film role as the main character in the John Landis film An American Werewolf in London.
In 1986, the movie Short Circuit included many advertisements for Dr Pepper, including the old slogan ("Wouldn't you like to be a Pepper too?") used by the main protagonist Johnny 5. In the "Hate Plague" story arc in the Transformers animated series, the character Wreck-Gar infects Rodimus Prime with the line "I'm a Pepper. Wouldn't you like to be a Pepper too?" In the movie The Life Aquatic with Steve Zissou, Jeff Goldblum's character can be seen wearing an "I'm A Pepper" shirt while he's being held captive by pirates. Also, in the 1981 film, The Cannonball Run, actor Dom DeLuise (as Victor Prinzim) can be seen singing the "I'm a Pepper" jingle while running out of a Mini-Mart.
Dr Pepper has also been featured outside of the "I'm a Pepper" motif:
- The original title of the Beatles' 'Sgt Pepper's Lonely Hearts Club Band' was 'Dr Pepper's Lonely Hearts Club Band'. Whether this was a reference to the soft drink is unknown, but a Dr Pepper bottle can be seen in the film Let It Be.
- The beverage was involved in cross-promotion with several Marvel Comics movies, including X-Men 2, Spider-Man, and Spider-Man 2. Likewise, characters from the respective movies appeared on Dr Pepper cans around the time of each film's release.
- The Return of Godzilla had new scenes shot in the U.S., and in one a Dr Pepper machine can be seen very prominently at the end of a hallway. There were also Godzilla Dr Pepper commercials.
- Dr Pepper is featured in many of Tom Hanks' movies, most notably in Forrest Gump and Cast Away. Bottles of Dr Pepper are also shown on a table behind the characters in That Thing You Do! when they are examining their new Play-Tone record.
- An empty Dr Pepper bottle is featured in the book Ragweed by Newbery Award-winning author Avi; the book’s illustrator, Brian Floca, is the son of a Dr Pepper bottler.
- In the video game Pikmin 2, one of the collectable treasures is a Dr Pepper bottle's cap. It is labeled as the "Drought Ender".
- In the movie Family Guy Presents: Stewie Griffin: The Untold Story, Brian and Stewie are in the desert and see a Dr Pepper Machine on the top of a hill. They are disappointed to discover it to be mirage (it's actually an R.C. Cola machine).
- A small packet of Dr Pepper is used to locate the leak in the spaceship in the film Mission to Mars, with scenes of a Dr Pepper can floating prominently in view.
- In the movie S.W.A.T., Dr Pepper is featured throughout the film, including dialogue with the brand's name.
- In the movie Blast from the Past, in which the character played by Christopher Walken has his wife (played by Sissy Spacek) prepare hot Dr Pepper for him. There was an actual campaign in the early 1960's to serve Dr. Pepper hot with slices of lemon as a winter drink. The police investigators at the beginning of the film can be seen reeling in disgust at his having it prepared hot.
- In the museum, on the second floor, classic commercials for Dr Pepper can be viewed. Chris Rock is shown in one of these, as a child enjoying a Dr Pepper.
Dr Pepper's "Be You" advertising campaign centered around commercials featuring pairs of popular musicians, including LeAnn Rimes with Reba McEntire, Paulina Rubio with Celia Cruz, Thalía with Tito Puente, B2K with Smokey Robinson, Anastacia with Cyndi Lauper, Patricia Manterola with Ana Gabriel, and LL Cool J with Run-D.M.C. The campaign also featured individual musicians, notably Garth Brooks.
Dr Pepper was introduced to the Australian market in 1997 with a short-lived TV advertising campaign and low priced 280 ml cans sold through supermarkets. Dr Pepper was subsequently sold in 1.25 litre plastic bottles alongside other major brands until 2003. Cadbury Schweppes stated that the product did not gain acceptance by Australians, whose detractors complained that the drink tasted like "cough syrup" (a tag also given to Sarsaparilla). A report on the soft drink industry by IBIS accused Cadbury Schweppes of failing in their marketing of the brand, given its global appeal.
After withdrawing from the Australian market, Dr Pepper arrived without fanfare in New Zealand. Cans imported from the U.S. are available in some specialty stores in New Zealand and Australia.
On the 2000-12-20 episode of the Late Show with David Letterman, Letterman jokingly referred to Dr Pepper as "liquid manure". After a representative of Dr Pepper complained, CBS agreed not to rerun the Dec. 20 episode. Letterman repeatedly made assurances on the show that he was joking.
Several ads for Diet Cherry Vanilla Dr Pepper appeared on television in 2005. In one, a young woman on a blind date at a restaurant who sips into the beverage, suddenly making her date, restaurant patrons, and even a waitress all part of a musical sequence involving The Muppets version of the song "Mah Nà Mah Nà".
Recently, a new campaign was introduced, which features the Queen song "I Want It All".
# Dr Pepper slogans
- 1889–1914: "King of Beverages."
- 1920s–1930s: "Drink a Bite to Eat at 10, 2, and 4 o'clock."
- 1940s: "Good For Life."
- 1950s: "The Friendly Pepper Upper."
- 1960s: "America's Most Misunderstood Soft Drink."
- 1970s: "The Most Original Soft Drink Ever."
- 1977–1985: "Be a Pepper.", "Wouldn't you like to Be a Pepper too?"
- 1986–1997: "Hold Out For the Out of the Ordinary."
- c. 1997: "It's Dr Pepper Flavour, Silly!" Australia
- 1997: "Now's the Time. This is the Place. Dr Pepper Is The Taste."
- 2000: "Dr Pepper, It Makes the World Taste Better."
- 2000–Present: "Just What The Dr Ordered."
- c. 2001 "Dr Pepper, so misunderstood"
- 2002–2004: "Be You."
- 2002–Present: "Solves All Your Problems." (used in Europe)
- 2003 "Dr Pepper, to try it, is to love it" (used in the UK)
- 2004–Present "Dr Pepper, what's the worst that could happen?" (used in the UK)
- 2005–Present: "One Taste & You Get It."
- 2006: "Can You Handle The Taste?" (seen in Denmark, Finland, Netherlands and Poland)
- 2006: "Authentic blend of 23 flavors." USA, Canada
- 2006: "Dr Pepper,makes the world go round."
- 2006: "Dr Pepper, nothing better." USA
- 2006: "The Dr knows the right touch." (used in Europe)
- 2006: "There's more to it." USA
- c. 2006: "Get Berried in Cream" USA
- 2007: "I Want It All." USA
# Other flavors
- Dietetic Dr Pepper was introduced in 1962 (cans) and 1963 (bottles). Sales were slow partly due to the public misconception that the drink was for diabetics, and the company soon renamed the product Diet Dr Pepper. The product was renamed Sugar Free Dr Pepper in May 1971, and in 1991 it was reformulated to use aspartame and renamed Diet Dr Pepper. According to Cadbury Schweppes, Diet Dr Pepper is a top 10 soft drink in the United States, and the leading non-cola diet soft drink. Its slogan involves it tasting like the original compared to other soft drinks and their diet counterparts.
- Dr Pepper Red Fusion was available from 2002 - 2004, only in the US
- Cherry Vanilla Dr Pepper was released in some areas on October 15, 2004. The beverage tastes similar to Dr Pepper but has stronger cherry and vanilla flavors added. Cherry Vanilla Dr Pepper is the first drink in the planned "Fountain Classics" line of beverages from Dr Pepper, a range of drinks designed to taste similar to popular soda fountain drinks from the 1950s. It is now available in all areas of the U.S.
- Diet Cherry Vanilla Dr Pepper, which has zero calories, is also available. It was the pilot and was on the shelves before the non-diet version. The Diet version of the drink is now a pilot in Canada. Although disappearing for a short period of time, it has resurfaced in Canada, with the new logo design, however this product is not sold outside of North America.
- Dr Pepper Berries & Cream, and its diet version, were released in most US locations in April 2006. It is the second beverage in Dr Pepper's "Fountain Classics" line of drinks.
- Caffeine Free Dr Pepper, and its diet version, are new products, without caffeine.
- United Kingdom's version of Dr Pepper has a different taste, very similar to Coca-Cola Cherry and is manufactured with sugar instead of high fructose corn syrup. Along with Sprite and Fanta soft drinks, a 'Zero' version was introduced, meaning no added sugar.
# Other Products
- Dr Pepper has a successful line of Jelly Beans made with the Jelly Belly company.
- Dr Pepper recently joined forces with Vita Food Products to produce Dr Pepper Sweet & Kickin' BBQ Sauce Dr Pepper More than Mesquite Marinade.
# Imitations
Many imitations of Dr Pepper exist and can often be identified by the use of "Dr" or "Mr" in their name. One of the most well-known competitors is Pibb Xtra, formerly called "Mr PiBB". It is made by The Coca-Cola Company.
SoBe Beverages took its ginseng-infused approach with "Mr. Green".
Several other imitations include:
- "Dr. Path" sold in PathMark Supermarkets.
- "Country Doctor" sold in Fareway Stores.
- "Dr. Topper" Rocky Top, Clover Valley, sold in Dollar General stores.
- "Dr. Dazzle" distributed by ALDI Inc.
- "Dr. Slice", "Dr. Faygo" marketed by Faygo Family Beverages Inc.
- "Dr. Smooth" marketed by President's Choice
- "Dr. Hy-Top" marketed by Federated Group
- "Dr. Chek" in Winn-Dixie supermarkets
- "Dr. IGA" in IGA supermarkets
- "Dr. Perky" in Food Lion supermarkets
- "Dr. Thunder" distributed in Wal-Mart stores
- "Dr. Bash" distributed by Bashas' stores
- "Dr. Bob" sold in Stop & Shop Supermarkets
- "Dr. Weis" Distributed by Weis Markets, and "Dr. Celeste" marketed by The Pantry, Inc.
- "Dr. Spice" distributed in Target Stores
- "Dr. Hy-Vee" distributed at Hy-Vee grocery stores
- "Pepper, MD" sold in Path Right stores
- "Dr. Fresh" distributed at Marsh supermarkets
- "Dr. Rocket" distributed at K-mart stores
- "Dr. Radical", made by Adirondack Beverage Company
- "Dr. Shaw's", made by Shaw's Supermarkets, Inc.
- "Dr. Wild", made by J G Meyer First Choice
- "Dr. Publix" made by Publix
- "Dr. Wow", distributed by Topco.
- "Dr. Riffic", distributed by Eckerd
- "Dr. Bold" and "Dr A+" in Albertsons supermarkets
- "Dr. B" in H-E-B grocery stores
- "Dr. K" distributed at Costco, Kroger and Fred Meyer locations
- "Dr. M" made by Meijer,
- "Dr. U" distributed by United Supermarkets
- "Dr. W" distributed by Wegmans
- Dr. Goodguy" distributed by Kalil
- "Dr. Shasta" made by Shasta (soft drink)
- "Dr. Salt" distributed at Albert Heijn,
- "Pibb Xtra" sold by Coca-Cola
- "Dr. Skipper" distributed by Safeway grocery stores
- "Dr.Perky" sold in Food Lion stores
- "Dr. Pop" sold in Save A Lot grocery stores and Morrisons stores in the UK (although this is a different product
- "Dr. Phizz" sold in Schnucks Supermarkets
- "Dr. Zeppa" sold in Store 24 convenience stores
- "Dr Zip" sold in Sobeys supermarkets
- "Dr. Nehi" sold by Nehi/Royal Crown Cola
- "Dr Western" sold in Oregon
- "Dr. Becker" made by the Blue Sky Beverage Company
Other generic versions are "Dr. Wells," "Mr. Ahhhh," "Doc Rocket" (from Trader Joe's) and "Dr. Foots."
The version sold at Safeway Stores was called "The Skipper" throughout the 1980s. Sometime in the 1990s it was renamed "Dr. Skipper", then "Dr. Select", and then "The Dr." After Safeway (UK)'s takeover by Morrisons, its version was renamed "Dr Pop".
# Legal/trade history
Dr Pepper was a frequent role player in the 1990s antitrust history of the United States. As part of these activities, economists and the courts have even weighed in with the opinion that Dr Pepper is a "Pepper" flavored drink and not a "Cola." In 1995, the FTC blocked a merger between The Coca-Cola Company and Dr Pepper on grounds that included concerns about a monopoly of the "Pepper" flavor category of soft drinks. In 1996, Dr Pepper was involved in an antitrust case involving Jerry Jones, the Dallas Cowboys, NFL Properties, Nike, and other commercial interests active at Texas Stadium in Irving, Texas. In 1998, the "Pepper" flavor soda category was a major part of the analysis supporting an antitrust case between Coca-Cola and Pepsi.
# Sources
- Rodengen, Jeffrey L. (1995). The Legend of Dr Pepper/Seven-Up. Write Stuff Syndicate, Inc. ISBN 0-945903-49-9..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}
- "History of Dr Pepper". Retrieved 2007-07-04. | Dr Pepper
Template:Infobox Beverage
Dr Pepper is a caramel-colored, carbonated soft drink marketed in North America by Cadbury Schweppes Americas Beverages (CSAB), a unit of Cadbury Schweppes. The headquarters of CSAB are situated in Plano, Texas, a suburb of Dallas. The ownership of the trademark varies in other countries, although most non-U.S. territories are controlled by Coca-Cola Company. There is also a no-calorie version, Diet Dr Pepper, as well as many other flavors.
# Overview and history
The drink was first sold in Waco, Texas, in 1885. It was introduced nationally in the United States at the 1904 Louisiana Purchase Exposition as a new kind of cola. Dr. Pepper is not a kind of root beer. The exact date of Dr Pepper's conception is unknown, but the U.S. Patent Office recognizes December 1, 1885 as the first time Dr Pepper was served.
It was formulated by German pharmacist Charles Alderton in Morrison's Old Corner Drug Store in Waco.[1]To test his new drink, he first offered it to store owner Wade Morrison, who also found it to his liking. After repeated sample testing by the two, Alderton was ready to offer his new drink to some of the fountain customers. Other patrons at Morrison's soda fountain soon learned of Alderton's new drink and began ordering a "Waco". Alderton gave the formula to Morrison. A popular belief is that the drink was named after Morrison's former employer in Texas, but this has been disputed by the Dr Pepper company itself. They state that before moving to Texas, Morrison lived in Wythe County, Virginia near a Dr. Charles T. Pepper, and may have been close to Pepper's daughter at the time. The name is also reinforced by being an obvious play on "pep", i.e. providing quick energy to its consumer.
Unlike Coca-Cola and Pepsi, Dr Pepper is not marketed as a cola. Dr Pepper's flavor is allegedly derived from a mixture of soda fountain flavors popular when the drink was first devised. A partial list of these flavors can be seen at the bottling plant in Dublin, Texas, although the formula itself (with its twenty-three ingredients) is a closely guarded secret. There is a long-lived urban legend that Dr Pepper contains prune juice. However, according to the manufacturer, prune juice is not and never has been an ingredient of the drink.[2][3]
There is also a Dr Pepper Museum in downtown Waco. It is located in the Artesian Manufacturing and Bottling Company building in downtown Waco, and opened to the public in 1991. The Artesian Manufacturing and Bottling Company building was the first building to be built specifically to bottle Dr Pepper. The building was completed in 1906 and Dr Pepper was bottled there until the 1960s. The museum has three floors of exhibits, a working old-fashioned soda fountain, and a gift store full of Dr Pepper memorabilia. (As the picture shows, the building has differing color bricks, since it was heavily damaged by the Waco Tornado.)
Dr Pepper almost became a Coca-Cola brand in the mid-to-late 1980s. Dr Pepper became insolvent in the early 1980s, prompting an investment group to take the company private. Several years later, Coca-Cola attempted to acquire Dr Pepper, but was blocked from doing so by the United States Federal Trade Commission (FTC). Around the same time, Seven Up was acquired from Phillip Morris by the same investment company that bailed out Dr Pepper. Upon the failure of the Coca-Cola merger, Dr Pepper and Seven Up merged (creating Dr Pepper/Seven Up, Inc., or DPSU), giving up international branding rights in the process. After the DPSU merger, Coca-Cola obtained most non-U.S. rights to the Dr Pepper name (with PepsiCo taking the Seven Up rights).
Template:Infobox nutrition facts
## Distribution
In the United States, Cadbury Schweppes Americas Beverages (CSAB) does not have a complete network of bottlers and distributors, so the drink is sometimes bottled under contract by Coca-Cola or Pepsi bottlers. Prior to the initial Cadbury Schweppes investment-turned-buyout, 30% of Dr Pepper/Seven Up products were produced and distributed by Pepsi bottlers, and another 30% by Coca-Cola bottlers. The remaining 40% was produced and distributed by independent bottlers (mainly consisting of pre-Dr Pepper/Seven Up-merger regional bottlers) and the Dr Pepper/Seven Up Bottling Group.
Presently, Dr Pepper is mostly reliant on the Cadbury Schweppes Bottling Group (known as Dr Pepper/Seven Up Bottling Group until June, 2006) to bottle and distribute its products in 30+ states. Coca-Cola and Pepsi have essentially stopped bottling and distributing CSAB products in favor of in-house alternatives, although regional exceptions can be found. It is notable that Pepsi bottlers have been dropping Dr Pepper without an equivalent replacement. Previously a Pepsi bottler without a Dr Pepper franchise would typically bottle Dr. Wells, and Coke bottlers would make Mr. Pibb.
In Canada and Poland, Cadbury-Schweppes has licensed distribution rights to PepsiCo. In Mexico, Germany, France, Italy, Sweden, The Netherlands, Slovakia, Finland, Austria, Czech Republic, Belgium, and Norway, Cadbury-Schweppes owns the trademark and distributes the product. In Spain, Turkey, and Greece it is almost impossible to find as it is usually imported from the United Kingdom in particular supermarkets. In almost all of the other countries of the world, The Coca-Cola Company purchased the trademark from Cadbury-Schweppes and distributes the product. This mixed worldwide ownership of the trademark is due to antitrust regulations which prevented Coca-Cola from purchasing the rights everywhere. Dr Pepper is also available in Japan, New Zealand and South Korea.
## Dr Pepper and high fructose corn syrup
Much of the soft drink industry in the United States stopped using sugar in the 1980s, in response to a series of price supports and import quotas introduced beginning in 1982 that increased the price of sugar above the global market price. As a result, most U.S. soft drinks, including Dr Pepper, now use high fructose corn syrup instead of sugar.
A handful of U.S. bottling plants still use sugar to sweeten Dr Pepper. Perhaps best known is the Dr Pepper bottling plant in Dublin, Texas, the product of which is known as Dublin Dr Pepper. In the 1980s, plant owner Bill Kloster (1918 – 1999) refused to convert the plant to high fructose corn syrup. Since 2003, Dublin Dr Pepper has expanded its distribution to most of Texas and the Internet. Other bottlers still using sugar include Temple Bottling Company, in Temple, Texas, Ab-Tex in Abilene, and West Jefferson Dr Pepper (WJDP) of West Jefferson, NC.
On March 25, 2007, Coca-Cola bottlers in the Dr Pepper Heartland commenced sales of 16 ounce cans of Dr Pepper made with cane sugar and featuring a logo with 'Old Doc' himself on them. This product is scheduled to be a limited time release.
# Name formatting
The period (fullstop) after "Dr" was discarded for stylistic and legibility reasons in the 1950s. Dr Pepper's logo was redesigned and the text in this new logo was slanted. The period made "Dr." look like "Di:". After some debate, the period was removed for good (it had been used off and on in previous logos), as it would also help remove any medical connotation with the product.
# Miscellany
Dr Pepper is the name of a poker variant, whereby in addition to jokers, the cards 10, 2, and 4 are wild cards (taken from a previous advertising slogan which encouraged customers to drink a Dr Pepper at 10, 2, and 4 o'clock).
The company sells more Dr Pepper in the Roanoke Valley area of Virginia than any other metropolitan area east of the Mississippi River. Roanoke is approximately 90 miles east of the hometown of Dr Charles T. Pepper, which is Rural Retreat, Virginia. In the past, the city has been named the "Dr Pepper Capital of the World," and broke world records for its mass consumption of Dr Pepper in the late 1950s. [5] Dr Pepper donated a portion of its sales revenue in the Roanoke area to finance restoration of a circa-1950s neon Dr Pepper sign, which has the company's "10, 2, 4" logo from the time, in downtown Roanoke.
# Advertising and product placement
Arguably the most famous of Dr Pepper's advertising campaigns was their "Be a Pepper" series. These commercials referred to fans of Dr Pepper as "Peppers," and often featured crowd dance scenes with elaborate, over-the-top choreography. One popular ad included the jingle:
This became grist for a number of pop culture references and parodies. One of the first was a sketch on the program SCTV, in which an overly-excited injured man (Eugene Levy) extols the work of a "Dr. Shekter" (Rick Moranis) who's been treating him. Levy and a group of patients wearing casts and crutches engage in their own elaborate dancing and singing (Wouldn't you like to have my doctor, too?), all to the alarm of Shekter (These people should not be dancing!).
Perhaps the most familiar face of these "I'm a Pepper" commercials, David Naughton, later had his breakthrough film role as the main character in the John Landis film An American Werewolf in London.
In 1986, the movie Short Circuit included many advertisements for Dr Pepper, including the old slogan ("Wouldn't you like to be a Pepper too?") used by the main protagonist Johnny 5. In the "Hate Plague" story arc in the Transformers animated series, the character Wreck-Gar infects Rodimus Prime with the line "I'm a Pepper. Wouldn't you like to be a Pepper too?" In the movie The Life Aquatic with Steve Zissou, Jeff Goldblum's character can be seen wearing an "I'm A Pepper" shirt while he's being held captive by pirates. Also, in the 1981 film, The Cannonball Run, actor Dom DeLuise (as Victor Prinzim) can be seen singing the "I'm a Pepper" jingle while running out of a Mini-Mart.
Dr Pepper has also been featured outside of the "I'm a Pepper" motif:
- The original title of the Beatles' 'Sgt Pepper's Lonely Hearts Club Band' was 'Dr Pepper's Lonely Hearts Club Band'. Whether this was a reference to the soft drink is unknown, but a Dr Pepper bottle can be seen in the film Let It Be.[citation needed]
- The beverage was involved in cross-promotion with several Marvel Comics movies, including X-Men 2, Spider-Man, and Spider-Man 2. Likewise, characters from the respective movies appeared on Dr Pepper cans around the time of each film's release.
- The Return of Godzilla had new scenes shot in the U.S., and in one a Dr Pepper machine can be seen very prominently at the end of a hallway. There were also Godzilla Dr Pepper commercials.
- Dr Pepper is featured in many of Tom Hanks' movies, most notably in Forrest Gump and Cast Away. Bottles of Dr Pepper are also shown on a table behind the characters in That Thing You Do! when they are examining their new Play-Tone record.
- An empty Dr Pepper bottle is featured in the book Ragweed by Newbery Award-winning author Avi; the book’s illustrator, Brian Floca, is the son of a Dr Pepper bottler.
- In the video game Pikmin 2, one of the collectable treasures is a Dr Pepper bottle's cap. It is labeled as the "Drought Ender".
- In the movie Family Guy Presents: Stewie Griffin: The Untold Story, Brian and Stewie are in the desert and see a Dr Pepper Machine on the top of a hill. They are disappointed to discover it to be mirage (it's actually an R.C. Cola machine).
- A small packet of Dr Pepper is used to locate the leak in the spaceship in the film Mission to Mars, with scenes of a Dr Pepper can floating prominently in view.
- In the movie S.W.A.T., Dr Pepper is featured throughout the film, including dialogue with the brand's name.
- In the movie Blast from the Past, in which the character played by Christopher Walken has his wife (played by Sissy Spacek) prepare hot Dr Pepper for him. There was an actual campaign in the early 1960's to serve Dr. Pepper hot with slices of lemon as a winter drink. The police investigators at the beginning of the film can be seen reeling in disgust at his having it prepared hot.
- In the museum, on the second floor, classic commercials for Dr Pepper can be viewed. Chris Rock is shown in one of these, as a child enjoying a Dr Pepper.
Dr Pepper's "Be You" advertising campaign centered around commercials featuring pairs of popular musicians, including LeAnn Rimes with Reba McEntire, Paulina Rubio with Celia Cruz, Thalía with Tito Puente, B2K with Smokey Robinson, Anastacia with Cyndi Lauper, Patricia Manterola with Ana Gabriel, and LL Cool J with Run-D.M.C. The campaign also featured individual musicians, notably Garth Brooks.
Dr Pepper was introduced to the Australian market in 1997 with a short-lived TV advertising campaign and low priced 280 ml cans sold through supermarkets. Dr Pepper was subsequently sold in 1.25 litre plastic bottles alongside other major brands until 2003. Cadbury Schweppes stated that the product did not gain acceptance by Australians, whose detractors complained that the drink tasted like "cough syrup"[citation needed] (a tag also given to Sarsaparilla). A report on the soft drink industry by IBIS accused Cadbury Schweppes of failing in their marketing of the brand, given its global appeal[citation needed].
After withdrawing from the Australian market, Dr Pepper arrived without fanfare in New Zealand. Cans imported from the U.S. are available in some specialty stores in New Zealand and Australia.
On the 2000-12-20 episode of the Late Show with David Letterman, Letterman jokingly referred to Dr Pepper as "liquid manure". After a representative of Dr Pepper complained, CBS agreed not to rerun the Dec. 20 episode. Letterman repeatedly made assurances on the show that he was joking.[4]
Several ads for Diet Cherry Vanilla Dr Pepper appeared on television in 2005. In one, a young woman on a blind date at a restaurant who sips into the beverage, suddenly making her date, restaurant patrons, and even a waitress all part of a musical sequence involving The Muppets version of the song "Mah Nà Mah Nà".
Recently, a new campaign was introduced, which features the Queen song "I Want It All".
# Dr Pepper slogans
- 1889–1914: "King of Beverages."
- 1920s–1930s: "Drink a Bite to Eat at 10, 2, and 4 o'clock."
- 1940s: "Good For Life."
- 1950s: "The Friendly Pepper Upper."
- 1960s: "America's Most Misunderstood Soft Drink."
- 1970s: "The Most Original Soft Drink Ever."
- 1977–1985: "Be a Pepper.", "Wouldn't you like to Be a Pepper too?"
- 1986–1997: "Hold Out For the Out of the Ordinary."
- c. 1997: "It's Dr Pepper Flavour, Silly!" Australia
- 1997: "Now's the Time. This is the Place. Dr Pepper Is The Taste."
- 2000: "Dr Pepper, It Makes the World Taste Better."
- 2000–Present: "Just What The Dr Ordered."
- c. 2001 "Dr Pepper, so misunderstood"
- 2002–2004: "Be You."
- 2002–Present: "Solves All Your Problems." (used in Europe)
- 2003 "Dr Pepper, to try it, is to love it" (used in the UK)
- 2004–Present "Dr Pepper, what's the worst that could happen?" (used in the UK)
- 2005–Present: "One Taste & You Get It."
- 2006: "Can You Handle The Taste?"[5] (seen in Denmark, Finland, Netherlands and Poland)
- 2006: "Authentic blend of 23 flavors." USA, Canada
- 2006: "Dr Pepper,makes the world go round."
- 2006: "Dr Pepper, nothing better." USA
- 2006: "The Dr knows the right touch." (used in Europe)
- 2006: "There's more to it." USA
- c. 2006: "Get Berried in Cream" USA
- 2007: "I Want It All." USA
# Other flavors
- Dietetic Dr Pepper was introduced in 1962 (cans) and 1963 (bottles). Sales were slow partly due to the public misconception that the drink was for diabetics, and the company soon renamed the product Diet Dr Pepper. The product was renamed Sugar Free Dr Pepper in May 1971, and in 1991 it was reformulated to use aspartame and renamed Diet Dr Pepper. According to Cadbury Schweppes, Diet Dr Pepper is a top 10 soft drink in the United States, and the leading non-cola diet soft drink. Its slogan involves it tasting like the original compared to other soft drinks and their diet counterparts.[6][7]
- Dr Pepper Red Fusion was available from 2002 - 2004, only in the US
- Cherry Vanilla Dr Pepper was released in some areas on October 15, 2004. The beverage tastes similar to Dr Pepper but has stronger cherry and vanilla flavors added. Cherry Vanilla Dr Pepper is the first drink in the planned "Fountain Classics" line of beverages from Dr Pepper, a range of drinks designed to taste similar to popular soda fountain drinks from the 1950s. It is now available in all areas of the U.S.
- Diet Cherry Vanilla Dr Pepper, which has zero calories, is also available. It was the pilot and was on the shelves before the non-diet version. The Diet version of the drink is now a pilot in Canada. Although disappearing for a short period of time, it has resurfaced in Canada, with the new logo design, however this product is not sold outside of North America.
- Dr Pepper Berries & Cream, and its diet version, were released in most US locations in April 2006. It is the second beverage in Dr Pepper's "Fountain Classics" line of drinks.
- Caffeine Free Dr Pepper, and its diet version, are new products, without caffeine.
- United Kingdom's version of Dr Pepper has a different taste, very similar to Coca-Cola Cherry and is manufactured with sugar instead of high fructose corn syrup. Along with Sprite and Fanta soft drinks, a 'Zero' version was introduced, meaning no added sugar.
# Other Products
- Dr Pepper has a successful line of Jelly Beans made with the Jelly Belly company.
- Dr Pepper recently joined forces with Vita Food Products to produce Dr Pepper Sweet & Kickin' BBQ Sauce Dr Pepper More than Mesquite Marinade. [8]
# Imitations
Many imitations of Dr Pepper exist and can often be identified by the use of "Dr" or "Mr" in their name. One of the most well-known competitors is Pibb Xtra, formerly called "Mr PiBB". It is made by The Coca-Cola Company.
SoBe Beverages took its ginseng-infused approach with "Mr. Green".
Several other imitations include:
- "Dr. Path" sold in PathMark Supermarkets.
- "Country Doctor" sold in Fareway Stores.
- "Dr. Topper" Rocky Top, Clover Valley, sold in Dollar General stores.
- "Dr. Dazzle" distributed by ALDI Inc.
- "Dr. Slice", "Dr. Faygo" marketed by Faygo Family Beverages Inc.
- "Dr. Smooth" marketed by President's Choice
- "Dr. Hy-Top" marketed by Federated Group
- "Dr. Chek" in Winn-Dixie supermarkets
- "Dr. IGA" in IGA supermarkets
- "Dr. Perky" in Food Lion supermarkets
- "Dr. Thunder" distributed in Wal-Mart stores
- "Dr. Bash" distributed by Bashas' stores
- "Dr. Bob" sold in Stop & Shop Supermarkets
- "Dr. Weis" Distributed by Weis Markets, and "Dr. Celeste" marketed by The Pantry, Inc.
- "Dr. Spice" distributed in Target Stores
- "Dr. Hy-Vee" distributed at Hy-Vee grocery stores
- "Pepper, MD" sold in Path Right stores
- "Dr. Fresh" distributed at Marsh supermarkets
- "Dr. Rocket" distributed at K-mart stores
- "Dr. Radical", made by Adirondack Beverage Company
- "Dr. Shaw's", made by Shaw's Supermarkets, Inc.
- "Dr. Wild", made by J G Meyer First Choice
- "Dr. Publix" made by Publix
- "Dr. Wow", distributed by Topco.
- "Dr. Riffic", distributed by Eckerd
- "Dr. Bold" and "Dr A+" in Albertsons supermarkets
- "Dr. B" in H-E-B grocery stores
- "Dr. K" distributed at Costco, Kroger and Fred Meyer locations
- "Dr. M" made by Meijer,
- "Dr. U" distributed by United Supermarkets
- "Dr. W" distributed by Wegmans
- Dr. Goodguy" distributed by Kalil
- "Dr. Shasta" made by Shasta (soft drink)
- "Dr. Salt" distributed at Albert Heijn,
- "Pibb Xtra" sold by Coca-Cola
- "Dr. Skipper" distributed by Safeway grocery stores
- "Dr.Perky" sold in Food Lion stores
- "Dr. Pop" sold in Save A Lot grocery stores and Morrisons stores in the UK (although this is a different product
- "Dr. Phizz" sold in Schnucks Supermarkets
- "Dr. Zeppa" sold in Store 24 convenience stores
- "Dr Zip" sold in Sobeys supermarkets
- "Dr. Nehi" sold by Nehi/Royal Crown Cola
- "Dr Western" sold in Oregon
- "Dr. Becker" made by the Blue Sky Beverage Company
Other generic versions are "Dr. Wells," "Mr. Ahhhh," "Doc Rocket" (from Trader Joe's) and "Dr. Foots."
The version sold at Safeway Stores was called "The Skipper" throughout the 1980s. Sometime in the 1990s it was renamed "Dr. Skipper", then "Dr. Select", and then "The Dr." After Safeway (UK)'s takeover by Morrisons, its version was renamed "Dr Pop".
# Legal/trade history
Dr Pepper was a frequent role player in the 1990s antitrust history of the United States. As part of these activities, economists and the courts have even weighed in with the opinion that Dr Pepper is a "Pepper" flavored drink and not a "Cola." In 1995, the FTC blocked a merger between The Coca-Cola Company and Dr Pepper on grounds that included concerns about a monopoly of the "Pepper" flavor category of soft drinks. In 1996, Dr Pepper was involved in an antitrust case involving Jerry Jones, the Dallas Cowboys, NFL Properties, Nike, and other commercial interests active at Texas Stadium in Irving, Texas. In 1998, the "Pepper" flavor soda category was a major part of the analysis supporting an antitrust case between Coca-Cola and Pepsi.
# Sources
- Rodengen, Jeffrey L. (1995). The Legend of Dr Pepper/Seven-Up. Write Stuff Syndicate, Inc. ISBN 0-945903-49-9..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}
- "History of Dr Pepper". Retrieved 2007-07-04. | https://www.wikidoc.org/index.php/Dr_Pepper | |
3ed233b0436dbe11980e9b704f8eca96f7d74e84 | wikidoc | Droxidopa | Droxidopa
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# Black Box Warning
# Overview
Droxidopa is a Sympathomimetic that is FDA approved for the treatment of neurogenic orthostatic hypotension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Headache, dizziness, nausea, hypertension, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- NORTHERA is indicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure (Parkinson's disease (PD), multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Effectiveness beyond 2 weeks of treatment has not been established. The continued effectiveness of NORTHERA should be assessed periodically.
### Dosage
- The recommended starting dose of NORTHERA is 100 mg, taken orally three times daily: upon arising in the morning, at midday, and in the late afternoon at least 3 hours prior to bedtime (to reduce the potential for supine hypertension during sleep). Administer NORTHERA consistently, either with food or without food. Take NORTHERA capsule whole. Titrate to symptomatic response, in increments of 100 mg three times daily every 24 to 48 hours up to a maximum dose of 600 mg three times daily (i.e., a maximum total daily dose of 1,800 mg).
- Monitor supine blood pressure prior to initiating NORTHERA and after increasing the dose.
- Patients who miss a dose of NORTHERA should take their next scheduled dose.
### DOSAGE FORMS AND STRENGTHS
- NORTHERA capsules are available in 100 mg, 200 mg, and 300 mg strengths as specified below.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Droxidopa in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Droxidopa in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Droxidopa in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Droxidopa in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Droxidopa in pediatric patients.
# Contraindications
- None
# Warnings
- NORTHERA therapy may cause or exacerbate supine hypertension in patients with NOH. Patients should be advised to elevate the head of the bed when resting or sleeping. Monitor blood pressure, both in the supine position and in the recommended head-elevated sleeping position. Reduce or discontinue NORTHERA if supine hypertension persists. If supine hypertension is not well-managed, NORTHERA may increase the risk of cardiovascular events.
- Post-marketing cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported with NORTHERA use during post-marketing surveillance in Japan. Observe patients carefully when the dosage of NORTHERA is changed or when concomitant levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
- NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes. The early diagnosis of this condition is important for the appropriate management of these patients.
- NORTHERA may exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure. Careful consideration should be given to this potential risk prior to initiating therapy in patients with these conditions.
- This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions with NORTHERA are included in more detail in the Warnings and Precautions section of the label:
- Supine Hypertension
- Hyperpyrexia and Confusion
- May exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure
- 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.
- The safety evaluation of NORTHERA is based on two placebo-controlled studies 1 to 2 weeks in duration (Studies 301 and 302), one 8-week placebo-controlled study (Study 306), and two long-term, open-label extension studies (Studies 303 and 304). In the placebo-controlled studies, a total of 485 patients with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or non-diabetic autonomic neuropathy were randomized and treated, 245 with NORTHERA and 240 with placebo.
- The most commonly observed adverse reactions (those occurring at an incidence of greater than 5% in the NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group) in NORTHERA-treated patients during the three placebo-controlled trials were headache, dizziness, nausea, hypertension. The most common adverse reactions leading to discontinuation from NORTHERA were hypertension or increased blood pressure and nausea.
- Note: n=number of patients. Table displays adverse reactions that were reported in greater than 5% of patients in the NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group.
- In the long-term, open-label extension studies, a total of 422 patients, mean age 65 years, were treated with NORTHERA for a mean total exposure of approximately one year. The commonly reported adverse events were falls (24%), urinary tract infections (15%), headache (13%), syncope (13%), and dizziness (10%).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Droxidopa in the drug label.
# Drug Interactions
- Drugs that Increase Blood Pressure
- Administering NORTHERA in combination with other agents that increase blood pressure (e.g., norepinephrine, ephedrine, midodrine, and triptans) would be expected to increase the risk for supine hypertension.
- Parkinson's Medications
- Dopa-decarboxylase inhibitors may require dose adjustments for NORTHERA.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled trials in pregnant women.
- Following consecutive oral administration at doses of 60, 200, and 600 mg/kg/day to pregnant Sprague Dawley rats, increased incidences of lower body weight and occurrence of undulant rib were noted in fetuses, but they were slight and spontaneously reversed after birth. Based on dose per unit body surface area, these three doses correspond to approximately 0.3, 1, and 3 times, respectively, the maximum recommended total daily dose of 1,800 mg in a 60 kg patient. Shortening of the gestation period was observed in rats at 600 mg/kg/day. Low incidences of renal lesions (cysts, indentations, or renal pelvic dilation) were observed on the surface of the kidneys of female rats treated with droxidopa during the period of fetal organogenesis. No other potentially teratogenic effects have been observed in rats or rabbits.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Droxidopa in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Droxidopa during labor and delivery.
### Nursing Mothers
- Choose nursing or NORTHERA. In rats, droxidopa is excreted in breast milk, and when the drug was administered to the nursing dams during the period of lactation, reduced weight gain and reduced survival were observed in the offspring.
### Pediatric Use
- The safety and effectiveness of NORTHERA in pediatric patients have not been established.
### Geriatic Use
- A total of 197 patients with symptomatic NOH aged 75 years or above were included in the NORTHERA clinical program. 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.
### Gender
There is no FDA guidance on the use of Droxidopa with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Droxidopa with respect to specific racial populations.
### Renal Impairment
- NORTHERA and its metabolites are primarily cleared renally. Patients with mild or moderate renal impairment (GFR greater than 30 mL/min) were included in clinical trials and did not have a higher frequency of adverse reactions. Clinical experience with NORTHERA in patients with severe renal function impairment (GFR less than 30 mL/min) is limited.
### Hepatic Impairment
There is no FDA guidance on the use of Droxidopa in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Droxidopa in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Droxidopa in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses.
# IV Compatibility
There is limited information regarding IV Compatibility of Droxidopa in the drug label.
# Overdosage
- There was one case of overdose reported during post-marketing surveillance in Japan. The patient ingested 7,700 mg of NORTHERA and experienced a hypertensive crisis that resolved promptly with treatment.
- There is no known antidote for NORTHERA overdosage. In case of an overdose that may result in an excessively high blood pressure, discontinue NORTHERA and treat with appropriate symptomatic and supportive therapy. Counsel patients to remain in a standing or seated position until their blood pressure drops below an acceptable limit.
# Pharmacology
## Mechanism of Action
- The exact mechanism of action of NORTHERA in the treatment of neurogenic orthostatic hypotension is unknown. NORTHERA is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which is extensively distributed throughout the body. NORTHERA is believed to exert its pharmacological effects through norepinephrine and not through the parent molecule or other metabolites. Norepinephrine increases blood pressure by inducing peripheral arterial and venous vasoconstriction. NORTHERA in humans induces small and transient rises in plasma norepinephrine.
## Structure
- NORTHERA capsules contain droxidopa, which is a synthetic amino acid precursor of norepinephrine, for oral administration. Chemically, droxidopa is (–)-threo-3-(3,4-Dihydroxyphenyl)-L-serine. It has the following structural formula:
- Droxidopa is an odorless, tasteless, white to off-white crystals or crystalline powder. It is slightly soluble in water, and practically insoluble in methanol, glacial acetic acid, ethanol, acetone, ether, and chloroform. It is soluble in dilute hydrochloric acid. It has a molecular weight of 213.19 and a molecular formula of C9H11NO5.
- NORTHERA capsules also contain the following inactive ingredients: mannitol, corn starch, and magnesium stearate. The capsule shell is printed with black ink. The black inks contain shellac glaze, ethanol, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide. The capsule shell contains the following inactive ingredients: 100 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black and red iron oxide; 200 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black and yellow iron oxide; 300 mg – gelatin, titanium dioxide, FD&C Blue No. 1, FD&C Yellow No. 5 (tartrazine), and FD&C Red No. 40. NORTHERA capsules differ in size and color by strength
## Pharmacodynamics
- Peak droxidopa plasma concentrations are associated with increases in systolic and diastolic blood pressures. Droxidopa has no clinically significant effect on standing or supine heart rates in patients with autonomic failure.
- Cardiac Electrophysiology
- No prolongation of the QTc interval was observed with NORTHERA at single oral doses up to 2,000 mg, as shown in a dedicated thorough QT study.
## Pharmacokinetics
- Peak plasma concentrations (Cmax) of droxidopa were reached by 1 to 4 hours post-dose (mean of approximately 2 hours) in healthy volunteers. High-fat meals have a moderate impact on droxidopa exposure with Cmax and area under the plasma concentration-time curve (AUC) decreasing by 35% and 20%, respectively. The Cmax was delayed by approximately 2 hours with a high-fat meal.
- Pre-clinical studies suggest that droxidopa can cross the blood brain barrier. Droxidopa exhibits plasma protein binding of 75% at 100 ng/mL and 26% at 10,000 ng/mL. The estimated apparent volume of distribution of droxidopa is about 200 L in humans.
- The metabolism of droxidopa is mediated by catecholamine pathway and not through the cytochrome P450 system. Droxidopa is initially converted to methoxylated dihydroxyphenylserine (3-OM-DOPS), a major metabolite, by catechol-O-methyltransferase (COMT), to norepinephrine by DOPA decarboxylase (DDC), or to protocatechualdehyde by DOPS aldolase. After oral dosing in humans, plasma norepinephrine levels peak within 3 to 4 hours but are generally very low (less than 1 ng/mL) and variable with no consistent relationship with dose. The contribution of the metabolites of droxidopa other than norepinephrine to its pharmacological effects is not well understood.
- The mean elimination half-life of droxidopa is approximately 2.5 hours in humans. The major route of elimination of droxidopa and its metabolites is via the kidneys in both animals and in humans. Studies in animals showed that ~75% of the radiolabeled dose was excreted in urine within 24 hours of oral dosing.
- There are no clinically relevant effects of age, body mass index, or sex on the pharmacokinetics of droxidopa. A population pharmacokinetic analysis suggests that hepatic function, assessed by aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin, did not influence the exposure to droxidopa. The controlled clinical trials included patients with mild to moderate renal impairment. No dose adjustments are required in patients with mild to moderate renal impairment.
- No dedicated drug-drug interaction studies were performed for droxidopa. Patients in the Phase 3 trials with NORTHERA received concomitant levodopa/carbidopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors and other medications used to treat Parkinson’s disease. Carbidopa, a peripheral dopa-decarboxylase inhibitor, could prevent the conversion of NORTHERA to norepinephrine outside of the central nervous system (CNS). Patients taking NORTHERA with L-DOPA/dopa-decarboxylase inhibitor combination drugs had decreased clearance of NORTHERA, an increase in exposure (AUC) to droxidopa of approximately 100%, and an increase in exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events. Dopamine agonists, amantadine derivatives, and MAO-B inhibitors do not appear to affect NORTHERA clearance, and no dose adjustments are required.
## Nonclinical Toxicology
- Long-term studies have been conducted at dosages up to 1,000 mg/kg/day in mice and up to 100 mg/kg/day in rats with no indication of carcinogenic effects. Based on dose per unit body surface area, these two doses correspond to approximately 3 and 0.5 times, respectively, the maximum recommended total daily dose of 1,800 mg in a 60 kg patient. Droxidopa was clastogenic in Chinese hamster ovary cells (chromosome aberration assay), but was not mutagenic in bacteria (Ames assay), and was not clastogenic in a mouse micronucleus assay.
- Studies in rats show that droxidopa has no effect on fertility.
- Rats and mice treated for 52 and 80 weeks, respectively, at doses similar to human doses (100 to 300 mg/kg/day for rats and 300 to 1,000 mg/kg/day for mice) had increased incidences of renal and cardiac lesions (rats and mice) and deaths (rats only). No signs of toxicity were observed in monkeys or dogs given droxidopa for 13 weeks at doses 32 times (3,000 mg/kg/day) and 37 times (2,000 mg/kg/day), respectively, the maximum recommended total daily dose of 1,800 mg in a 60 kg patient, when based on body surface area.
# Clinical Studies
- Clinical studies (described below) examined the efficacy of NORTHERA in the short-term (1 to 2 weeks) and over longer-term periods (8 weeks; 3 months). Studies 301 and 306B showed a treatment effect of NORTHERA at Week 1, but none of the studies demonstrated continued efficacy beyond 2 weeks of treatment.
- Study 306B was a multi-center, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic NOH and Parkinson’s disease. Patients entering the study were required to have a decrease of at least 20 mm Hg or 10 mm Hg, respectively, in systolic or diastolic blood pressure, within 3 minutes after standing, as well as symptoms associated with neurogenic orthostatic hypotension. The study had an initial dose titration period that lasted up to 2 weeks in which patients received placebo or 100 to 600 mg of NORTHERA three times daily, followed by an 8-week treatment period.
- Efficacy was measured using the OHSA Item #1 score (“dizziness, lightheadedness, feeling faint, and feeling like you might black out”) at Week 1, in patients who had completed titration and 1 week of maintenance therapy.
- A total of 171 patients were enrolled, and 147 patients were included in the efficacy analysis. The mean age was 72 years, and patients were mostly Caucasian. During the study, 94% of placebo-treated patients and 88% on NORTHERA were taking dopa-decarboxylase inhibitors; 17% of placebo-treated patients and 26% on NORTHERA were taking fludrocortisone. There were more premature discontinuations in the NORTHERA group (28%) than in the placebo group (20%).
- In both groups, the mean baseline dizziness score was 5.1 on an 11-point scale. At Week 1, patients showed a statistically significant mean 0.9-unit decrease in dizziness with NORTHERA versus placebo (P=0.028), but the effect did not persist beyond Week 1. The data at all time points are shown in Figure 1.
- Patients receiving NORTHERA also had a greater increase, compared to placebo, in the Week 1 lowest standing systolic blood pressure within 3 minutes after standing (5.6 mm Hg; P=0.032).
- Study 301 was a multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic neurogenic orthostatic hypotension. The study included an initial open-label dose titration period, a 7-day washout period, and a randomized double-blind 7-day treatment period. To be eligible for enrollment, patients were required to have a decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within 3 minutes after standing. The study was enriched, such that only patients who had been identified as ‘responders’ during the titration period were randomized to NORTHERA or placebo. To be considered a responder, a patient had to demonstrate improvement on the OHSA Item #1 score by at least 1 point, as well as an increase in systolic blood pressure of at least 10 mm Hg post-standing, during the open-label dose titration period. Patients who dropped out during the titration period because of side effects or other reasons were also not included in the double-blind portion of the study.
- Patients had a primary diagnosis of Parkinson’s disease (n=60), pure autonomic failure (n=36), or multiple system atrophy (n=26). The mean age was 60 years, and most were Caucasian. 45% of patients were taking dopa-decarboxylase inhibitors, and 29% were taking fludrocortisone.
- Efficacy was measured using the Orthostatic Hypotension Questionnaire (OHQ), a patient-reported outcome that measures symptoms of NOH and their impact on the patient’s ability to perform daily activities that require standing and walking. The OHQ includes OHSA Item #1 as one of several components. A statistically significant treatment effect was not demonstrated on OHQ (treatment effect of 0.4 unit, P=0.19).
- The mean baseline dizziness score on OHSA Item #1 (“dizziness, lightheadedness, feeling faint, and feeling like you might black out”) was 5.2 units on an 11-point scale. At Week 1 of treatment, patients showed a mean 0.7-unit decrease in dizziness with NORTHERA versus placebo (P=0.06).
- Study 302 (n=101) was a placebo-controlled, 2-week randomized withdrawal study of NORTHERA in patients with symptomatic NOH. Study 303 (n=75) was an extension of Studies 301 and 302, where patients received their titrated dose of NORTHERA for 3 months and then entered a 2-week randomized withdrawal phase. Neither study showed a statistically significant difference between treatment arms on its primary endpoint. Considering these data, the effectiveness of NORTHERA beyond 2 weeks is uncertain, and patients should be evaluated periodically to determine whether NORTHERA is continuing to provide a benefit.
# How Supplied
- NORTHERA capsules are supplied in the following dosage strengths:
## Storage
- NORTHERA capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Elevations in Blood Pressure
- Counsel patients that NORTHERA causes elevations in blood pressure and increases the risk of supine hypertension, which could lead to strokes, heart attacks, and death. Instruct patients to rest and sleep in an upper-body elevated position and monitor blood pressure. Instruct patients how to manage observed blood pressure elevations. To reduce the risk of supine hypertension, in addition to raising the upper body, the late afternoon dose of NORTHERA should be taken at least three hours before bedtime.
- Concomitant Treatments
- Counsel patients about the concomitant use of drugs to treat other conditions that may have an additive effect with NORTHERA .
- Pregnancy
- Counsel patients to consult a physician if they are nursing, pregnant, or planning to become pregnant while taking NORTHERA.
- Food
- Patients should take NORTHERA the same way each time, either with food or without food.
- Missed Dose
- If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose.
# Precautions with Alcohol
- Alcohol-Droxidopa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Northera®
# Look-Alike Drug Names
There is limited information regarding Droxidopa Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Droxidopa
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Black Box Warning
# Overview
Droxidopa is a Sympathomimetic that is FDA approved for the treatment of neurogenic orthostatic hypotension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Headache, dizziness, nausea, hypertension, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- NORTHERA is indicated for the treatment of orthostatic dizziness, lightheadedness, or the “feeling that you are about to black out” in adult patients with symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure (Parkinson's disease (PD), multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy. Effectiveness beyond 2 weeks of treatment has not been established. The continued effectiveness of NORTHERA should be assessed periodically.
### Dosage
- The recommended starting dose of NORTHERA is 100 mg, taken orally three times daily: upon arising in the morning, at midday, and in the late afternoon at least 3 hours prior to bedtime (to reduce the potential for supine hypertension during sleep). Administer NORTHERA consistently, either with food or without food. Take NORTHERA capsule whole. Titrate to symptomatic response, in increments of 100 mg three times daily every 24 to 48 hours up to a maximum dose of 600 mg three times daily (i.e., a maximum total daily dose of 1,800 mg).
- Monitor supine blood pressure prior to initiating NORTHERA and after increasing the dose.
- Patients who miss a dose of NORTHERA should take their next scheduled dose.
### DOSAGE FORMS AND STRENGTHS
- NORTHERA capsules are available in 100 mg, 200 mg, and 300 mg strengths as specified below.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Droxidopa in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Droxidopa in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Droxidopa in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Droxidopa in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Droxidopa in pediatric patients.
# Contraindications
- None
# Warnings
- NORTHERA therapy may cause or exacerbate supine hypertension in patients with NOH. Patients should be advised to elevate the head of the bed when resting or sleeping. Monitor blood pressure, both in the supine position and in the recommended head-elevated sleeping position. Reduce or discontinue NORTHERA if supine hypertension persists. If supine hypertension is not well-managed, NORTHERA may increase the risk of cardiovascular events.
- Post-marketing cases of a symptom complex resembling neuroleptic malignant syndrome (NMS) have been reported with NORTHERA use during post-marketing surveillance in Japan. Observe patients carefully when the dosage of NORTHERA is changed or when concomitant levodopa is reduced abruptly or discontinued, especially if the patient is receiving neuroleptics.
- NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes. The early diagnosis of this condition is important for the appropriate management of these patients.
- NORTHERA may exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure. Careful consideration should be given to this potential risk prior to initiating therapy in patients with these conditions.
- This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions with NORTHERA are included in more detail in the Warnings and Precautions section of the label:
- Supine Hypertension
- Hyperpyrexia and Confusion
- May exacerbate existing ischemic heart disease, arrhythmias, and congestive heart failure
- 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.
- The safety evaluation of NORTHERA is based on two placebo-controlled studies 1 to 2 weeks in duration (Studies 301 and 302), one 8-week placebo-controlled study (Study 306), and two long-term, open-label extension studies (Studies 303 and 304). In the placebo-controlled studies, a total of 485 patients with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or non-diabetic autonomic neuropathy were randomized and treated, 245 with NORTHERA and 240 with placebo.
- The most commonly observed adverse reactions (those occurring at an incidence of greater than 5% in the NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group) in NORTHERA-treated patients during the three placebo-controlled trials were headache, dizziness, nausea, hypertension. The most common adverse reactions leading to discontinuation from NORTHERA were hypertension or increased blood pressure and nausea.
- Note: n=number of patients. Table displays adverse reactions that were reported in greater than 5% of patients in the NORTHERA group and with at least a 3% greater incidence in the NORTHERA group than in the placebo group.
- In the long-term, open-label extension studies, a total of 422 patients, mean age 65 years, were treated with NORTHERA for a mean total exposure of approximately one year. The commonly reported adverse events were falls (24%), urinary tract infections (15%), headache (13%), syncope (13%), and dizziness (10%).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Droxidopa in the drug label.
# Drug Interactions
- Drugs that Increase Blood Pressure
- Administering NORTHERA in combination with other agents that increase blood pressure (e.g., norepinephrine, ephedrine, midodrine, and triptans) would be expected to increase the risk for supine hypertension.
- Parkinson's Medications
- Dopa-decarboxylase inhibitors may require dose adjustments for NORTHERA.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled trials in pregnant women.
- Following consecutive oral administration at doses of 60, 200, and 600 mg/kg/day to pregnant Sprague Dawley rats, increased incidences of lower body weight and occurrence of undulant rib were noted in fetuses, but they were slight and spontaneously reversed after birth. Based on dose per unit body surface area, these three doses correspond to approximately 0.3, 1, and 3 times, respectively, the maximum recommended total daily dose of 1,800 mg in a 60 kg patient. Shortening of the gestation period was observed in rats at 600 mg/kg/day. Low incidences of renal lesions (cysts, indentations, or renal pelvic dilation) were observed on the surface of the kidneys of female rats treated with droxidopa during the period of fetal organogenesis. No other potentially teratogenic effects have been observed in rats or rabbits.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Droxidopa in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Droxidopa during labor and delivery.
### Nursing Mothers
- Choose nursing or NORTHERA. In rats, droxidopa is excreted in breast milk, and when the drug was administered to the nursing dams during the period of lactation, reduced weight gain and reduced survival were observed in the offspring.
### Pediatric Use
- The safety and effectiveness of NORTHERA in pediatric patients have not been established.
### Geriatic Use
- A total of 197 patients with symptomatic NOH aged 75 years or above were included in the NORTHERA clinical program. 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.
### Gender
There is no FDA guidance on the use of Droxidopa with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Droxidopa with respect to specific racial populations.
### Renal Impairment
- NORTHERA and its metabolites are primarily cleared renally. Patients with mild or moderate renal impairment (GFR greater than 30 mL/min) were included in clinical trials and did not have a higher frequency of adverse reactions. Clinical experience with NORTHERA in patients with severe renal function impairment (GFR less than 30 mL/min) is limited.
### Hepatic Impairment
There is no FDA guidance on the use of Droxidopa in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Droxidopa in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Droxidopa in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Monitor supine blood pressure prior to and during treatment and more frequently when increasing doses.
# IV Compatibility
There is limited information regarding IV Compatibility of Droxidopa in the drug label.
# Overdosage
- There was one case of overdose reported during post-marketing surveillance in Japan. The patient ingested 7,700 mg of NORTHERA and experienced a hypertensive crisis that resolved promptly with treatment.
- There is no known antidote for NORTHERA overdosage. In case of an overdose that may result in an excessively high blood pressure, discontinue NORTHERA and treat with appropriate symptomatic and supportive therapy. Counsel patients to remain in a standing or seated position until their blood pressure drops below an acceptable limit.
# Pharmacology
## Mechanism of Action
- The exact mechanism of action of NORTHERA in the treatment of neurogenic orthostatic hypotension is unknown. NORTHERA is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which is extensively distributed throughout the body. NORTHERA is believed to exert its pharmacological effects through norepinephrine and not through the parent molecule or other metabolites. Norepinephrine increases blood pressure by inducing peripheral arterial and venous vasoconstriction. NORTHERA in humans induces small and transient rises in plasma norepinephrine.
## Structure
- NORTHERA capsules contain droxidopa, which is a synthetic amino acid precursor of norepinephrine, for oral administration. Chemically, droxidopa is (–)-threo-3-(3,4-Dihydroxyphenyl)-L-serine. It has the following structural formula:
- Droxidopa is an odorless, tasteless, white to off-white crystals or crystalline powder. It is slightly soluble in water, and practically insoluble in methanol, glacial acetic acid, ethanol, acetone, ether, and chloroform. It is soluble in dilute hydrochloric acid. It has a molecular weight of 213.19 and a molecular formula of C9H11NO5.
- NORTHERA capsules also contain the following inactive ingredients: mannitol, corn starch, and magnesium stearate. The capsule shell is printed with black ink. The black inks contain shellac glaze, ethanol, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide. The capsule shell contains the following inactive ingredients: 100 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black and red iron oxide; 200 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black and yellow iron oxide; 300 mg – gelatin, titanium dioxide, FD&C Blue No. 1, FD&C Yellow No. 5 (tartrazine), and FD&C Red No. 40. NORTHERA capsules differ in size and color by strength
## Pharmacodynamics
- Peak droxidopa plasma concentrations are associated with increases in systolic and diastolic blood pressures. Droxidopa has no clinically significant effect on standing or supine heart rates in patients with autonomic failure.
- Cardiac Electrophysiology
- No prolongation of the QTc interval was observed with NORTHERA at single oral doses up to 2,000 mg, as shown in a dedicated thorough QT study.
## Pharmacokinetics
- Peak plasma concentrations (Cmax) of droxidopa were reached by 1 to 4 hours post-dose (mean of approximately 2 hours) in healthy volunteers. High-fat meals have a moderate impact on droxidopa exposure with Cmax and area under the plasma concentration-time curve (AUC) decreasing by 35% and 20%, respectively. The Cmax was delayed by approximately 2 hours with a high-fat meal.
- Pre-clinical studies suggest that droxidopa can cross the blood brain barrier. Droxidopa exhibits plasma protein binding of 75% at 100 ng/mL and 26% at 10,000 ng/mL. The estimated apparent volume of distribution of droxidopa is about 200 L in humans.
- The metabolism of droxidopa is mediated by catecholamine pathway and not through the cytochrome P450 system. Droxidopa is initially converted to methoxylated dihydroxyphenylserine (3-OM-DOPS), a major metabolite, by catechol-O-methyltransferase (COMT), to norepinephrine by DOPA decarboxylase (DDC), or to protocatechualdehyde by DOPS aldolase. After oral dosing in humans, plasma norepinephrine levels peak within 3 to 4 hours but are generally very low (less than 1 ng/mL) and variable with no consistent relationship with dose. The contribution of the metabolites of droxidopa other than norepinephrine to its pharmacological effects is not well understood.
- The mean elimination half-life of droxidopa is approximately 2.5 hours in humans. The major route of elimination of droxidopa and its metabolites is via the kidneys in both animals and in humans. Studies in animals showed that ~75% of the radiolabeled dose was excreted in urine within 24 hours of oral dosing.
- There are no clinically relevant effects of age, body mass index, or sex on the pharmacokinetics of droxidopa. A population pharmacokinetic analysis suggests that hepatic function, assessed by aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and total bilirubin, did not influence the exposure to droxidopa. The controlled clinical trials included patients with mild to moderate renal impairment. No dose adjustments are required in patients with mild to moderate renal impairment.
- No dedicated drug-drug interaction studies were performed for droxidopa. Patients in the Phase 3 trials with NORTHERA received concomitant levodopa/carbidopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors and other medications used to treat Parkinson’s disease. Carbidopa, a peripheral dopa-decarboxylase inhibitor, could prevent the conversion of NORTHERA to norepinephrine outside of the central nervous system (CNS). Patients taking NORTHERA with L-DOPA/dopa-decarboxylase inhibitor combination drugs had decreased clearance of NORTHERA, an increase in exposure (AUC) to droxidopa of approximately 100%, and an increase in exposure to 3-OM-DOPS of approximately 50%. However, in clinical trials, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events. Dopamine agonists, amantadine derivatives, and MAO-B inhibitors do not appear to affect NORTHERA clearance, and no dose adjustments are required.
## Nonclinical Toxicology
- Long-term studies have been conducted at dosages up to 1,000 mg/kg/day in mice and up to 100 mg/kg/day in rats with no indication of carcinogenic effects. Based on dose per unit body surface area, these two doses correspond to approximately 3 and 0.5 times, respectively, the maximum recommended total daily dose of 1,800 mg in a 60 kg patient. Droxidopa was clastogenic in Chinese hamster ovary cells (chromosome aberration assay), but was not mutagenic in bacteria (Ames assay), and was not clastogenic in a mouse micronucleus assay.
- Studies in rats show that droxidopa has no effect on fertility.
- Rats and mice treated for 52 and 80 weeks, respectively, at doses similar to human doses (100 to 300 mg/kg/day for rats and 300 to 1,000 mg/kg/day for mice) had increased incidences of renal and cardiac lesions (rats and mice) and deaths (rats only). No signs of toxicity were observed in monkeys or dogs given droxidopa for 13 weeks at doses 32 times (3,000 mg/kg/day) and 37 times (2,000 mg/kg/day), respectively, the maximum recommended total daily dose of 1,800 mg in a 60 kg patient, when based on body surface area.
# Clinical Studies
- Clinical studies (described below) examined the efficacy of NORTHERA in the short-term (1 to 2 weeks) and over longer-term periods (8 weeks; 3 months). Studies 301 and 306B showed a treatment effect of NORTHERA at Week 1, but none of the studies demonstrated continued efficacy beyond 2 weeks of treatment.
- Study 306B was a multi-center, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic NOH and Parkinson’s disease. Patients entering the study were required to have a decrease of at least 20 mm Hg or 10 mm Hg, respectively, in systolic or diastolic blood pressure, within 3 minutes after standing, as well as symptoms associated with neurogenic orthostatic hypotension. The study had an initial dose titration period that lasted up to 2 weeks in which patients received placebo or 100 to 600 mg of NORTHERA three times daily, followed by an 8-week treatment period.
- Efficacy was measured using the OHSA Item #1 score (“dizziness, lightheadedness, feeling faint, and feeling like you might black out”) at Week 1, in patients who had completed titration and 1 week of maintenance therapy.
- A total of 171 patients were enrolled, and 147 patients were included in the efficacy analysis. The mean age was 72 years, and patients were mostly Caucasian. During the study, 94% of placebo-treated patients and 88% on NORTHERA were taking dopa-decarboxylase inhibitors; 17% of placebo-treated patients and 26% on NORTHERA were taking fludrocortisone. There were more premature discontinuations in the NORTHERA group (28%) than in the placebo group (20%).
- In both groups, the mean baseline dizziness score was 5.1 on an 11-point scale. At Week 1, patients showed a statistically significant mean 0.9-unit decrease in dizziness with NORTHERA versus placebo (P=0.028), but the effect did not persist beyond Week 1. The data at all time points are shown in Figure 1.
- Patients receiving NORTHERA also had a greater increase, compared to placebo, in the Week 1 lowest standing systolic blood pressure within 3 minutes after standing (5.6 mm Hg; P=0.032).
- Study 301 was a multicenter, multinational, double-blind, randomized, placebo-controlled, parallel-group study in patients with symptomatic neurogenic orthostatic hypotension. The study included an initial open-label dose titration period, a 7-day washout period, and a randomized double-blind 7-day treatment period. To be eligible for enrollment, patients were required to have a decrease in systolic or diastolic blood pressure of at least 20 or 10 mm Hg, respectively, within 3 minutes after standing. The study was enriched, such that only patients who had been identified as ‘responders’ during the titration period were randomized to NORTHERA or placebo. To be considered a responder, a patient had to demonstrate improvement on the OHSA Item #1 score by at least 1 point, as well as an increase in systolic blood pressure of at least 10 mm Hg post-standing, during the open-label dose titration period. Patients who dropped out during the titration period because of side effects or other reasons were also not included in the double-blind portion of the study.
- Patients had a primary diagnosis of Parkinson’s disease (n=60), pure autonomic failure (n=36), or multiple system atrophy (n=26). The mean age was 60 years, and most were Caucasian. 45% of patients were taking dopa-decarboxylase inhibitors, and 29% were taking fludrocortisone.
- Efficacy was measured using the Orthostatic Hypotension Questionnaire (OHQ), a patient-reported outcome that measures symptoms of NOH and their impact on the patient’s ability to perform daily activities that require standing and walking. The OHQ includes OHSA Item #1 as one of several components. A statistically significant treatment effect was not demonstrated on OHQ (treatment effect of 0.4 unit, P=0.19).
- The mean baseline dizziness score on OHSA Item #1 (“dizziness, lightheadedness, feeling faint, and feeling like you might black out”) was 5.2 units on an 11-point scale. At Week 1 of treatment, patients showed a mean 0.7-unit decrease in dizziness with NORTHERA versus placebo (P=0.06).
- Study 302 (n=101) was a placebo-controlled, 2-week randomized withdrawal study of NORTHERA in patients with symptomatic NOH. Study 303 (n=75) was an extension of Studies 301 and 302, where patients received their titrated dose of NORTHERA for 3 months and then entered a 2-week randomized withdrawal phase. Neither study showed a statistically significant difference between treatment arms on its primary endpoint. Considering these data, the effectiveness of NORTHERA beyond 2 weeks is uncertain, and patients should be evaluated periodically to determine whether NORTHERA is continuing to provide a benefit.
# How Supplied
- NORTHERA capsules are supplied in the following dosage strengths:
## Storage
- NORTHERA capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
### Ingredients and Appearance
# Patient Counseling Information
- Elevations in Blood Pressure
- Counsel patients that NORTHERA causes elevations in blood pressure and increases the risk of supine hypertension, which could lead to strokes, heart attacks, and death. Instruct patients to rest and sleep in an upper-body elevated position and monitor blood pressure. Instruct patients how to manage observed blood pressure elevations. To reduce the risk of supine hypertension, in addition to raising the upper body, the late afternoon dose of NORTHERA should be taken at least three hours before bedtime.
- Concomitant Treatments
- Counsel patients about the concomitant use of drugs to treat other conditions that may have an additive effect with NORTHERA [see Drug Interactions (7)].
- Pregnancy
- Counsel patients to consult a physician if they are nursing, pregnant, or planning to become pregnant while taking NORTHERA.
- Food
- Patients should take NORTHERA the same way each time, either with food or without food.
- Missed Dose
- If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose.
# Precautions with Alcohol
- Alcohol-Droxidopa interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Northera®[1]
# Look-Alike Drug Names
There is limited information regarding Droxidopa Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Droxidopa | |
5090242af4fa1ebc809ce5c0a406f81482be7bdd | wikidoc | Drug test | Drug test
# Overview
A drug test is commonly a technical examination of urine samples to determine the presence or absence of specified drugs or their metabolized traces.
# General information
Drug tests can be divided into two general groups. The first group is the kind most people are familiar with. This type of testing involves the donor giving a sample of some bodily fluid or hair to an employer, doctor, law enforcement official, or a dedicated testing center. This is normally a sample of urine, blood, hair, or saliva/oral fluid. After collection from the donor, the sample with a credibility oblem of "beating the tests" (otherwise known as sample adulteration or substitution) can be virtually eliminated. On-site screens provide qualitative results, and when supplemented with laboratory-based confirmation tests, can be defended in a court of law.
This article will focus primarily on the first type of test, but will refer to the latter when appropriate.
# The NIDA 5
Drug testing in the United States began in the late 1980s with the testing of certain federal employees and specified DOT regulated occupations. Drug testing guidelines and processes, in these areas exclusively, are established and regulated (by the Substance Abuse and Mental Health Services Administration or SAMHSA, formerly under the direction of the National Institute on Drug Abuse or NIDA) require that companies who use professional drivers, specified safety sensitive transportation and/or oil and gas related occupations, and certain federal employers, test them for the presence of certain drugs. These test classes were established decades ago, and include five specific drug groups. They do not account for current drug usage patterns. For example, the tests do not include semi-synthetic opioids, such as oxycodone, oxymorphone, hydrocodone, hydromorphone, etc., compounds that are highly abused in Africa
- Cannabinoids (marijuana, hashish - TEST SPECIFICALLY SCREENS FOR METABOLITE THCCOOH)
- Cocaine (cocaine, benzoylecognine, cocaethylene)- TEST SPECIFICALLY SCREENS FOR COCAINE METABOLITE - BE
- Amphetamines (amphetamine, methamphetamine)
- Opiates (heroin, opium, codeine, morphine, 6-AM)
- Phencyclidine (PCP)
While SAMHSA/NIDA guidelines only allow labs to report quantitative results for the "NIDA-5" on their official NIDA tests, many drug testing labs and on-site tests also offer a wider or "more appropriate" set of drug screens which may be more reflective of current drug abuse patterns. As noted above, these tests include synthetic pain killers such as Oxycodone, Oxymorphone, Hydrocodone, Hydromorphone, benzodiazepines (Valium, Xanax, Klonopin, Restoril) and barbiturates in other drug panels (a "panel" is a predetermined list of tests to run). The confirmation test (usually GCMS, or LC/MS/MS) can tell the difference between chemically similar drugs such as methamphetamine and ecstasy, and in the absence of detectable amounts of methamphetamine in the sample, the lab will either report the sample as negative or report it as positive for MDMA. What the lab reports to the client depends upon whether MDMA was included in the panel as something to be tested for.
Gamma-hydroxy-butyrate (GHB) was not routinely tested for in the early 1990s, but due to increasing use, some labs have added it as an optional test. GHB is rare in pre-employment screening, but is commonly checked for in suspected cases of drug overdose, date rape, and post-mortem toxicology tests. Ketamine (Special K) may or may not be tested for, depending upon the preferences of the entity paying for the test, though testing for it is uncommon. In general, the greater the number of drugs tested for, the higher the price of the test, so many employers stick to the NIDA 5 for financial reasons.
Other drugs, such as meperidine (Demerol), fentanyl, propoxyphene, and methadone are not commonly tested for in most pre-employment situations. These drugs are more likely to be included in tests for certain demographic groups (such as healthcare workers, drug rehab patients, etc.)
Hallucinogens other than cannabis and PCP, such as mushrooms (psilocybin), LSD, and peyote (mescaline) are rarely tested for.
# Detection periods
The following chart from LabCorp gives approximate detection periods for each substance by test type.
The ranges depend on amount and frequency of use, metabolic rate, body mass, age, overall health, and urine pH. For ease of use, the detection times of metabolites have been incorporated into each parent drug. For example, heroin and cocaine can only be detected for a few hours after use, but their metabolites can be detected for several days in urine. In this type of situation, we will report the (longer) detection times of the metabolites.
- NOTE 1: Oral fluid or saliva testing results for the most part mimic that of blood. The only exception is THC. Oral fluid will likely detect THC from ingestion up to a maximum period of 18-24 hours
- NOTE 2: Urine can not detect current drug use. It takes approximately 6–8 hrs. or more post-consumption for drug to be metabolized and excreted in urine. Similarly, hair requires two weeks, and sweat, seven days.
# Common types of drug tests
## Urine drug screen
Also known as urinalysis, this procedure requires that one provide a sample of urine. Either a test card is used on site for immediate results (see "General" section), or the sample is sent away to a lab to undergo gas chromatography/mass spectrometry (also known as GCMS), high performance liquid chromatography or immunoassay analysis. The majority of tests administered in pre-hire and even most probate scenarios are of the immediate, and less accurate "at home" variety. Most "dip stick" type tests have higher thresholds for a postive than do the GCMS tests. If a positive result (drug presence indicated) is found, the sample is usually sent to a lab for GCMS confirmation. This is largely due to the costliness of GCMS labaratory testing and time it takes to process and receive results.
The efficacy of urine testing is debatable. It is widely reported that sample substitution and adulteration occur frequently, and both are effective methods of avoiding would be positive tests. There are numerous online retailers of synthetic urine and even prosthetic penises for men to use to excrete this substance under direct supervision. Heat pads are used to keep the substitute sample at a temperature comparable to that of the human body. There are also a number of adulterant "masking" agents that are sold, though they are often nothing more than a simple diuretic and are rarely more effective than caffeine. Some people drink copious amounts of water to successfully dilute the concentration of drug metabolites in their urine below detectable thresholds. Often times this results in clear samples that may be rejected on the grounds of being too dilute, although a complex B vitamin will make urine yellow despite this practice of waterloading. Specific Gravity testing can be done to identify whether or not the sample is of dilute nature, though this is a costly laboratory procedure that is used infrequently on otherwise inconspicuous samples. The substance Niacin is also frequently used for its reported "flushing" effect, though this is also of disputable adeptness. Some types of urinalysis can detect the use of these "detox" product, though they are rarely used unless some facet of the sample is suspicious. Also, the wide availability of at home drug screens allows one to take their own test before they receive one, thus knowing the results ahead of time- giving the user further opportunity to dilute the sample or to find a substitute.
## Hair drug testing
Hair testing is quite accurate and can go back normally 3 months (6 months or longer possible with specialty tests), showing any drugs of abuse used in the detection window. As hair grows out, any drugs used are encased in the hair shaft, so the longer the hair, the longer back in the individual's drug history the lab can detect. Accredited hair drug testing labs, however, only use hair within about 2.5–4 cm of the scalp, and discard the rest. With head hair each 0.5 inch (1.27 cm) corresponds to about 30 days. This limits the detection history to about 90 days, depending upon the rate at which the individual's hair grows. Some people attempt to circumvent this through shaving their heads. In the absence of the required amount of hair on the scalp, body hair can be used as an acceptable substitute.
Additionally, for pre-employment hair testing, the inability to obtain a sample may be grounds for not hiring the individual. Hair Testing labs are regulated by CLIA or SAMHSA (not FDA). There is a growing trend in major companies and law enforcement agencies to utilize hair analysis on account of its efficiency and reputation as the gold standard when considering test accuracy. This technology makes use of radioimmunoassay technology with subsequent confirmation by mass spectrometry.
In recent years hair testing has been the subject of a number of law suits. Studies have shown that different ethnic groups have different hair structure leading to false-positives..
## Hair alcohol testing
As the hair grows, it absorbs special markers called fatty acid ethyl esters (FAEE’s) and ethyl glucuronide (EtG) into its structure, which remain in the hair indefinitely. These patented markers are only produced when there is alcohol in the bloodstream, and the more markers there are, the more alcohol you drink.
What makes this analysis revolutionary is that it gives a history going back month-by-month or even years if required. No other method can do this. Afterwards, an alcoholic’s treatment can be monitored periodically as their hair grows.
Ethyl glucuronide or EtG is a metabolite only produced when alcohol is in the bloodstream. It is identified as a marker in alcohol hair testing, through a patented analytical process that provides forensic evidence of the pattern of alcohol abuse - or absence of it. The more alcohol a person consumes the greater amount of EtG markers are present in the hair. EtG alcohol testing is unique compared to other alcohol tests in that it allows you to segment testing results into months instead of only days.
The process and test was commercialised for the first time by Trimega Laboratories Limited of London.
## Saliva drug screen / Oral fluid-based drug screen
Saliva / oral fluid-based drug tests can generally detect use during the previous few days. Saliva or oral fluid based drug tests are becoming more prevalent because of their convenience and the fact that they can not be adulterated. Furthermore, on-site oral based tests in particular enable the implementation of random testing programs, proven to be the most effective type of drug screening. Oral fluid based tests are as accurate as urine and can be obtained from quality suppliers in the United States.
Testing is usually performed by employers, for either pre-employment, random, post-accident, reasonable suspicion, or return-to-duty testing. Oral fluid based testing most closely mimics results found with blood and is preferable for detecting on-the-job drug use or in post-accident applications in this case because the degree of intoxication can be approximated based on the amount of substance
Detection in saliva tests begins immediately upon use:
- marijuana and Hashish (THC): From time of ingestion, up to 24 hours.
- Cocaine (including crack): From time of ingestion up to 2 to 3 days.
- Opiates: From time of ingestion up to 2 to 3 days
- Methamphetamine and Ecstasy (MDMA, "Crank," "Ice"): From time of ingestion up to 2 to 3 days.
- Benzodiazepines: From time of ingestion up to 2 to 3 days.
## Sweat drug screen
Sweat tests are patches attached to the skin to collect sweat over a long period of time (10–14 days). These are almost exclusively used by child protective services, parole departments, and other government institutions concerned with drug use over long periods, when urine testing is not practical. The patches have security features that keep them from being covertly removed and then reapplied without the knowledge of the testing agency. At the end of the test period, the patch is removed by a social worker or parole officer and sent to a lab for analysis. If the person has used any drugs during the period that the patch was in place, they will test positive for that drug. This type of testing has fallen out of favor with government agencies due to documented problems with certain drugs.
# Drug testing methodologies
The different types of drug tests are tested in very similar ways. Before testing the sample, the tamper-evident seal is checked for integrity. If it appears to have been tampered with or was damaged in transit, the lab rejects the sample and does not test it.
One of the first steps for all drug tests is to make the sample testable. Urine and oral fluid can be used "as is" for some tests, but other tests require the drugs to be extracted from urine beforehand. Strands of hair, patches, and blood must be prepared before testing. Hair is washed in order to eliminate second-hand sources of drugs on the surface of the hair, then the keratin is broken down using enzymes. Blood plasma may need to be separated by centrifuge from blood cells prior to testing. Sweat patches are opened up and the sweat collection component is soaked in a solvent to dissolve any drugs present.
Laboratory-based drug testing is done in a two-tiered fashion using two different types of detection methods. The first is known as the screening test, and this is applied to all samples that go through the lab. The second, known as the confirmation test, is only applied to samples that test positive during the screening test. Screening tests are usually done by immunoassay (EMIT, ELISA, and RIA are the most common). A "dipstick" drug testing method which could at some future time provide screening test capabilities to field investigators has been developed at the University of Illinois. Screening tests are typically less sensitive and more prone to false positives and false negatives than the confirmation test.
Once a suspected positive sample is detected during screening, the sample is flagged and tested using the confirmation test. Samples that are negative on the screening test are discarded and reported as negative. The confirmation test in most labs (and all SAMHSA certified labs) is performed using mass spectrometry, and is extremely precise but also fairly expensive to run. False positive samples from the screening test will be negative on the confirmation test. Samples testing positive during both screening and confirmation tests are reported as positive to the entity that ordered the test. Most labs save positive samples for some period of months or years in the event of a disputed result or lawsuit.
D.O.T. mandated tests require a Medical Review Officer, an M.D. or a D.O., to contact the donor to determine if an alternative medical explanation justifies the presence of the drug identified by the lab. Doctors need not be licensed in the state where the donor resides nor where the test was administered. They must be a licensed physician in one state within the U.S. to participate as an MRO. This substantially limits the degree of influence from out of state medical review boards. In addition, many courts do not allow a private cause of action against MROs, labs, collectors, etc. If an MRO and a D.O.T. participating employer conspire to falsify drug test results, the innocent donor has little if any recourse. The perception that American citizens are "innocent until proven guilty" is just that. Specific mandated drug testing regulations which entitle access to drug testing chain of custody and procedural evidence from the commercial sector may be discounted or ignored by the ODAPC and government agencies. In other words, the government may chose not to enforce their own regulations. To address negligence and abuse, agencies may utilize a PIE (Public Interest Exclusion) to restrict doctors, labs, hospitals and others from participating in D.O.T. testing. Since the implementation of this kind of testing over a decade ago with tens of millions of tests performed, a PIE not has been issued.
# Types of testing
## Pre-employment drug testing
This is by far the most common type of drug test used by businesses. It has the advantage of being inexpensive, since only one test per employee needs to be paid for by the company. However, since most pre-employment drug testing is urine-based and subject to sample adulteration or substitution, the effectiveness of this approach has been questioned by federal legislators. Some organizations have a witness in the room at the time of the testing, but the privacy implications of this, as well as the potential for shy bladder syndrome has limited the use of witnesses outside jails and drug treatment programs. Companies and testing centers that do not use witnesses normally disconnect sources of water from the testing room to discourage dilution, and if there is water in the toilet, it is dyed blue. Other countermeasures, such as making the donor change into a gown, may also be used.
## Random drug testing
This is both the most effective drug deterrence method and the most controversial type of drug testing. Random drug testing is mandated by the U.S. Department of Transportation, which means that many employers in the USA have no choice but to implement random drug testing programs. Even when random drug testing is not legally required, many organizations use small scale random drug testing as an effective deterrence. Random drug testing is not a violation of the Fourth Amendment to the United States Constitution which protects the right of citizens "to be secure in their persons, houses, papers, and effects, against unreasonable searches and seizures." The United States Supreme Court ruled in Skinner v. Railway Labor Assn., 489 U.S. 602 (1989) that random drug testing is permissible for employees in safety sensitive positions. Justice Kennedy, speaking for the majority, wrote:
he Government interest in testing without a showing of individualized suspicion is compelling. Employees subject to the tests discharge duties fraught with such risks of injury to others that even a momentary lapse of attention can have disastrous consequences based on the interest of the general public While no procedure can identify all impaired employees with ease and perfect accuracy, the FRA regulations supply an effective means of deterring employees engaged in safety-sensitive tasks from using controlled substances or alcohol in the first place.
The dissenting opinion by Justices Marshall and Brennan illustrates the other side of the controversy:
The issue in this case is not whether declaring a war on illegal drugs is good public policy. The importance of ridding our society of such drugs is, by now, apparent to all. Rather, the issue here is whether the Government's deployment in that war of a particularly Draconian weapon - the compulsory collection and chemical testing of railroad workers' blood and urine - comports with the Fourth Amendment. Precisely because the need for action against the drug scourge is manifest, the need for vigilance against unconstitutional excess is great. History teaches that grave threats to liberty often come in times of urgency, when constitutional rights seem too extravagant to endure. The World War II relocation-camp cases, Hirabayashi v. United States, 320 U.S. 81 (1943); Korematsu v. United States, 323 U.S. 214 (1944), and the Red scare and McCarthy-era internal subversion cases, Schenck v. United States, 249 U.S. 47 (1919); Dennis v. United States, 341 U.S. 494 (1951), are only the most extreme reminders that when we allow fundamental freedoms to be sacrificed in the name of real or perceived exigency, we invariably come to regret it.
In the United States today, random drug testing is used by a growing number of corporations, drug rehab centers, prisons, the military, police and fire departments, government agencies, and more recently, schools. This method may also be used on teens by their parents, or mandated to be performed on teens at school. The point of a random drug test is deterrence, as the threat of detection is much higher versus other testing methods. Various questionable methods are utilized to determine who gets tested, ranging from drawing names out of a hat, (Government mandated testing requires a scientifically provable method of selection.) to using more defensible methods such as robust random number generators. However, many random drug testing selection systems are legally indefensible because there is nothing to prevent users from targeting individuals by regenerating names with the random generator until the desired result is produced. (Computer generated random selection should have traceable data to validate the legitimacy of the selection.) Most systems have no tamper-proof audit trail (database records are easy to change, so employers or their testing agents must not have access to the audit trail records for the random selection to be defensible). Finally, hiring third parties to randomly select drug testing subjects is not legally defensible because there is no way of proving that there was no collusion to select a specific individual. (I don't believe this is true. A scientifically random selection process is legally defensible.) You are correct that many loopholes plague this system and many people have lost their jobs, reputations, college savings and their homes without as much as an apology from the drug testing giants and the government.
Many apparent conflicts-of-interest exist among service providers and government authorities. In fact, forbidden relationships thrive. The firewalls assuring separation and impartiality don't work. By cultivating relationships forbidden by the regulations the credibility of the entire government sponsored testing program is jeopardized.
While a goal of random drug testing may be to discourage illegal drug use among employees, etc. a goal of so-called "random" testing may be to destroy the career of the tested person, or to prevent the reunification of a family, too. The goals of drug testing vary depending on the motives of those conducting the tests. D.O.T. mandated testing, as codified in CFR 49 parts 40 and 382, define and establish thousands of specific, highly detailed and requisite protocol which must be followed. However, without an effective governing body to monitor, to investigate allegations of non-compliance, and to enforce these regulations, the stated goals of the government are meaningless.
Unfortunately, courts throughout the United States are divided on the issue of the right of individuals to bring lawsuits regarding violations of these regulations. In other words, if a laboratory failed to maintain quality controls and your specimen was contaminated at the lab, (this happens) resulting in your termination, many courts deny you and me a legal remedy. Some courts hold that the government created and published strict criteria for laboratories and all other service providers to follow to prevent this kind of failure, thereby giving us substantial "built-in" protection.
Through the denial of a private cause of action in these kinds of cases, someone could sabotage your test intentionally with complete impunity. In Drake, after 10 years of legal battles, mostly pro-se, a New York appeals court concluded recently that the language of the 1991 Omnibus Employee Testing Act does not bar common law torts. This is a significant break through for the tested, at-will employee. It is just a beginning, but it is an important legal step in the direction of protecting innocent workers.
Eisenhower warned America of the dangers of a "military industrial complex." The same dynamics have created a collaboration between our government and the commercial drug testing industry.
The goal of random testing is to discourage drug use among employees, inmates, or students by not telling anyone who or when they are to be tested in advance. However, critics claim that random testing introduces a presumption of guilt, and is a violation of privacy if the user is not actually intoxicated during working hours. In addition, random testing is more likely to catch cannabis users, since THC metabolites are fat soluble and have a longer duration in the body than those of many other drugs. Many people believe that this indirectly encourages the use of much more dangerous and harmful drugs that are excreted from the body faster.
## Post-incident drug testing
This is not a very commonly administered test compared to the other two, but the financial ramifications of not testing employees after an accident (or other incident) on the job makes this test worthwhile for most businesses. The point of this test isn't necessarily to cause the employee to lose his or her job, but rather to protect the company from liability in the event that the individual is under the influence at the time of the accident. If drugs or alcohol are detected in any significant quantity, the argument can be made in court that the individual was intoxicated on the job, and for that reason, the company should not be held liable for injuries sustained by the employee. This argument, however, can only reasonably be made if blood or oral fluid / saliva testing is used. Urine, hair, or sweat based testing can only detect past drug use. Depending upon the facts of each case, this may help a company avoid litigation completely or may do nothing to help their case. DUI testing would also fall into this category. Another time this type of test may be used is if an employee shows up for work intoxicated, has alcohol on his or her breath, or appears to be impaired in some other way. The goal of these tests is to protect the entity from litigation, so they are only given on an as needed basis.
It should be noted that in most areas, blood testing is the only legally defensible means for detecting drug use after an incident, although saliva testing is gaining acceptance. The sample should follow chain of custody requirements and should always be sent to a lab after collection. Positive on-site tests that may affect an employee's position or situation should always be followed up with a laboratory test before any action is taken against the employee. Laboratory tests (urine or blood) are the only legally recognized tests in most states as well as in most non-U.S. countries.
# Pros and Cons of Drug Testing Methods
There is no perfect drug testing method. Each method has some advantages and disadvantages. What makes a drug testing method good or not so good is more related to the needs of the person.
## Urine Drug Testing
Pros: Urine drug test kits are available as on-site tests, or laboratory analysis. Referred to as "the gold standard", urinalysis is the most common test type and used by federally mandated drug testing programs.
Cons: The main disadvantages of urine-based drug test kits is are (1.) the ease at which they can be "cheated" via sample adulteration or substitution, unless specimen collection is directly observed, (2.) inability to detect current / on-the-job drug abuse, (3.) the need for bathroom facilities, and (4.) with respect to SAMHSA-5, or NIDA-5, the inability to test for drugs used in current society.
## Saliva Drug Testing
Pros: Saliva (Oral) drug test kits are very donor friendly, non-invasive and easy to collect the specimen. There is no need for a bathroom to administer the tests. Saliva drug testing is great at detecting very recent drug use. Also these drug tests are harder to adulterate than the urine drug tests since the sample can be obtained under direct supervision. Results can be read in minutes and there is no need for a lab. Depending on the test, up to 8 (5 or 6 at a time) different drugs could be detected. This method is the best method for determining current use and impairment.
Cons: The main disadvantage of saliva based drug testing is lack of awareness in the market, as well as misinformation spread largely by laboratories and TPAs (third party administrators), who stand to lose money as saliva testing continues to replace traditional urine-based techniques.
## Spray (Sweat) Drug Testing
Pros: Spray (Sweat) drug test kits are non-invasive and donor friendly. It is very easy to collect the specimen and no bathroom is needed for taking the specimen. The detection window is long and usually can detect drug use up to a couple of weeks. These drug tests are relatively tamper proof since they are hard to manipulate. There is no need for a lab and you can get results in minutes.
Cons: The main disadvantage of spray or sweat based drug testing is the fact that they are open to contamination. Also large variations of sweat production rates of possible donors make some results inconclusive. There is not much variety in these drug tests since they are not as popular as urine or saliva drug testing kits. Their prices tend to be a little higher per test conducted. One main disadvantage of this testing method is the limited number of drugs that can be detected.
## Hair Drug Testing
Pros: Hair Alcohol Testing can provide a much longer window of detection.
Cons: Costs more than urine testing. Cannot be used if a donor has no hair.
# Legality and ethics of mandatory drugs testing
## United Kingdom
The legal position of drug tests on the UK is not clear. A recent study by the independent Inquiry into Drug Testing at Work found that attempts by employers to force could be challenged as a violation of privacy under the Human Rights Act 1998 and Article 8 of the European Convention of Human Rights. However, this may not extend to industries where drug testing is a matter of safety rather than productivity. | Drug test
# Overview
A drug test is commonly a technical examination of urine samples to determine the presence or absence of specified drugs or their metabolized traces.
# General information
Drug tests can be divided into two general groups. The first group is the kind most people are familiar with. This type of testing involves the donor giving a sample of some bodily fluid or hair to an employer, doctor, law enforcement official, or a dedicated testing center. This is normally a sample of urine, blood, hair, or saliva/oral fluid. After collection from the donor, the sample with a credibility oblem of "beating the tests" (otherwise known as sample adulteration or substitution) can be virtually eliminated. On-site screens provide qualitative results, and when supplemented with laboratory-based confirmation tests, can be defended in a court of law.
This article will focus primarily on the first type of test, but will refer to the latter when appropriate.
# The NIDA 5
Drug testing in the United States began in the late 1980s with the testing of certain federal employees and specified DOT regulated occupations. Drug testing guidelines and processes, in these areas exclusively, are established and regulated (by the Substance Abuse and Mental Health Services Administration or SAMHSA, formerly under the direction of the National Institute on Drug Abuse or NIDA) require that companies who use professional drivers, specified safety sensitive transportation and/or oil and gas related occupations, and certain federal employers, test them for the presence of certain drugs. These test classes were established decades ago, and include five specific drug groups. They do not account for current drug usage patterns. For example, the tests do not include semi-synthetic opioids, such as oxycodone, oxymorphone, hydrocodone, hydromorphone, etc., compounds that are highly abused in Africa
- Cannabinoids (marijuana, hashish - TEST SPECIFICALLY SCREENS FOR METABOLITE THCCOOH)
- Cocaine (cocaine, benzoylecognine, cocaethylene)- TEST SPECIFICALLY SCREENS FOR COCAINE METABOLITE - BE
- Amphetamines (amphetamine, methamphetamine)
- Opiates (heroin, opium, codeine, morphine, 6-AM)
- Phencyclidine (PCP)
While SAMHSA/NIDA guidelines only allow labs to report quantitative results for the "NIDA-5" on their official NIDA tests, many drug testing labs and on-site tests also offer a wider or "more appropriate" set of drug screens which may be more reflective of current drug abuse patterns. As noted above, these tests include synthetic pain killers such as Oxycodone, Oxymorphone, Hydrocodone, Hydromorphone, benzodiazepines (Valium, Xanax, Klonopin, Restoril) and barbiturates in other drug panels (a "panel" is a predetermined list of tests to run). The confirmation test (usually GCMS, or LC/MS/MS) can tell the difference between chemically similar drugs such as methamphetamine and ecstasy, and in the absence of detectable amounts of methamphetamine in the sample, the lab will either report the sample as negative or report it as positive for MDMA. What the lab reports to the client depends upon whether MDMA was included in the panel as something to be tested for.
Gamma-hydroxy-butyrate (GHB) was not routinely tested for in the early 1990s, but due to increasing use, some labs have added it as an optional test. GHB is rare in pre-employment screening, but is commonly checked for in suspected cases of drug overdose, date rape, and post-mortem toxicology tests. Ketamine (Special K) may or may not be tested for, depending upon the preferences of the entity paying for the test, though testing for it is uncommon. In general, the greater the number of drugs tested for, the higher the price of the test, so many employers stick to the NIDA 5 for financial reasons.
Other drugs, such as meperidine (Demerol), fentanyl, propoxyphene, and methadone are not commonly tested for in most pre-employment situations. These drugs are more likely to be included in tests for certain demographic groups (such as healthcare workers, drug rehab patients, etc.)
Hallucinogens other than cannabis and PCP, such as mushrooms (psilocybin), LSD, and peyote (mescaline) are rarely tested for.
# Detection periods
The following chart from LabCorp gives approximate detection periods for each substance by test type.[1]
The ranges depend on amount and frequency of use, metabolic rate, body mass, age, overall health, and urine pH. For ease of use, the detection times of metabolites have been incorporated into each parent drug. For example, heroin and cocaine can only be detected for a few hours after use, but their metabolites can be detected for several days in urine. In this type of situation, we will report the (longer) detection times of the metabolites.
- NOTE 1: Oral fluid or saliva testing results for the most part mimic that of blood. The only exception is THC. Oral fluid will likely detect THC from ingestion up to a maximum period of 18-24 hours
- NOTE 2: Urine can not detect current drug use. It takes approximately 6–8 hrs. or more post-consumption for drug to be metabolized and excreted in urine. Similarly, hair requires two weeks, and sweat, seven days.
# Common types of drug tests
## Urine drug screen
Also known as urinalysis, this procedure requires that one provide a sample of urine. Either a test card is used on site for immediate results (see "General" section), or the sample is sent away to a lab to undergo gas chromatography/mass spectrometry (also known as GCMS), high performance liquid chromatography or immunoassay analysis. The majority of tests administered in pre-hire and even most probate scenarios are of the immediate, and less accurate "at home" variety. Most "dip stick" type tests have higher thresholds for a postive than do the GCMS tests. If a positive result (drug presence indicated) is found, the sample is usually sent to a lab for GCMS confirmation. This is largely due to the costliness of GCMS labaratory testing and time it takes to process and receive results.
The efficacy of urine testing is debatable. It is widely reported that sample substitution and adulteration occur frequently, and both are effective methods of avoiding would be positive tests. There are numerous online retailers of synthetic urine and even prosthetic penises for men to use to excrete this substance under direct supervision. Heat pads are used to keep the substitute sample at a temperature comparable to that of the human body. There are also a number of adulterant "masking" agents that are sold, though they are often nothing more than a simple diuretic and are rarely more effective than caffeine. Some people drink copious amounts of water to successfully dilute the concentration of drug metabolites in their urine below detectable thresholds. Often times this results in clear samples that may be rejected on the grounds of being too dilute, although a complex B vitamin will make urine yellow despite this practice of waterloading. Specific Gravity testing can be done to identify whether or not the sample is of dilute nature, though this is a costly laboratory procedure that is used infrequently on otherwise inconspicuous samples. The substance Niacin is also frequently used for its reported "flushing" effect, though this is also of disputable adeptness. Some types of urinalysis can detect the use of these "detox" product, though they are rarely used unless some facet of the sample is suspicious. Also, the wide availability of at home drug screens allows one to take their own test before they receive one, thus knowing the results ahead of time- giving the user further opportunity to dilute the sample or to find a substitute.
## Hair drug testing
Hair testing is quite accurate and can go back normally 3 months (6 months or longer possible with specialty tests), showing any drugs of abuse used in the detection window. As hair grows out, any drugs used are encased in the hair shaft, so the longer the hair, the longer back in the individual's drug history the lab can detect. Accredited hair drug testing labs, however, only use hair within about 2.5–4 cm of the scalp, and discard the rest. With head hair each 0.5 inch (1.27 cm) corresponds to about 30 days. This limits the detection history to about 90 days, depending upon the rate at which the individual's hair grows. Some people attempt to circumvent this through shaving their heads. In the absence of the required amount of hair on the scalp, body hair can be used as an acceptable substitute.
Additionally, for pre-employment hair testing, the inability to obtain a sample may be grounds for not hiring the individual. Hair Testing labs are regulated by CLIA or SAMHSA (not FDA). There is a growing trend in major companies and law enforcement agencies to utilize hair analysis on account of its efficiency and reputation as the gold standard when considering test accuracy. This technology makes use of radioimmunoassay technology with subsequent confirmation by mass spectrometry.
In recent years hair testing has been the subject of a number of law suits. Studies have shown that different ethnic groups have different hair structure leading to false-positives..
## Hair alcohol testing
As the hair grows, it absorbs special markers called fatty acid ethyl esters (FAEE’s) and ethyl glucuronide (EtG) into its structure, which remain in the hair indefinitely. These patented markers are only produced when there is alcohol in the bloodstream, and the more markers there are, the more alcohol you drink.
What makes this analysis revolutionary is that it gives a history going back month-by-month or even years if required. No other method can do this. Afterwards, an alcoholic’s treatment can be monitored periodically as their hair grows.
Ethyl glucuronide or EtG is a metabolite only produced when alcohol is in the bloodstream. It is identified as a marker in alcohol hair testing, through a patented analytical process that provides forensic evidence of the pattern of alcohol abuse - or absence of it. The more alcohol a person consumes the greater amount of EtG markers are present in the hair. EtG alcohol testing is unique compared to other alcohol tests in that it allows you to segment testing results into months instead of only days.
The process and test was commercialised for the first time by Trimega Laboratories Limited of London.
## Saliva drug screen / Oral fluid-based drug screen
Saliva / oral fluid-based drug tests can generally detect use during the previous few days. Saliva or oral fluid based drug tests are becoming more prevalent because of their convenience and the fact that they can not be adulterated. Furthermore, on-site oral based tests in particular enable the implementation of random testing programs, proven to be the most effective type of drug screening. Oral fluid based tests are as accurate as urine and can be obtained from quality suppliers in the United States.
Testing is usually performed by employers, for either pre-employment, random, post-accident, reasonable suspicion, or return-to-duty testing. Oral fluid based testing most closely mimics results found with blood and is preferable for detecting on-the-job drug use or in post-accident applications in this case because the degree of intoxication can be approximated based on the amount of substance
Detection in saliva tests begins immediately upon use:
- marijuana and Hashish (THC): From time of ingestion, up to 24 hours.
- Cocaine (including crack): From time of ingestion up to 2 to 3 days.
- Opiates: From time of ingestion up to 2 to 3 days
- Methamphetamine and Ecstasy (MDMA, "Crank," "Ice"): From time of ingestion up to 2 to 3 days.
- Benzodiazepines: From time of ingestion up to 2 to 3 days.
## Sweat drug screen
Sweat tests are patches attached to the skin to collect sweat over a long period of time (10–14 days). These are almost exclusively used by child protective services, parole departments, and other government institutions concerned with drug use over long periods, when urine testing is not practical. The patches have security features that keep them from being covertly removed and then reapplied without the knowledge of the testing agency. At the end of the test period, the patch is removed by a social worker or parole officer and sent to a lab for analysis. If the person has used any drugs during the period that the patch was in place, they will test positive for that drug. This type of testing has fallen out of favor with government agencies due to documented problems with certain drugs[2].
# Drug testing methodologies
The different types of drug tests are tested in very similar ways. Before testing the sample, the tamper-evident seal is checked for integrity. If it appears to have been tampered with or was damaged in transit, the lab rejects the sample and does not test it.
One of the first steps for all drug tests is to make the sample testable. Urine and oral fluid can be used "as is" for some tests, but other tests require the drugs to be extracted from urine beforehand. Strands of hair, patches, and blood must be prepared before testing. Hair is washed in order to eliminate second-hand sources of drugs on the surface of the hair, then the keratin is broken down using enzymes. Blood plasma may need to be separated by centrifuge from blood cells prior to testing. Sweat patches are opened up and the sweat collection component is soaked in a solvent to dissolve any drugs present.
Laboratory-based drug testing is done in a two-tiered fashion using two different types of detection methods. The first is known as the screening test, and this is applied to all samples that go through the lab. The second, known as the confirmation test, is only applied to samples that test positive during the screening test. Screening tests are usually done by immunoassay (EMIT, ELISA, and RIA are the most common). A "dipstick" drug testing method which could at some future time provide screening test capabilities to field investigators has been developed at the University of Illinois.[3] Screening tests are typically less sensitive and more prone to false positives and false negatives than the confirmation test.
Once a suspected positive sample is detected during screening, the sample is flagged and tested using the confirmation test. Samples that are negative on the screening test are discarded and reported as negative. The confirmation test in most labs (and all SAMHSA certified labs) is performed using mass spectrometry, and is extremely precise but also fairly expensive to run. False positive samples from the screening test will be negative on the confirmation test. Samples testing positive during both screening and confirmation tests are reported as positive to the entity that ordered the test. Most labs save positive samples for some period of months or years in the event of a disputed result or lawsuit.
D.O.T. mandated tests require a Medical Review Officer, an M.D. or a D.O., to contact the donor to determine if an alternative medical explanation justifies the presence of the drug identified by the lab. Doctors need not be licensed in the state where the donor resides nor where the test was administered. They must be a licensed physician in one state within the U.S. to participate as an MRO. This substantially limits the degree of influence from out of state medical review boards. In addition, many courts do not allow a private cause of action against MROs, labs, collectors, etc. If an MRO and a D.O.T. participating employer conspire to falsify drug test results, the innocent donor has little if any recourse. The perception that American citizens are "innocent until proven guilty" is just that. Specific mandated drug testing regulations which entitle access to drug testing chain of custody and procedural evidence from the commercial sector may be discounted or ignored by the ODAPC and government agencies. In other words, the government may chose not to enforce their own regulations. To address negligence and abuse, agencies may utilize a PIE (Public Interest Exclusion) to restrict doctors, labs, hospitals and others from participating in D.O.T. testing. Since the implementation of this kind of testing over a decade ago with tens of millions of tests performed, a PIE not has been issued. [needs citation as to accuracy of tests]
# Types of testing
## Pre-employment drug testing
This is by far the most common type of drug test used by businesses. It has the advantage of being inexpensive, since only one test per employee needs to be paid for by the company. However, since most pre-employment drug testing is urine-based and subject to sample adulteration or substitution, the effectiveness of this approach has been questioned by federal legislators. Some organizations have a witness in the room at the time of the testing, but the privacy implications of this, as well as the potential for shy bladder syndrome has limited the use of witnesses outside jails and drug treatment programs. Companies and testing centers that do not use witnesses normally disconnect sources of water from the testing room to discourage dilution, and if there is water in the toilet, it is dyed blue. Other countermeasures, such as making the donor change into a gown, may also be used.
## Random drug testing
This is both the most effective drug deterrence method and the most controversial type of drug testing. Random drug testing is mandated by the U.S. Department of Transportation, which means that many employers in the USA have no choice but to implement random drug testing programs. Even when random drug testing is not legally required, many organizations use small scale random drug testing as an effective deterrence. Random drug testing is not a violation of the Fourth Amendment to the United States Constitution which protects the right of citizens "to be secure in their persons, houses, papers, and effects, against unreasonable searches and seizures." The United States Supreme Court ruled in Skinner v. Railway Labor Assn., 489 U.S. 602 (1989) that random drug testing is permissible for employees in safety sensitive positions. Justice Kennedy, speaking for the majority, wrote:
[T]he Government interest in testing without a showing of individualized suspicion is compelling. Employees subject to the tests discharge duties fraught with such risks of injury to others that even a momentary lapse of attention can have disastrous consequences based on the interest of the general public [...] While no procedure can identify all impaired employees with ease and perfect accuracy, the FRA regulations supply an effective means of deterring employees engaged in safety-sensitive tasks from using controlled substances or alcohol in the first place.
The dissenting opinion by Justices Marshall and Brennan illustrates the other side of the controversy:
The issue in this case is not whether declaring a war on illegal drugs is good public policy. The importance of ridding our society of such drugs is, by now, apparent to all. Rather, the issue here is whether the Government's deployment in that war of a particularly Draconian weapon - the compulsory collection and chemical testing of railroad workers' blood and urine - comports with the Fourth Amendment. Precisely because the need for action against the drug scourge is manifest, the need for vigilance against unconstitutional excess is great. History teaches that grave threats to liberty often come in times of urgency, when constitutional rights seem too extravagant to endure. The World War II relocation-camp cases, Hirabayashi v. United States, 320 U.S. 81 (1943); Korematsu v. United States, 323 U.S. 214 (1944), and the Red scare and McCarthy-era internal subversion cases, Schenck v. United States, 249 U.S. 47 (1919); Dennis v. United States, 341 U.S. 494 (1951), are only the most extreme reminders that when we allow fundamental freedoms to be sacrificed in the name of real or perceived exigency, we invariably come to regret it.
In the United States today, random drug testing is used by a growing number of corporations, drug rehab centers, prisons, the military, police and fire departments, government agencies, and more recently, schools. This method may also be used on teens by their parents, or mandated to be performed on teens at school. The point of a random drug test is deterrence, as the threat of detection is much higher versus other testing methods. Various questionable methods are utilized to determine who gets tested, ranging from drawing names out of a hat, (Government mandated testing requires a scientifically provable method of selection.) to using more defensible methods such as robust random number generators. However, many random drug testing selection systems are legally indefensible because there is nothing to prevent users from targeting individuals by regenerating names with the random generator until the desired result is produced. (Computer generated random selection should have traceable data to validate the legitimacy of the selection.) Most systems have no tamper-proof audit trail (database records are easy to change, so employers or their testing agents must not have access to the audit trail records for the random selection to be defensible). Finally, hiring third parties to randomly select drug testing subjects is not legally defensible because there is no way of proving that there was no collusion to select a specific individual. (I don't believe this is true. A scientifically random selection process is legally defensible.) You are correct that many loopholes plague this system and many people have lost their jobs, reputations, college savings and their homes without as much as an apology from the drug testing giants and the government.
Many apparent conflicts-of-interest exist among service providers and government authorities. In fact, forbidden relationships thrive. The firewalls assuring separation and impartiality don't work. By cultivating relationships forbidden by the regulations the credibility of the entire government sponsored testing program is jeopardized.
While a goal of random drug testing may be to discourage illegal drug use among employees, etc. a goal of so-called "random" testing may be to destroy the career of the tested person, or to prevent the reunification of a family, too. The goals of drug testing vary depending on the motives of those conducting the tests. D.O.T. mandated testing, as codified in CFR 49 parts 40 and 382, define and establish thousands of specific, highly detailed and requisite protocol which must be followed. However, without an effective governing body to monitor, to investigate allegations of non-compliance, and to enforce these regulations, the stated goals of the government are meaningless.
Unfortunately, courts throughout the United States are divided on the issue of the right of individuals to bring lawsuits regarding violations of these regulations. In other words, if a laboratory failed to maintain quality controls and your specimen was contaminated at the lab, (this happens) resulting in your termination, many courts deny you and me a legal remedy. Some courts hold that the government created and published strict criteria for laboratories and all other service providers to follow to prevent this kind of failure, thereby giving us substantial "built-in" protection.
Through the denial of a private cause of action in these kinds of cases, someone could sabotage your test intentionally with complete impunity. In Drake, after 10 years of legal battles, mostly pro-se, a New York appeals court concluded recently that the language of the 1991 Omnibus Employee Testing Act does not bar common law torts. This is a significant break through for the tested, at-will employee. It is just a beginning, but it is an important legal step in the direction of protecting innocent workers.
Eisenhower warned America of the dangers of a "military industrial complex." The same dynamics have created a collaboration between our government and the commercial drug testing industry.
The goal of random testing is to discourage drug use among employees, inmates, or students by not telling anyone who or when they are to be tested in advance. However, critics claim that random testing introduces a presumption of guilt, and is a violation of privacy if the user is not actually intoxicated during working hours. In addition, random testing is more likely to catch cannabis users, since THC metabolites are fat soluble and have a longer duration in the body than those of many other drugs. Many people believe that this indirectly encourages the use of much more dangerous and harmful drugs that are excreted from the body faster.
## Post-incident drug testing
This is not a very commonly administered test compared to the other two, but the financial ramifications of not testing employees after an accident (or other incident) on the job makes this test worthwhile for most businesses. The point of this test isn't necessarily to cause the employee to lose his or her job, but rather to protect the company from liability in the event that the individual is under the influence at the time of the accident. If drugs or alcohol are detected in any significant quantity, the argument can be made in court that the individual was intoxicated on the job, and for that reason, the company should not be held liable for injuries sustained by the employee. This argument, however, can only reasonably be made if blood or oral fluid / saliva testing is used. Urine, hair, or sweat based testing can only detect past drug use. Depending upon the facts of each case, this may help a company avoid litigation completely or may do nothing to help their case. DUI testing would also fall into this category. Another time this type of test may be used is if an employee shows up for work intoxicated, has alcohol on his or her breath, or appears to be impaired in some other way. The goal of these tests is to protect the entity from litigation, so they are only given on an as needed basis.
It should be noted that in most areas, blood testing is the only legally defensible means for detecting drug use after an incident, although saliva testing is gaining acceptance. The sample should follow chain of custody requirements and should always be sent to a lab after collection. Positive on-site tests that may affect an employee's position or situation should always be followed up with a laboratory test before any action is taken against the employee. Laboratory tests (urine or blood) are the only legally recognized tests in most states as well as in most non-U.S. countries.
# Pros and Cons of Drug Testing Methods
There is no perfect drug testing method. Each method has some advantages and disadvantages. What makes a drug testing method good or not so good is more related to the needs of the person.
## Urine Drug Testing
Pros: Urine drug test kits are available as on-site tests, or laboratory analysis. Referred to as "the gold standard", urinalysis is the most common test type and used by federally mandated drug testing programs.
Cons: The main disadvantages of urine-based drug test kits is are (1.) the ease at which they can be "cheated" via sample adulteration or substitution, unless specimen collection is directly observed, (2.) inability to detect current / on-the-job drug abuse, (3.) the need for bathroom facilities, and (4.) with respect to SAMHSA-5, or NIDA-5, the inability to test for drugs used in current society.
## Saliva Drug Testing
Pros: Saliva (Oral) drug test kits are very donor friendly, non-invasive and easy to collect the specimen. There is no need for a bathroom to administer the tests. Saliva drug testing is great at detecting very recent drug use. Also these drug tests are harder to adulterate than the urine drug tests since the sample can be obtained under direct supervision. Results can be read in minutes and there is no need for a lab. Depending on the test, up to 8 (5 or 6 at a time) different drugs could be detected. This method is the best method for determining current use and impairment.
Cons: The main disadvantage of saliva based drug testing is lack of awareness in the market, as well as misinformation spread largely by laboratories and TPAs (third party administrators), who stand to lose money as saliva testing continues to replace traditional urine-based techniques.
## Spray (Sweat) Drug Testing
Pros: Spray (Sweat) drug test kits are non-invasive and donor friendly. It is very easy to collect the specimen and no bathroom is needed for taking the specimen. The detection window is long and usually can detect drug use up to a couple of weeks. These drug tests are relatively tamper proof since they are hard to manipulate. There is no need for a lab and you can get results in minutes.
Cons: The main disadvantage of spray or sweat based drug testing is the fact that they are open to contamination. Also large variations of sweat production rates of possible donors make some results inconclusive. There is not much variety in these drug tests since they are not as popular as urine or saliva drug testing kits. Their prices tend to be a little higher per test conducted. One main disadvantage of this testing method is the limited number of drugs that can be detected.
## Hair Drug Testing
Pros: Hair Alcohol Testing can provide a much longer window of detection.
Cons: Costs more than urine testing. Cannot be used if a donor has no hair.
# Legality and ethics of mandatory drugs testing
## United Kingdom
The legal position of drug tests on the UK is not clear. A recent study by the independent Inquiry into Drug Testing at Work found that attempts by employers to force could be challenged as a violation of privacy under the Human Rights Act 1998 and Article 8 of the European Convention of Human Rights. However, this may not extend to industries where drug testing is a matter of safety rather than productivity. | https://www.wikidoc.org/index.php/Drug_test | |
84ef6ec340382c66b703a7a28ee640ca3183493f | wikidoc | Dry enema | Dry enema
A dry enema is an alternative technique for cleansing the human rectum either for reasons of health, or for sexual hygiene. It is accomplished by introducing a small amount of sterile lubricant into the rectum, resulting in a bowel movement more quickly and with less violence than can be achieved by an oral laxative.
It is called "dry" by contrast to the more usual wet enema, because no water is used.
A rudimentary form of 'dry' enema is the use of a non-medicated glycerin suppository. However due to the relative hardness of the suppository - necessary for its insertion into the human body - before the glycerin can act, it must be melted by the heat of the body, and hence it does not take effect for up to an hour. Often the hygroscopic glycerin irritates the sensitive membranes of the rectum resulting in forceful expulsion of the suppository without any laxative effects.
A quicker form of the dry enema utilizes the injection of a small amount of water-based lubricant such as K-Y into the rectum via a non-hypodermic syringe, such as an oral syringe, or from some other source.
The usual amount of lubricant applied is about 2 tsp (10 cc), which will produce a movement in 30 minutes or less. The movement will be produced in a compact body, rather than in the more copious liquid form produced by a wet enema; and since no water is used, none will be retained higher up in the colon, to be expelled at some later, and presumably, inconvenient time.
A further advantage of this technique for sexual hygiene is that any slight remaining traces of fecal material will - due to the presence of the lubricant - tend to adhere to the wall of the rectum rather than to any foreign object which may subsequently be inserted. | Dry enema
A dry enema is an alternative technique for cleansing the human rectum either for reasons of health, or for sexual hygiene. It is accomplished by introducing a small amount of sterile lubricant into the rectum, resulting in a bowel movement more quickly and with less violence than can be achieved by an oral laxative.
It is called "dry" by contrast to the more usual wet enema, because no water is used.
A rudimentary form of 'dry' enema is the use of a non-medicated glycerin suppository. However due to the relative hardness of the suppository - necessary for its insertion into the human body - before the glycerin can act, it must be melted by the heat of the body, and hence it does not take effect for up to an hour. Often the hygroscopic glycerin irritates the sensitive membranes of the rectum resulting in forceful expulsion of the suppository without any laxative effects.
A quicker form of the dry enema utilizes the injection of a small amount of water-based lubricant such as K-Y into the rectum via a non-hypodermic syringe, such as an oral syringe, or from some other source.
The usual amount of lubricant applied is about 2 tsp (10 cc), which will produce a movement in 30 minutes or less. The movement will be produced in a compact body, rather than in the more copious liquid form produced by a wet enema; and since no water is used, none will be retained higher up in the colon, to be expelled at some later, and presumably, inconvenient time.
A further advantage of this technique for sexual hygiene is that any slight remaining traces of fecal material will - due to the presence of the lubricant - tend to adhere to the wall of the rectum rather than to any foreign object which may subsequently be inserted. | https://www.wikidoc.org/index.php/Dry_enema | |
d1167ef199c0150fd0a7d62e871c4778eef8efa8 | wikidoc | Ductility | Ductility
Ductility is a mechanical property used to describe the extent to which materials can be deformed plastically without fracture. Ductility is the most important parameter to consider in metal forming operations such as rolling, extrusion, and drawing. Examples of highly ductile metals are silver, gold, copper, and aluminium. The ductility of steel varies depending on the alloying constituents. Increasing levels of carbon decreases ductility, i.e., the steel becomes more brittle.
Ductility can be quantified by the fracture strain \varepsilon_f, which is the engineering strain at which a test specimen fractures during a uniaxial tensile test. Another commonly used measure is the reduction of area at fracture q.
# Scientific fields
## Geology
In Earth science the brittle-ductile transition zone is a zone, at an approximate depth of 15 km in continental crust, at which rock becomes less likely to fracture and more likely to deform ductilely. In glacial ice this zone is at approximately 30 metres depth. It is not impossible for material above a brittle-ductile transition zone to deform ductilely, nor for material below to deform brittly. The zone exists because as depth increases confining pressure increases, and brittle strength increases with confining pressure whilst ductile strength decreases with increasing temperature. The transition zone occurs at the point where brittle strength exceeds ductile strength.
## Materials science
In materials science the ductile-brittle transition temperature (DBTT), nil ductility temperature (NDT), or nil ductility transition temperature of a material represents the point at which the fracture energy passes below a pre-determined point (for steels typically 40 J for a standard Charpy impact test). DBTT is important since, once a material is cooled below the DBTT, it has a much greater tendency to shatter on impact instead of bending or deforming. For example, ZAMAK 3 exhibits good ductility at room temperature but shatters at sub zero temperatures when impacted. DBTT is a very important consideration in materials selection when the material in question is subject to mechanical stresses. See the section on glass transition temperature for a related discussion.
In some materials this transition is sharper than others. For example, the transition is generally sharper in materials with a body-centered cubic (BCC) lattice than those with a face-centered cubic (FCC) lattice. DBTT can also be influenced by external factors such as neutron radiation, which leads to an increase in internal lattice defects and a corresponding decrease in ductility and increase in DBTT.
The most accurate method of measuring the BDT or DBT temperature or a material is by fracture testing. Typically four point bend testing at a range of temperatures is performed on pre-cracked bars of polished material. For experiments conducted at higher temperatures dislocation activity increases. At a certain temperature dislocations shield the crack tip to such an extent the applied deformation rate is not sufficient for the stress intensity at the crack-tip to reach the critical value for fracture (KiC). The temperature at which this occurs is the ductile-brittle transition temperature. If experiments are performed at a higher strain rate more dislocation shielding is required to prevent brittle fracture and the transition temperature is raised. | Ductility
Ductility is a mechanical property used to describe the extent to which materials can be deformed plastically without fracture. Ductility is the most important parameter to consider in metal forming operations such as rolling, extrusion, and drawing. Examples of highly ductile metals are silver, gold, copper, and aluminium. The ductility of steel varies depending on the alloying constituents. Increasing levels of carbon decreases ductility, i.e., the steel becomes more brittle.
Ductility can be quantified by the fracture strain <math>\varepsilon_f</math>, which is the engineering strain at which a test specimen fractures during a uniaxial tensile test. Another commonly used measure is the reduction of area at fracture <math>q</math>.[1]
# Scientific fields
## Geology
In Earth science the brittle-ductile transition zone is a zone, at an approximate depth of 15 km in continental crust, at which rock becomes less likely to fracture and more likely to deform ductilely. In glacial ice this zone is at approximately 30 metres depth. It is not impossible for material above a brittle-ductile transition zone to deform ductilely, nor for material below to deform brittly. The zone exists because as depth increases confining pressure increases, and brittle strength increases with confining pressure whilst ductile strength decreases with increasing temperature. The transition zone occurs at the point where brittle strength exceeds ductile strength.
## Materials science
In materials science the ductile-brittle transition temperature (DBTT), nil ductility temperature (NDT), or nil ductility transition temperature of a material represents the point at which the fracture energy passes below a pre-determined point (for steels typically 40 J[2] for a standard Charpy impact test). DBTT is important since, once a material is cooled below the DBTT, it has a much greater tendency to shatter on impact instead of bending or deforming. For example, ZAMAK 3 exhibits good ductility at room temperature but shatters at sub zero temperatures when impacted. DBTT is a very important consideration in materials selection when the material in question is subject to mechanical stresses. See the section on glass transition temperature for a related discussion.
In some materials this transition is sharper than others. For example, the transition is generally sharper in materials with a body-centered cubic (BCC) lattice than those with a face-centered cubic (FCC) lattice. DBTT can also be influenced by external factors such as neutron radiation, which leads to an increase in internal lattice defects and a corresponding decrease in ductility and increase in DBTT.
The most accurate method of measuring the BDT or DBT temperature or a material is by fracture testing. Typically four point bend testing at a range of temperatures is performed on pre-cracked bars of polished material. For experiments conducted at higher temperatures dislocation activity increases. At a certain temperature dislocations shield the crack tip to such an extent the applied deformation rate is not sufficient for the stress intensity at the crack-tip to reach the critical value for fracture (KiC). The temperature at which this occurs is the ductile-brittle transition temperature. If experiments are performed at a higher strain rate more dislocation shielding is required to prevent brittle fracture and the transition temperature is raised. | https://www.wikidoc.org/index.php/Ductile | |
ad1e174c95ad537f4b113d3f888a1710f7e2dc60 | wikidoc | Dupilumab | Dupilumab
# 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
Dupilumab is a human monoclonal IgG4 antibody that is FDA approved for the treatment of moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Common adverse reactions include injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, and dry eye.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dupilumab is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupilumab can be used with or without topical corticosteroids.
- Dupilumab is administered by subcutaneous injection.
- The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week.
- Dupilumab can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas.
- If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
- Dupilumab is a clear to slightly opalescent, colorless to pale yellow solution available as:
- Injection: 300 mg/2 mL in a single-dose pre-filled syringe with needle shield
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding dupilumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding dupilumab 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 Dupilumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding dupilumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding dupilumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Dupilumab is contraindicated in patients who have known hypersensitivity to dupilumab or any of its excipients.
# Warnings
- Hypersensitivity reactions, including generalized urticaria and serum sickness or serum sickness-like reactions, were reported in less than 1% of subjects who received dupilumab in clinical trials. Two subjects experienced serum sickness or serum sickness-like reactions that were associated with high titers of antibodies to dupilumab. If a clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue dupilumab.
- Conjunctivitis and keratitis occurred more frequently in subjects who received dupilumab. Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis recovered or were recovering during the treatment period.
- Keratitis was reported in <1% of the dupilumab group (1 per 100 subject-years) and in 0% of the placebo group (0 per 100 subject-years) in the 16-week monotherapy trials. In the 52-week dupilumab + topical corticosteroids (TCS) trial, keratitis was reported in 4% of the dupilumab + TCS group (12 per 100 subject-years) and in 0% of the placebo + TCS group (0 per 100 subject-years). Most subjects with keratitis recovered or were recovering during the treatment period.
- Advise patients to report new onset or worsening eye symptoms to their healthcare provider.
- Safety and efficacy of dupilumab have not been established in the treatment of asthma. Advise patients with comorbid asthma not to adjust or stop their asthma treatments without consultation with their physicians.
- Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if dupilumab will influence the immune response against helminth infections.
# 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.
- Three randomized, double-blind, placebo-controlled, multicenter trials (Trials 1, 2, and 3) and one dose-ranging trial (Trial 4) evaluated the safety of dupilumab in subjects with moderate-to-severe atopic dermatitis. The safety population had a mean age of 38 years; 41% of subjects were female, 67% were white, 24% were Asian, and 6% were black; in terms of comorbid conditions, 48% of the subjects had asthma, 49% had allergic rhinitis, 37% had food allergy, and 27% had allergic conjunctivitis. In these 4 trials, 1472 subjects were treated with subcutaneous injections of dupilumab, with or without concomitant topical corticosteroids (TCS).
- A total of 739 subjects were treated with dupilumab for at least 1 year in the development program for moderate-to-severe atopic dermatitis.
- Trials 1, 2, and 4 compared the safety of dupilumab monotherapy to placebo through Week 16. Trial 3 compared the safety of dupilumab + TCS to placebo + TCS through Week 52.
- In dupilumab monotherapy trials (Trials 1, 2, and 4) through Week 16, the proportion of subjects who discontinued treatment because of adverse events was 1.9% in both the dupilumab 300 mg Q2W and placebo groups.
- Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% in the dupilumab 300 mg Q2W monotherapy groups, and in the dupilumab + TCS group, all at a higher rate than in their respective comparator groups during the first 16 weeks of treatment.
- In the dupilumab with concomitant TCS trial (Trial 3) through Week 52, the proportion of subjects who discontinued treatment because of adverse events was 1.8% in dupilumab 300 mg Q2W + TCS group and 7.6% in the placebo + TCS group. Two subjects discontinued dupilumab because of adverse reactions: atopic dermatitis (1 subject) and exfoliative dermatitis (1 subject).
- The safety profile of dupilumab + TCS through Week 52 was generally consistent with the safety profile observed at Week 16.
Conjunctivitis
- During the 52-week treatment period of concomitant therapy trial (Trial 3), conjunctivitis was reported in 16% of the dupilumab 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years).
Eczema Herpeticum and Herpes Zoster
- The rate of eczema herpeticum was similar in the placebo and dupilumab groups.
- Herpes zoster was reported in <0.1% of the dupilumab groups (<1 per 100 subject-years) and in <1% of the placebo group (1 per 100 subject-years) in the 16-week monotherapy trials. In the 52-week dupilumab + TCS trial, herpes zoster was reported in 1% of the dupilumab + TCS group (1 per 100 subject-years) and 2% of the placebo + TCS group (2 per 100 subject-years).
Hypersensitivity Reactions
- Hypersensitivity reactions were reported in <1% of dupilumab-treated subjects. These included serum sickness reaction, serum sickness-like reaction, and generalized urticaria.
Eosinophils
- Dupilumab-treated subjects had a greater mean initial increase from baseline in eosinophil count compared to subjects treated with placebo in the monotherapy trials. Eosinophil counts declined to near baseline levels by Week 16. The initial increase in eosinophils was not observed in the 52-week dupilumab + TCS trial.
- In Trials 1, 2, and 3, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in dupilumab and placebo groups. In Trials 1, 2, and 3, treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in <1% of dupilumab-treated patients and none in placebo-treated patients. In most cases, eosinophil counts declined to near baseline during study treatment.
- As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to dupilumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- Approximately 7% of subjects with atopic dermatitis who received dupilumab 300 mg Q2W for 16 weeks developed antibodies to dupilumab. Of the subjects who developed antibodies to dupilumab, approximately 30% (2% of all subjects receiving dupilumab) had antibodies that were classified as neutralizing.
- Of the subjects with atopic dermatitis who received dupilumab 300 mg Q2W + TCS for 52 weeks, approximately 7% developed antibodies to dupilumab and approximately 2% had persistent antibody responses, defined as having at least 2 consecutive positive post-baseline samples. Of the subjects who developed antibodies to dupilumab, approximately 14% (1% of all subjects receiving dupilumab + TCS) had antibodies that were classified as neutralizing.
- In subjects who received dupilumab, development of antibodies to dupilumab was associated with lower serum dupilumab concentrations.
- Antibodies to dupilumab were detected in approximately 2% and 8% of subjects with atopic dermatitis in the placebo or the placebo + TCS groups, respectively.
- The antibody titers detected in both dupilumab and placebo subjects were generally low. Two subjects developed serum sickness or serum sickness-like reactions and high titers of antibodies to dupilumab during dupilumab therapy.
## Postmarketing Experience
There is limited information regarding Dupilumab Postmarketing Experience in the drug label.
# Drug Interactions
- Live Vaccines
- Non-Live Vaccines
- Avoid use of live vaccines in patients treated with dupilumab.
- Immune responses to vaccination were assessed in a study in which subjects with atopic dermatitis were treated once weekly for 16 weeks with 300 mg of dupilumab (twice the recommended dosing frequency). After 12 weeks of dupilumab administration, subjects were vaccinated with a Tdap vaccine (Adacel®) and a meningococcal polysaccharide vaccine (Menomune®). Antibody responses to tetanus toxoid and serogroup C meningococcal polysaccharide were assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-treated and placebo-treated subjects. Immune responses to the other active components of the Adacel and Menomune vaccines were not assessed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no available data on dupilumab use in pregnant women to inform any drug associated risk. Human IgG antibodies are known to cross the placental barrier; therefore, dupilumab may be transmitted from the mother to the developing fetus. In an enhanced pre- and post-natal developmental study, no adverse developmental effects were observed in offspring born to pregnant monkeys after subcutaneous administration of a homologous antibody against interleukin-4-receptor alpha (IL-4Rα) during organogenesis through parturition at doses up to 10-times the maximum recommended human dose (MRHD) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- In an enhanced pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of homologous antibody against IL-4Rα up to 10 times the MRHD (on a mg/kg basis of 100 mg/kg/week) from the beginning of organogenesis to parturition. No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dupilumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dupilumab during labor and delivery.
### Nursing Mothers
- There are no data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk. The effects of local gastrointestinal and limited systemic exposure to dupilumab on the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for dupilumab and any potential adverse effects on the breastfed child from dupilumab or from the underlying maternal condition.
### Pediatric Use
- Safety and efficacy in pediatric patients (<18 years of age) have not been established.
### Geriatic Use
- Of the 1472 subjects with atopic dermatitis exposed to dupilumab in a dose-ranging study and placebo-controlled trials, 67 subjects were 65 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Dupilumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dupilumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dupilumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dupilumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dupilumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dupilumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Dupilumab is intended for use under the guidance of a healthcare provider. A patient may self-inject dupilumab after training in subcutaneous injection technique using the pre-filled syringe. Provide proper training to patients and/or caregivers on the preparation and administration of dupilumab prior to use according to the "Instructions for Use".
- For the initial 600 mg dose, administer each of the two dupilumab 300 mg injections at different injection sites.
- Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.
- Rotate the injection site with each injection. DO NOT inject dupilumab into skin that is tender, damaged, bruised, or scarred.
- The dupilumab "Instructions for Use" contains more detailed instructions on the preparation and administration of dupilumab
- Before injection, remove dupilumab pre-filled syringe from the refrigerator and allow dupilumab to reach room temperature (45 minutes) without removing the needle cap.
- Inspect dupilumab visually for particulate matter and discoloration prior to administration. dupilumab is a clear to slightly opalescent, colorless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discolored or cloudy (other than clear to slightly opalescent, colorless to pale yellow). Dupilumab does not contain preservatives; therefore, discard any unused product remaining in the pre-filled syringe.
### Monitoring
- Improvement in disease severity and reduction in pruritus indicates efficacy.
# IV Compatibility
There is limited information regarding the compatibility of Dupilumab and IV administrations.
# Overdosage
- There is no specific treatment for dupilumab overdose. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.
# Pharmacology
## Mechanism of Action
- Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor.
- Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced responses, including the release of proinflammatory cytokines, chemokines and IgE.
## Structure
There is limited information regarding Dupilumab Structure in the drug label.
## Pharmacodynamics
- Consistent with receptor blockade, serum levels of IL-4 and IL-13 were increased following dupilumab treatment. The relationship between the pharmacodynamic activity and the mechanism(s) by which dupilumab exerts its clinical effects is unknown.
## Pharmacokinetics
- Following an initial subcutaneous (SC) dose of 600 mg, dupilumab reached peak mean ±SD concentrations (Cmax) of 70.1±24.1 mcg/mL by approximately 1 week post dose.
- Steady-state concentrations were achieved by Week 16 following the administration of 600 mg starting dose and 300 mg dose either weekly (twice the recommended dosing frequency) or every other week. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 73.3±40.0 mcg/mL to 79.9±41.4 mcg/mL for 300 mg administered every 2 weeks and from 173±75.9 mcg/mL to 193±77.0 mcg/mL for 300 mg administered weekly.
- The bioavailability of dupilumab following a SC dose is estimated to be 64%.
- The estimated total volume of distribution was approximately 4.8±1.3 L.
- The metabolic pathway of dupilumab has not been characterized. As a human monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. After the last steady-state dose of 300 mg Q2W or 300 mg QW dupilumab, the median times to non-detectable concentration (<78 ng/mL) are 10 and 13 weeks, respectively.
- Dupilumab exhibited nonlinear target-mediated pharmacokinetics with exposures increasing in a greater than dose-proportional manner. The systemic exposure increased by 30-fold when the dose increased 8-fold following a single dose of dupilumab from 75 mg to 600 mg (i.e., 0.25-times to 2-times the recommended dose).
- Dupilumab trough concentrations were lower in subjects with higher body weight.
- Development of antibodies to dupilumab was associated with lower serum dupilumab concentrations. A few subjects who had high antibody titers also had no detectable serum dupilumab concentrations.
Geriatric Patients
- In subjects who are 65 years and older, the mean ±SD steady-state trough concentrations of dupilumab were 69.4±31.4 mcg/mL and 166±62.3 mcg/mL, respectively, for 300 mg administered every 2 weeks and weekly. No dose adjustment in this population is recommended.
Renal or Hepatic Impairment
- No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of dupilumab was conducted.
Cytochrome P450 Substrates
- The effects of dupilumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), metoprolol (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in a study with 12-13 evaluable subjects with atopic dermatitis (a SC loading dose of 600 mg followed by 300 mg SC weekly for six weeks). No clinically significant changes in AUC were observed. The largest effect was observed for metoprolol (CYP2D6) with an increase in AUC of 29%.
## Nonclinical Toxicology
- Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of dupilumab.
- No effects on fertility parameters such as reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature mice that were subcutaneously administered a homologous antibody against IL-4Rα at doses up to 200 mg/kg/week.
# Clinical Studies
- Three randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3) enrolled a total of 2119 subjects 18 years of age and older with moderate-to-severe atopic dermatitis (AD) not adequately controlled by topical medication(s). Disease severity was defined by an Investigator's Global Assessment (IGA) score ≥3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area involvement of ≥10%. At baseline, 59% of subjects were male, 67% were white, 52% of subjects had a baseline IGA score of 3 (moderate AD), and 48% of subjects had a baseline IGA of 4 (severe AD). The baseline mean EASI score was 33 and the baseline weekly averaged peak pruritus Numeric Rating Scale (NRS) was 7 on a scale of 0-10.
- In all three trials, subjects in the dupilumab group received subcutaneous injections of dupilumab 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the monotherapy trials (Trials 1 and 2), subjects received dupilumab or placebo for 16 weeks.
- In the concomitant therapy trial (Trial 3), subjects received dupilumab or placebo with concomitant topical corticosteroids (TCS) and as needed topical calcineurin inhibitors for problem areas only, such as the face, neck, intertriginous and genital areas for 52 weeks.
- All three trials assessed the primary endpoint, the change from baseline to Week 16 in the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement. Other endpoints included the proportion of subjects with EASI-75 (improvement of at least 75% in EASI score from baseline), and reduction in itch as defined by at least a 4-point improvement in the peak pruritus NRS from baseline to Week 16.
- The results of the DUPIXENT monotherapy trials (Trials 1 and 2) and the DUPIXENT with concomitant TCS trial (Trial 3) are presented in Table 2.
- In Trial 3, of the 421 subjects, 353 had been on study for 52 weeks at the time of data analysis. Of these 353 subjects, responders at Week 52 represent a mixture of subjects who maintained their efficacy from Week 16 (e.g., 53% of dupilumab IGA 0 or 1 responders at Week 16 remained responders at Week 52) and subjects who were non-responders at Week 16 who later responded to treatment (e.g., 24% of dupilumab IGA 0 or 1 non-responders at Week 16 became responders at Week 52). Results of supportive analyses of the 353 subjects in the dupilumab with concomitant TCS trial (Trial 3) are presented in Table 3.
- Treatment effects in subgroups (weight, age, gender, race, and prior treatment, including immunosuppressants) in Trials 1, 2, and 3 were generally consistent with the results in the overall study population.
- In Trials 1, 2, and 3, a third randomized treatment arm of dupilumab 300 mg QW did not demonstrate additional treatment benefit over dupilumab 300 mg Q2W.
- Subjects in Trials 1 and 2 who had an IGA 0 or 1 with a reduction of ≥2 points were re-randomized into Trial 5. Trial 5 evaluated multiple dupilumab monotherapy dose regimens for maintaining treatment response. The study included subjects randomized to continue with dupilumab 300 mg Q2W (62 subjects) or switch to placebo (31 subjects) for 36 weeks. IGA 0 or 1 responses at Week 36 were as follows: 33 (53%) in the Q2W group and 3 (10%) in the placebo group.
# How Supplied
- Dupilumab Injection is a clear to slightly opalescent, colorless to pale yellow solution, supplied in single-dose pre-filled syringes with needle shield. Each pre-filled syringe with needle shield is designed to deliver 300 mg of dupilumab in 2 mL solution.
- Dupilumab is available in cartons containing 2 pre-filled syringes with needle shield.
## Storage
- Dupilumab is sterile and preservative-free. Discard any unused portion.
- Store refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.
- If necessary, pre-filled syringes may be kept at room temperature up to 77°F (25°C) for a maximum of 14 days. Do not store above 77°F (25°C). After removal from the refrigerator, dupilumab must be used within 14 days or discarded.
- Do not expose the syringe to heat or direct sunlight.
- Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Do NOT freeze. Do NOT expose to heat. Do NOT shake
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patients and/or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use) before the patient starts using dupilumab and each time the prescription is renewed as there may be new information they need to know.
- Provide proper training to patients and/or caregivers on proper subcutaneous injection technique, including aseptic technique, and the preparation and administration of dupilumab prior to use. Advise patients to follow sharps disposal recommendations.
- Advise patients to discontinue dupilumab and to seek immediate medical attention if they experience any symptoms of systemic hypersensitivity reactions.
- Advise patients to consult their healthcare provider if new onset or worsening eye symptoms develop.
- Advise patients with comorbid asthma not to adjust or stop their asthma treatment without talking to their physicians.
# Precautions with Alcohol
Alcohol-Dupilumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Dupixent
# Look-Alike Drug Names
There is limited information regarding Dupilumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Dupilumab
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]
# 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
Dupilumab is a human monoclonal IgG4 antibody that is FDA approved for the treatment of moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Common adverse reactions include injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, and dry eye.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dupilumab is indicated for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupilumab can be used with or without topical corticosteroids.
- Dupilumab is administered by subcutaneous injection.
- The recommended dose of dupilumab for adult patients is an initial dose of 600 mg (two 300 mg injections), followed by 300 mg given every other week.
- Dupilumab can be used with or without topical corticosteroids. Topical calcineurin inhibitors may be used, but should be reserved for problem areas only, such as the face, neck, intertriginous and genital areas.
- If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If the missed dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule.
- Dupilumab is a clear to slightly opalescent, colorless to pale yellow solution available as:
- Injection: 300 mg/2 mL in a single-dose pre-filled syringe with needle shield
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding dupilumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding dupilumab 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 Dupilumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding dupilumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding dupilumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Dupilumab is contraindicated in patients who have known hypersensitivity to dupilumab or any of its excipients.
# Warnings
- Hypersensitivity reactions, including generalized urticaria and serum sickness or serum sickness-like reactions, were reported in less than 1% of subjects who received dupilumab in clinical trials. Two subjects experienced serum sickness or serum sickness-like reactions that were associated with high titers of antibodies to dupilumab. If a clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue dupilumab.
- Conjunctivitis and keratitis occurred more frequently in subjects who received dupilumab. Conjunctivitis was the most frequently reported eye disorder. Most subjects with conjunctivitis recovered or were recovering during the treatment period.
- Keratitis was reported in <1% of the dupilumab group (1 per 100 subject-years) and in 0% of the placebo group (0 per 100 subject-years) in the 16-week monotherapy trials. In the 52-week dupilumab + topical corticosteroids (TCS) trial, keratitis was reported in 4% of the dupilumab + TCS group (12 per 100 subject-years) and in 0% of the placebo + TCS group (0 per 100 subject-years). Most subjects with keratitis recovered or were recovering during the treatment period.
- Advise patients to report new onset or worsening eye symptoms to their healthcare provider.
- Safety and efficacy of dupilumab have not been established in the treatment of asthma. Advise patients with comorbid asthma not to adjust or stop their asthma treatments without consultation with their physicians.
- Patients with known helminth infections were excluded from participation in clinical studies. It is unknown if dupilumab will influence the immune response against helminth infections.
# 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.
- Three randomized, double-blind, placebo-controlled, multicenter trials (Trials 1, 2, and 3) and one dose-ranging trial (Trial 4) evaluated the safety of dupilumab in subjects with moderate-to-severe atopic dermatitis. The safety population had a mean age of 38 years; 41% of subjects were female, 67% were white, 24% were Asian, and 6% were black; in terms of comorbid conditions, 48% of the subjects had asthma, 49% had allergic rhinitis, 37% had food allergy, and 27% had allergic conjunctivitis. In these 4 trials, 1472 subjects were treated with subcutaneous injections of dupilumab, with or without concomitant topical corticosteroids (TCS).
- A total of 739 subjects were treated with dupilumab for at least 1 year in the development program for moderate-to-severe atopic dermatitis.
- Trials 1, 2, and 4 compared the safety of dupilumab monotherapy to placebo through Week 16. Trial 3 compared the safety of dupilumab + TCS to placebo + TCS through Week 52.
- In dupilumab monotherapy trials (Trials 1, 2, and 4) through Week 16, the proportion of subjects who discontinued treatment because of adverse events was 1.9% in both the dupilumab 300 mg Q2W and placebo groups.
- Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% in the dupilumab 300 mg Q2W monotherapy groups, and in the dupilumab + TCS group, all at a higher rate than in their respective comparator groups during the first 16 weeks of treatment.
- In the dupilumab with concomitant TCS trial (Trial 3) through Week 52, the proportion of subjects who discontinued treatment because of adverse events was 1.8% in dupilumab 300 mg Q2W + TCS group and 7.6% in the placebo + TCS group. Two subjects discontinued dupilumab because of adverse reactions: atopic dermatitis (1 subject) and exfoliative dermatitis (1 subject).
- The safety profile of dupilumab + TCS through Week 52 was generally consistent with the safety profile observed at Week 16.
Conjunctivitis
- During the 52-week treatment period of concomitant therapy trial (Trial 3), conjunctivitis was reported in 16% of the dupilumab 300 mg Q2W + TCS group (20 per 100 subject-years) and in 9% of the placebo + TCS group (10 per 100 subject-years).
Eczema Herpeticum and Herpes Zoster
- The rate of eczema herpeticum was similar in the placebo and dupilumab groups.
- Herpes zoster was reported in <0.1% of the dupilumab groups (<1 per 100 subject-years) and in <1% of the placebo group (1 per 100 subject-years) in the 16-week monotherapy trials. In the 52-week dupilumab + TCS trial, herpes zoster was reported in 1% of the dupilumab + TCS group (1 per 100 subject-years) and 2% of the placebo + TCS group (2 per 100 subject-years).
Hypersensitivity Reactions
- Hypersensitivity reactions were reported in <1% of dupilumab-treated subjects. These included serum sickness reaction, serum sickness-like reaction, and generalized urticaria.
Eosinophils
- Dupilumab-treated subjects had a greater mean initial increase from baseline in eosinophil count compared to subjects treated with placebo in the monotherapy trials. Eosinophil counts declined to near baseline levels by Week 16. The initial increase in eosinophils was not observed in the 52-week dupilumab + TCS trial.
- In Trials 1, 2, and 3, the incidence of treatment-emergent eosinophilia (≥500 cells/mcL) was similar in dupilumab and placebo groups. In Trials 1, 2, and 3, treatment-emergent eosinophilia (≥5,000 cells/mcL) was reported in <1% of dupilumab-treated patients and none in placebo-treated patients. In most cases, eosinophil counts declined to near baseline during study treatment.
- As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to dupilumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- Approximately 7% of subjects with atopic dermatitis who received dupilumab 300 mg Q2W for 16 weeks developed antibodies to dupilumab. Of the subjects who developed antibodies to dupilumab, approximately 30% (2% of all subjects receiving dupilumab) had antibodies that were classified as neutralizing.
- Of the subjects with atopic dermatitis who received dupilumab 300 mg Q2W + TCS for 52 weeks, approximately 7% developed antibodies to dupilumab and approximately 2% had persistent antibody responses, defined as having at least 2 consecutive positive post-baseline samples. Of the subjects who developed antibodies to dupilumab, approximately 14% (1% of all subjects receiving dupilumab + TCS) had antibodies that were classified as neutralizing.
- In subjects who received dupilumab, development of antibodies to dupilumab was associated with lower serum dupilumab concentrations.
- Antibodies to dupilumab were detected in approximately 2% and 8% of subjects with atopic dermatitis in the placebo or the placebo + TCS groups, respectively.
- The antibody titers detected in both dupilumab and placebo subjects were generally low. Two subjects developed serum sickness or serum sickness-like reactions and high titers of antibodies to dupilumab during dupilumab therapy.
## Postmarketing Experience
There is limited information regarding Dupilumab Postmarketing Experience in the drug label.
# Drug Interactions
- Live Vaccines
- Non-Live Vaccines
- Avoid use of live vaccines in patients treated with dupilumab.
- Immune responses to vaccination were assessed in a study in which subjects with atopic dermatitis were treated once weekly for 16 weeks with 300 mg of dupilumab (twice the recommended dosing frequency). After 12 weeks of dupilumab administration, subjects were vaccinated with a Tdap vaccine (Adacel®) and a meningococcal polysaccharide vaccine (Menomune®). Antibody responses to tetanus toxoid and serogroup C meningococcal polysaccharide were assessed 4 weeks later. Antibody responses to both tetanus vaccine and meningococcal polysaccharide vaccine were similar in dupilumab-treated and placebo-treated subjects. Immune responses to the other active components of the Adacel and Menomune vaccines were not assessed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no available data on dupilumab use in pregnant women to inform any drug associated risk. Human IgG antibodies are known to cross the placental barrier; therefore, dupilumab may be transmitted from the mother to the developing fetus. In an enhanced pre- and post-natal developmental study, no adverse developmental effects were observed in offspring born to pregnant monkeys after subcutaneous administration of a homologous antibody against interleukin-4-receptor alpha (IL-4Rα) during organogenesis through parturition at doses up to 10-times the maximum recommended human dose (MRHD) [see DATA]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- In an enhanced pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of homologous antibody against IL-4Rα up to 10 times the MRHD (on a mg/kg basis of 100 mg/kg/week) from the beginning of organogenesis to parturition. No treatment-related adverse effects on embryofetal toxicity or malformations, or on morphological, functional, or immunological development were observed in the infants from birth through 6 months of age.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dupilumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Dupilumab during labor and delivery.
### Nursing Mothers
- There are no data on the presence of dupilumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk. The effects of local gastrointestinal and limited systemic exposure to dupilumab on the breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for dupilumab and any potential adverse effects on the breastfed child from dupilumab or from the underlying maternal condition.
### Pediatric Use
- Safety and efficacy in pediatric patients (<18 years of age) have not been established.
### Geriatic Use
- Of the 1472 subjects with atopic dermatitis exposed to dupilumab in a dose-ranging study and placebo-controlled trials, 67 subjects were 65 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Dupilumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Dupilumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Dupilumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Dupilumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dupilumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Dupilumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Dupilumab is intended for use under the guidance of a healthcare provider. A patient may self-inject dupilumab after training in subcutaneous injection technique using the pre-filled syringe. Provide proper training to patients and/or caregivers on the preparation and administration of dupilumab prior to use according to the "Instructions for Use".
- For the initial 600 mg dose, administer each of the two dupilumab 300 mg injections at different injection sites.
- Administer subcutaneous injection into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. The upper arm can also be used if a caregiver administers the injection.
- Rotate the injection site with each injection. DO NOT inject dupilumab into skin that is tender, damaged, bruised, or scarred.
- The dupilumab "Instructions for Use" contains more detailed instructions on the preparation and administration of dupilumab
- Before injection, remove dupilumab pre-filled syringe from the refrigerator and allow dupilumab to reach room temperature (45 minutes) without removing the needle cap.
- Inspect dupilumab visually for particulate matter and discoloration prior to administration. dupilumab is a clear to slightly opalescent, colorless to pale yellow solution. Do not use if the liquid contains visible particulate matter, is discolored or cloudy (other than clear to slightly opalescent, colorless to pale yellow). Dupilumab does not contain preservatives; therefore, discard any unused product remaining in the pre-filled syringe.
### Monitoring
- Improvement in disease severity and reduction in pruritus indicates efficacy.
# IV Compatibility
There is limited information regarding the compatibility of Dupilumab and IV administrations.
# Overdosage
- There is no specific treatment for dupilumab overdose. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.
# Pharmacology
## Mechanism of Action
- Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor.
- Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced responses, including the release of proinflammatory cytokines, chemokines and IgE.
## Structure
There is limited information regarding Dupilumab Structure in the drug label.
## Pharmacodynamics
- Consistent with receptor blockade, serum levels of IL-4 and IL-13 were increased following dupilumab treatment. The relationship between the pharmacodynamic activity and the mechanism(s) by which dupilumab exerts its clinical effects is unknown.
## Pharmacokinetics
- Following an initial subcutaneous (SC) dose of 600 mg, dupilumab reached peak mean ±SD concentrations (Cmax) of 70.1±24.1 mcg/mL by approximately 1 week post dose.
- Steady-state concentrations were achieved by Week 16 following the administration of 600 mg starting dose and 300 mg dose either weekly (twice the recommended dosing frequency) or every other week. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 73.3±40.0 mcg/mL to 79.9±41.4 mcg/mL for 300 mg administered every 2 weeks and from 173±75.9 mcg/mL to 193±77.0 mcg/mL for 300 mg administered weekly.
- The bioavailability of dupilumab following a SC dose is estimated to be 64%.
- The estimated total volume of distribution was approximately 4.8±1.3 L.
- The metabolic pathway of dupilumab has not been characterized. As a human monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. After the last steady-state dose of 300 mg Q2W or 300 mg QW dupilumab, the median times to non-detectable concentration (<78 ng/mL) are 10 and 13 weeks, respectively.
- Dupilumab exhibited nonlinear target-mediated pharmacokinetics with exposures increasing in a greater than dose-proportional manner. The systemic exposure increased by 30-fold when the dose increased 8-fold following a single dose of dupilumab from 75 mg to 600 mg (i.e., 0.25-times to 2-times the recommended dose).
- Dupilumab trough concentrations were lower in subjects with higher body weight.
- Development of antibodies to dupilumab was associated with lower serum dupilumab concentrations. A few subjects who had high antibody titers also had no detectable serum dupilumab concentrations.
Geriatric Patients
- In subjects who are 65 years and older, the mean ±SD steady-state trough concentrations of dupilumab were 69.4±31.4 mcg/mL and 166±62.3 mcg/mL, respectively, for 300 mg administered every 2 weeks and weekly. No dose adjustment in this population is recommended.
Renal or Hepatic Impairment
- No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of dupilumab was conducted.
Cytochrome P450 Substrates
- The effects of dupilumab on the pharmacokinetics of midazolam (metabolized by CYP3A4), warfarin (metabolized by CYP2C9), omeprazole (metabolized by CYP2C19), metoprolol (metabolized by CYP2D6), and caffeine (metabolized by CYP1A2) were evaluated in a study with 12-13 evaluable subjects with atopic dermatitis (a SC loading dose of 600 mg followed by 300 mg SC weekly for six weeks). No clinically significant changes in AUC were observed. The largest effect was observed for metoprolol (CYP2D6) with an increase in AUC of 29%.
## Nonclinical Toxicology
- Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of dupilumab.
- No effects on fertility parameters such as reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature mice that were subcutaneously administered a homologous antibody against IL-4Rα at doses up to 200 mg/kg/week.
# Clinical Studies
- Three randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3) enrolled a total of 2119 subjects 18 years of age and older with moderate-to-severe atopic dermatitis (AD) not adequately controlled by topical medication(s). Disease severity was defined by an Investigator's Global Assessment (IGA) score ≥3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area involvement of ≥10%. At baseline, 59% of subjects were male, 67% were white, 52% of subjects had a baseline IGA score of 3 (moderate AD), and 48% of subjects had a baseline IGA of 4 (severe AD). The baseline mean EASI score was 33 and the baseline weekly averaged peak pruritus Numeric Rating Scale (NRS) was 7 on a scale of 0-10.
- In all three trials, subjects in the dupilumab group received subcutaneous injections of dupilumab 600 mg at Week 0, followed by 300 mg every other week (Q2W). In the monotherapy trials (Trials 1 and 2), subjects received dupilumab or placebo for 16 weeks.
- In the concomitant therapy trial (Trial 3), subjects received dupilumab or placebo with concomitant topical corticosteroids (TCS) and as needed topical calcineurin inhibitors for problem areas only, such as the face, neck, intertriginous and genital areas for 52 weeks.
- All three trials assessed the primary endpoint, the change from baseline to Week 16 in the proportion of subjects with an IGA 0 (clear) or 1 (almost clear) and at least a 2-point improvement. Other endpoints included the proportion of subjects with EASI-75 (improvement of at least 75% in EASI score from baseline), and reduction in itch as defined by at least a 4-point improvement in the peak pruritus NRS from baseline to Week 16.
- The results of the DUPIXENT monotherapy trials (Trials 1 and 2) and the DUPIXENT with concomitant TCS trial (Trial 3) are presented in Table 2.
- In Trial 3, of the 421 subjects, 353 had been on study for 52 weeks at the time of data analysis. Of these 353 subjects, responders at Week 52 represent a mixture of subjects who maintained their efficacy from Week 16 (e.g., 53% of dupilumab IGA 0 or 1 responders at Week 16 remained responders at Week 52) and subjects who were non-responders at Week 16 who later responded to treatment (e.g., 24% of dupilumab IGA 0 or 1 non-responders at Week 16 became responders at Week 52). Results of supportive analyses of the 353 subjects in the dupilumab with concomitant TCS trial (Trial 3) are presented in Table 3.
- Treatment effects in subgroups (weight, age, gender, race, and prior treatment, including immunosuppressants) in Trials 1, 2, and 3 were generally consistent with the results in the overall study population.
- In Trials 1, 2, and 3, a third randomized treatment arm of dupilumab 300 mg QW did not demonstrate additional treatment benefit over dupilumab 300 mg Q2W.
- Subjects in Trials 1 and 2 who had an IGA 0 or 1 with a reduction of ≥2 points were re-randomized into Trial 5. Trial 5 evaluated multiple dupilumab monotherapy dose regimens for maintaining treatment response. The study included subjects randomized to continue with dupilumab 300 mg Q2W (62 subjects) or switch to placebo (31 subjects) for 36 weeks. IGA 0 or 1 responses at Week 36 were as follows: 33 (53%) in the Q2W group and 3 (10%) in the placebo group.
# How Supplied
- Dupilumab Injection is a clear to slightly opalescent, colorless to pale yellow solution, supplied in single-dose pre-filled syringes with needle shield. Each pre-filled syringe with needle shield is designed to deliver 300 mg of dupilumab in 2 mL solution.
- Dupilumab is available in cartons containing 2 pre-filled syringes with needle shield.
## Storage
- Dupilumab is sterile and preservative-free. Discard any unused portion.
- Store refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.
- If necessary, pre-filled syringes may be kept at room temperature up to 77°F (25°C) for a maximum of 14 days. Do not store above 77°F (25°C). After removal from the refrigerator, dupilumab must be used within 14 days or discarded.
- Do not expose the syringe to heat or direct sunlight.
- Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Do NOT freeze. Do NOT expose to heat. Do NOT shake
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patients and/or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use) before the patient starts using dupilumab and each time the prescription is renewed as there may be new information they need to know.
- Provide proper training to patients and/or caregivers on proper subcutaneous injection technique, including aseptic technique, and the preparation and administration of dupilumab prior to use. Advise patients to follow sharps disposal recommendations.
- Advise patients to discontinue dupilumab and to seek immediate medical attention if they experience any symptoms of systemic hypersensitivity reactions.
- Advise patients to consult their healthcare provider if new onset or worsening eye symptoms develop.
- Advise patients with comorbid asthma not to adjust or stop their asthma treatment without talking to their physicians.
# Precautions with Alcohol
Alcohol-Dupilumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Dupixent
# Look-Alike Drug Names
There is limited information regarding Dupilumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Dupilumab | |
30ca5689260efec1d452b5cc1aec9403d3ed72ad | wikidoc | Dust cell | Dust cell
A dust cell (or alveolar macrophage) is a type of macrophage found in the pulmonary alveolus, near the pneumocytes, but separated from the wall.
Activity of the dust cells is relatively high, because they are located at one of the major boundaries between the body and the outside world.
Dust cells are another name for monocyte derivatives in the lungs that reside on respiratory surfaces and clean off particles such as dust or microorganisms.
Dust cells are frequently seen to contain granules of inorganic material such as carbon that they have picked up from respiratory surfaces. Such black granules may be especially common in smoker's lungs or long-term city dwellers. | Dust cell
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A dust cell (or alveolar macrophage) is a type of macrophage found in the pulmonary alveolus, near the pneumocytes, but separated from the wall.
Activity of the dust cells is relatively high, because they are located at one of the major boundaries between the body and the outside world.
Dust cells are another name for monocyte derivatives in the lungs that reside on respiratory surfaces and clean off particles such as dust or microorganisms.
Dust cells are frequently seen to contain granules of inorganic material such as carbon that they have picked up from respiratory surfaces. Such black granules may be especially common in smoker's lungs or long-term city dwellers.
# External links
- Template:EMedicineDictionary
- Histology image: 13906loa – Histology Learning System at Boston University - "Respiratory System: lung (human), alveolar macrophages"
- Template:Dorlands
- Histology at KUMC resp-resp16 "Alveoli"
- Slide at uchc.edu
- Slide at ufl.edu
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Dust_cell | |
c886623664b2c4acdf18182c8145b766d786224a | wikidoc | Dynorphin | Dynorphin
Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” This 32-amino acid molecule consists of both dynorphin A and dynorphin B.
Dynorphin A, dynorphin B, and big dynorphin all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively). Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the hypothalamus, medulla, pons, midbrain, and spinal cord. Dynorphins are stored in large (80-120 nm diameter) dense-core vesicles that are considerably larger than vesicles storing neurotransmitters. These large dense-core vesicles differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the synaptic cleft. Dense-core vesicle storage is characteristic of opioid peptides storage.
The first clues to the functionality of dynorphins came from Goldstein et al. in their work with opioid peptides. The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate. By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide. Goldstein et al. applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide. The peptide was called dynorphin (from the Greek dynamis=power) to describe its potency.
Dynorphins exert their effects primarily through the κ-opioid receptor (KOR), a G-protein-coupled receptor. Two subtypes of KORs have been identified: K1 and K2. Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the μ-opioid receptor (MOR), δ-opioid receptor (DOR), and the N-methyl-D-aspartic acid (NMDA)-type glutamate receptor. Different dynorphins show different receptor selectivities and potencies at receptors. Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin. Big dynorphin is more potent at KORs than is dynorphin A. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B.
# Production
Dynorphin is produced in many different parts of the brain, including the hypothalamus, the striatum, the hippocampus and the spinal cord. Gene expression patterns from the Allen Brain Atlases in mouse, macaque and humans can be seen here.
Dynorphin has many different physiological actions, depending upon its site of production.
- For example, dynorphin that is made in magnocellular vasopressin neurons of the supraoptic nucleus is important in the patterning of electrical activity. Dynorphin produced in magnocellular oxytocin neurons is a negative feedback inhibitor of oxytocin secretion.
- Dynorphin produced in the arcuate nucleus and in orexin neurons of the lateral hypothalamus affects the control of appetite.
# Analgesia
Dynorphin has been shown to be a modulator of pain response. Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency. Analgesia was partially eliminated by opioid antagonist naloxone.
Han and Xie found dynorphin to be 6-10 times more potent than morphine on a per mole basis. In addition, morphine tolerance did not reduce dynorphin-induced analgesia. Ren et al. demonstrated some of the complexities related to dynorphin induced analgesia. The authors found that combining subanalgesic levels of morphine and dynorphin A1-13, a version of dynorphin A containing only the first 13 amino acids of the peptide, in the rat spinal cord had additive effects. However, when dynorphin A1-13 was injected into the intracerebroventriulcar (ICV) region of the brain, it had an antagonist effect on morphine-induced analgesia.
A study by Lai et al. found that dynorphin might actually stimulate pain. The group found that it acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors. Lai et al. studied the effects of dynorphin A2-13 that did not contain the N-terminal tyrosine. Based on the results of dynorphin A2-13, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response.
According to this mechanism, dynorphin activates bradykinin receptors, which triggers the release of calcium ions into the cell through voltage-sensitive channels in the cell membrane. Blocking bradykinin receptors in the lumbar region of the spinal cord reversed persistent pain. A multiple pathway system might help explain the conflicting effects of dynorphin in the CNS.
Svensson et al. provided another possible mechanism by which dynorphin might cause pain in the spinal cord. The authors found that administration of truncated dynorphin A2-17, which does not bind to opioid receptors, causes an increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) in microglia in the dorsal horn of the spinal cord. Activated p38 has been previously linked to the NMDA-evoked prostaglandin release, which causes pain. Thus, dynorphin could also induce pain in the spinal cord through a non-opioid p38 pathway.
Other studies have identified a role for dynorphin and kappa opioid receptor stimulation in neuropathic pain. This same group also showed that the dynorphin-KOR system mediates astrocyte proliferation through the activation of p38 MAPK that was required for the effects of neuropathic pain on analgesic responses. Taken together, these reports suggest that dynorphin can elicit multiple effects on both Kappa opioid, and non-opioid pathways to modulate analgesic responses.
# Addiction
Cocaine addiction results from complex molecular changes in the brain following multiple exposures to cocaine. Dynorphins have been shown to be an important part of this process. Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures to the drug increases dynorphin concentrations in the striatum and substantia nigra in rats.
One proposed molecular mechanism for increased dynorphin levels involves transcriptional regulation by CREB (3’, 5’-monophosphate response element binding protein). According to the model proposed by Carlezon et al., use of cocaine increases the expression of cAMP and cAMP-dependent protein kinase (PKA). PKA leads to the activation of CREB, which increases the expression of dynorphin in the nucleus accumbens and dorsal striatum, brain areas important in addiction. Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals.
## Cocaine
Carlezon et al. performed several experiments to validate this model. They found that, when mice were injected with cocaine, they preferred to be in the place where they were injected (showed stronger place preference) significantly more than control mice (injected with saline) did. However, in mice overexpressing CREB under a constitutive promoter, place aversion was observed. This indicates that increasing CREB reverses the positive effects of cocaine. Northern blot analysis several days after CREB overexpression showed a marked increase in dynorphin mRNA in the nucleus accumbens.
Blocking KORs with an antagonist (norBNI) blocked the aversive effects caused by CREB overexpression. Thus, cocaine use ultimately appears to lead to an increase in the transcription of prodynorphin mRNA. Dynorphin inhibits dopamine release, which could account the reinforcing properties of cocaine.
There is also evidence suggesting that increased amounts of dynorphin can protect humans from cocaine addiction. According to research at Rockefeller University, the gene for dynorphin is present in two versions: a “high output” and a “low output” functional variation. The high output functional variation of the gene contains polymorphisms in the promoter regions that are speculated to cause it to produce more copies of dynorphin mRNA, which would give people carrying this variation a “built-in defense system” against drug addiction.
# Stress and depression
Land et al. first described a mechanism of dysphoria in which corticotropin-releasing factor (CRF) provokes dynorphin release. While control mice displayed aversive behaviors in response to forced swim tests and foot shocks, mice lacking dynorphin did not show any such signs of aversion. They noted that injecting CRF led to aversive behaviors in mice with functional genes for dynorphin even in the absence of stress, but not in those with dynorphin gene deletions. Place aversion was eliminated when the receptor CRF2 was blocked with an antagonist.
Together these results led Land et al. to conclude that dysphoric elements of stress occur when CRF2 stimulates dynorphin release and activates KOR. The group further postulated that this pathway might be involved in drug seeking behavior. In support of this, it was shown previously that stress can reinstate cocaine-seeking behavior in mice through a CRF mechanism.
Dynorphin has also been shown to influence drug seeking behavior and is required for stress-induced, but not prime-induced, reinstatement of cocaine seeking. A downstream element of this pathway was later identified by Bruchas et al. The authors found that KOR activates p38, a member of the mitogen-activated protein kinase (MAPK) family, through phosphorylation. Activation of p38 is necessary to produce KOR-dependent behaviors.
Because of its role in mediating dysphoria, dynorphin has also been investigated in relation to depression. Newton et al. studied the effects of CREB and dynorphin on learned helplessness (an animal model for depression) in mice. Overexpression of dominant negative CREB (mCREB) in transgenic mice had an antidepressant effect (in terms of behavior), whereas overexpressing wild-type CREB caused an increase in depression-like symptoms. As described previously, CREB increases transcription of prodynorphin, which gives rise to different dynorphin subtypes. Newton et al. supported this mechanism, as the mCREB was colocalized with decreased expression of prodynorphin. Also, direct antagonism of dynorphin caused antidepressant-like effects similar to those seen with mCREB expression. Thus, the CREB-dynorphin pathway regulates mood as well as cocaine rewards.
Shirayama et al. used several animal depression models in rats to describe the effects of dynorphins A and B in depression. The authors found that learned helplessness increases the levels of dynorphins A and B in the hippocampus and nucleus accumbens and that injecting KOR antagonist norBNI induces recovery from learned helplessness. Immobilization stress causes increases in the levels of both dynorphins A and B in the hippocampus and nucleus accumbens. Forced swim stress increases the levels of dynorphin A in the hippocampus. Shirayama et al. concluded that both dynorphins A and B were important in stress response. The authors proposed several mechanisms to account for the effects of the KOR antagonist norBNI on learned helplessness. First, increased dynorphin levels block the release of glutamate, a neurotransmitter involved in plasticity in the hippocampus, which would inhibit new learning.
Blocking dynorphin effects would allow glutamate to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness. In addition, blocking dynorphin would enhance dopamine signaling and thus reduce depressive symptoms associated with stress. The authors suggest that KOR antagonists might have potential in treating depression in humans.
# Appetite and circadian rhythms
Dynorphins are important in maintaining homeostasis through appetite control and circadian rhythms. Przewlocki et al. found that, during the day, dynorphins are naturally elevated in the neurointermediate lobe of the pituitary (NI pituitary) and depressed in the hypothalamus. This pattern is reversed at night. In addition, mice deprived of food and water, or of water alone, had increased levels of dynorphin in the hypothalamus during the day. Deprivation of water alone also decreased the dynorphin levels in the NI pituitary. These findings led Przewlocki et al. to conclude that dynorphins are essential in maintaining homeostasis.
Dynorphin has been implicated as an appetite stimulant. A number of studies in rats have shown that increasing the dynorphin levels stimulates eating. Opioid antagonists, such as naloxone, can reverse the effects of elevated dynorphin. This inhibition is especially strong in obese animals or animals that have access to particularly appealing food. Inui et al. found that administering dynorphin to dogs increased both their food and water intake. Dynorphin plays a role in the eating behavior of hibernating animals. Nizeilski et al. examined dynorphin levels in the ground squirrel, which undergoes periods of excessive eating and periods of starvation before winter. They found that dynorphin levels increased during the starvation periods. Berman et al. studied the levels of dynorphin during periods of food restriction. The group found that while food did not alter the expression of dynorphin B, it increases dynorphin A levels in several rat brain regions (hypothalamus, nucleus accumbens, and bed nucleus of the stria terminalis).
Recent research on dynorphin knockout mice did not find differences between knockout and control animals in food intake, but found that fat storage was reduced in male knockout mice. Fatty acids were oxidized more quickly in knockout animals.
Studies have also shown that ingesting a high-fat diet increases the gene expression of dynorphin in the hypothalamus. Thus, dynorphin may cause overeating when a high-fat diet is available. Morley & Levine were the first to describe the role of opioid peptides in stress-related eating. In their study, mice had their tails pinched (causes stress), which induced eating. Stress-related eating was reduced by injecting naloxone, an opioid peptide antagonist.
Mandenoff et al. proposed that, although endogenous opioids are not necessary to maintain body weight and energy expenditure under predictable circumstances, they become activated under stressful conditions. They found that endogenous opioids, such as dynorphin, stimulate appetite and decrease energy expenditure. Taken together, the studies above suggest an important evolutionary mechanism in which more food is eaten, more nutrients are stored, and less energy is expended by an organism during times of stress.
# Temperature regulation
In addition to their role in weight control, dynorphins have been found to regulate body temperature. Opioid peptides were first investigated in hyperthermia, where it was found that MOR agonists stimulate this response when injected into the periaqueductal gray (PAG) region of the brain. Xin et al. showed that delivery of dynorphin A1-17 (a KOR agonist) through microdialysis into the PAG region induced hypothermia in rats. The authors found that the severity of hypothermia was proportional to the dose of dynorphin A1-17 administered. Hypothermia could be prevented by administering KOR antagonist norBNI to the rat. Xin et al. hypothesized that while MOR agonists mediate hyperthermia, KOR agonists, such as dynorphin, mediate hypothermia.
Sharma and Alm found that subjecting rats to heat (38˚C) caused dynorphins to be upregulated in the cerebral cortex, hippocampus, cerebellum, and the brain stem. Further, authors found that administration of nitric oxide synthase (NOS) inhibitors reduced dynorphin A1-17 levels in the brain and attenuated symptoms related to heat stress. Sharma and Alm concluded that hyperthermia increases dynorphin levels, which may cause damage and promote heat stress reaction. They further hypothesized that nitric oxide was part of this mechanism. Ansonoff et al. found that hypothermic effects are mediated through K1 (κ-opioid receptor 1), but not K2. The authors applied a KOR agonist to K1 knockout mice, which eliminated hypothermic response. Thus, K2 does not appear to have a role in the hypothermic mechanism
# Clinical significance
Dynorphin derivatives are generally considered to be of little clinical use because of their very short duration of action. | Dynorphin
Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin.[1] Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal.[2] Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” This 32-amino acid molecule consists of both dynorphin A and dynorphin B.[3]
Dynorphin A, dynorphin B, and big dynorphin all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively).[4] Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the hypothalamus, medulla, pons, midbrain, and spinal cord.[5] Dynorphins are stored in large (80-120 nm diameter) dense-core vesicles that are considerably larger than vesicles storing neurotransmitters. These large dense-core vesicles differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the synaptic cleft. Dense-core vesicle storage is characteristic of opioid peptides storage.[6]
The first clues to the functionality of dynorphins came from Goldstein et al.[7] in their work with opioid peptides. The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate. By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide. Goldstein et al.[7] applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide. The peptide was called dynorphin (from the Greek dynamis=power) to describe its potency.[7]
Dynorphins exert their effects primarily through the κ-opioid receptor (KOR), a G-protein-coupled receptor. Two subtypes of KORs have been identified: K1 and K2.[3] Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the μ-opioid receptor (MOR), δ-opioid receptor (DOR), and the N-methyl-D-aspartic acid (NMDA)-type glutamate receptor.[6][8] Different dynorphins show different receptor selectivities and potencies at receptors. Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin. Big dynorphin is more potent at KORs than is dynorphin A. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B.[9]
# Production
Dynorphin is produced in many different parts of the brain, including the hypothalamus, the striatum, the hippocampus and the spinal cord. Gene expression patterns from the Allen Brain Atlases in mouse, macaque and humans can be seen here.
Dynorphin has many different physiological actions, depending upon its site of production.[10]
- For example, dynorphin that is made in magnocellular vasopressin neurons of the supraoptic nucleus is important in the patterning of electrical activity. Dynorphin produced in magnocellular oxytocin neurons is a negative feedback inhibitor of oxytocin secretion.[10]
- Dynorphin produced in the arcuate nucleus and in orexin neurons of the lateral hypothalamus affects the control of appetite.[10]
# Analgesia
Dynorphin has been shown to be a modulator of pain response. Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency.[11] Analgesia was partially eliminated by opioid antagonist naloxone.[11]
Han and Xie found dynorphin to be 6-10 times more potent than morphine on a per mole basis.[11] In addition, morphine tolerance did not reduce dynorphin-induced analgesia.[11] Ren et al. demonstrated some of the complexities related to dynorphin induced analgesia.[12] The authors found that combining subanalgesic levels of morphine and dynorphin A1-13, a version of dynorphin A containing only the first 13 amino acids of the peptide, in the rat spinal cord had additive effects. However, when dynorphin A1-13 was injected into the intracerebroventriulcar (ICV) region of the brain, it had an antagonist effect on morphine-induced analgesia.
A study by Lai et al. found that dynorphin might actually stimulate pain.[8] The group found that it acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors.[8] Lai et al. studied the effects of dynorphin A2-13 that did not contain the N-terminal tyrosine. Based on the results of dynorphin A2-13, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response.[8]
According to this mechanism, dynorphin activates bradykinin receptors, which triggers the release of calcium ions into the cell through voltage-sensitive channels in the cell membrane.[8] Blocking bradykinin receptors in the lumbar region of the spinal cord reversed persistent pain.[8] A multiple pathway system might help explain the conflicting effects of dynorphin in the CNS.
Svensson et al. provided another possible mechanism by which dynorphin might cause pain in the spinal cord.[13] The authors found that administration of truncated dynorphin A2-17, which does not bind to opioid receptors, causes an increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) in microglia in the dorsal horn of the spinal cord. Activated p38 has been previously linked to the NMDA-evoked prostaglandin release, which causes pain.[14] Thus, dynorphin could also induce pain in the spinal cord through a non-opioid p38 pathway.
Other studies have identified a role for dynorphin and kappa opioid receptor stimulation in neuropathic pain.[15] This same group also showed that the dynorphin-KOR system mediates astrocyte proliferation through the activation of p38 MAPK that was required for the effects of neuropathic pain on analgesic responses.[16] Taken together, these reports suggest that dynorphin can elicit multiple effects on both Kappa opioid, and non-opioid pathways to modulate analgesic responses.
# Addiction
Cocaine addiction results from complex molecular changes in the brain following multiple exposures to cocaine.[17] Dynorphins have been shown to be an important part of this process. Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures to the drug increases dynorphin concentrations in the striatum and substantia nigra in rats.[18]
One proposed molecular mechanism for increased dynorphin levels involves transcriptional regulation by CREB (3’, 5’-monophosphate response element binding protein). According to the model proposed by Carlezon et al., use of cocaine increases the expression of cAMP and cAMP-dependent protein kinase (PKA).[19] PKA leads to the activation of CREB, which increases the expression of dynorphin in the nucleus accumbens and dorsal striatum, brain areas important in addiction.[19] Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals.[20]
## Cocaine
Carlezon et al.[19] performed several experiments to validate this model. They found that, when mice were injected with cocaine, they preferred to be in the place where they were injected (showed stronger place preference) significantly more than control mice (injected with saline) did. However, in mice overexpressing CREB under a constitutive promoter, place aversion was observed.[19] This indicates that increasing CREB reverses the positive effects of cocaine. Northern blot analysis several days after CREB overexpression showed a marked increase in dynorphin mRNA in the nucleus accumbens.[19]
Blocking KORs with an antagonist (norBNI) blocked the aversive effects caused by CREB overexpression.[19] Thus, cocaine use ultimately appears to lead to an increase in the transcription of prodynorphin mRNA. Dynorphin inhibits dopamine release, which could account the reinforcing properties of cocaine.[21]
There is also evidence suggesting that increased amounts of dynorphin can protect humans from cocaine addiction. According to research at Rockefeller University, the gene for dynorphin is present in two versions: a “high output” and a “low output” functional variation.[22] The high output functional variation of the gene contains polymorphisms in the promoter regions that are speculated to cause it to produce more copies of dynorphin mRNA, which would give people carrying this variation a “built-in defense system” against drug addiction.[22]
# Stress and depression
Land et al. first described a mechanism of dysphoria in which corticotropin-releasing factor (CRF) provokes dynorphin release.[23] While control mice displayed aversive behaviors in response to forced swim tests and foot shocks, mice lacking dynorphin did not show any such signs of aversion. They noted that injecting CRF led to aversive behaviors in mice with functional genes for dynorphin even in the absence of stress, but not in those with dynorphin gene deletions. Place aversion was eliminated when the receptor CRF2 was blocked with an antagonist.[23]
Together these results led Land et al. to conclude that dysphoric elements of stress occur when CRF2 stimulates dynorphin release and activates KOR.[23] The group further postulated that this pathway might be involved in drug seeking behavior. In support of this, it was shown previously that stress can reinstate cocaine-seeking behavior in mice through a CRF mechanism.[24]
Dynorphin has also been shown to influence drug seeking behavior and is required for stress-induced, but not prime-induced, reinstatement of cocaine seeking.[25][26] A downstream element of this pathway was later identified by Bruchas et al.[27] The authors found that KOR activates p38, a member of the mitogen-activated protein kinase (MAPK) family, through phosphorylation. Activation of p38 is necessary to produce KOR-dependent behaviors.[27]
Because of its role in mediating dysphoria, dynorphin has also been investigated in relation to depression. Newton et al.[28] studied the effects of CREB and dynorphin on learned helplessness (an animal model for depression) in mice. Overexpression of dominant negative CREB (mCREB) in transgenic mice had an antidepressant effect (in terms of behavior), whereas overexpressing wild-type CREB caused an increase in depression-like symptoms.[28] As described previously, CREB increases transcription of prodynorphin, which gives rise to different dynorphin subtypes.[19] Newton et al.[28] supported this mechanism, as the mCREB was colocalized with decreased expression of prodynorphin. Also, direct antagonism of dynorphin caused antidepressant-like effects similar to those seen with mCREB expression.[28] Thus, the CREB-dynorphin pathway regulates mood as well as cocaine rewards.
Shirayama et al.[29] used several animal depression models in rats to describe the effects of dynorphins A and B in depression. The authors found that learned helplessness increases the levels of dynorphins A and B in the hippocampus and nucleus accumbens and that injecting KOR antagonist norBNI induces recovery from learned helplessness. Immobilization stress causes increases in the levels of both dynorphins A and B in the hippocampus and nucleus accumbens.[29] Forced swim stress increases the levels of dynorphin A in the hippocampus. Shirayama et al.[29] concluded that both dynorphins A and B were important in stress response. The authors proposed several mechanisms to account for the effects of the KOR antagonist norBNI on learned helplessness. First, increased dynorphin levels block the release of glutamate, a neurotransmitter involved in plasticity in the hippocampus, which would inhibit new learning.[29]
Blocking dynorphin effects would allow glutamate to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness. In addition, blocking dynorphin would enhance dopamine signaling and thus reduce depressive symptoms associated with stress.[29] The authors suggest that KOR antagonists might have potential in treating depression in humans.
# Appetite and circadian rhythms
Dynorphins are important in maintaining homeostasis through appetite control and circadian rhythms. Przewlocki et al.[30] found that, during the day, dynorphins are naturally elevated in the neurointermediate lobe of the pituitary (NI pituitary) and depressed in the hypothalamus. This pattern is reversed at night.[30] In addition, mice deprived of food and water, or of water alone, had increased levels of dynorphin in the hypothalamus during the day.[30] Deprivation of water alone also decreased the dynorphin levels in the NI pituitary.[30] These findings led Przewlocki et al.[30] to conclude that dynorphins are essential in maintaining homeostasis.
Dynorphin has been implicated as an appetite stimulant. A number of studies[31] in rats have shown that increasing the dynorphin levels stimulates eating. Opioid antagonists, such as naloxone, can reverse the effects of elevated dynorphin.[32] This inhibition is especially strong in obese animals or animals that have access to particularly appealing food.[33] Inui et al.[34] found that administering dynorphin to dogs increased both their food and water intake. Dynorphin plays a role in the eating behavior of hibernating animals. Nizeilski et al.[35] examined dynorphin levels in the ground squirrel, which undergoes periods of excessive eating and periods of starvation before winter. They found that dynorphin levels increased during the starvation periods. Berman et al.[36] studied the levels of dynorphin during periods of food restriction. The group found that while food did not alter the expression of dynorphin B, it increases dynorphin A levels in several rat brain regions (hypothalamus, nucleus accumbens, and bed nucleus of the stria terminalis).
Recent research on dynorphin knockout mice did not find differences between knockout and control animals in food intake, but found that fat storage was reduced in male knockout mice.[37] Fatty acids were oxidized more quickly in knockout animals.[37]
Studies have also shown that ingesting a high-fat diet increases the gene expression of dynorphin in the hypothalamus.[38] Thus, dynorphin may cause overeating when a high-fat diet is available.[38][39] Morley & Levine were the first to describe the role of opioid peptides in stress-related eating. In their study, mice had their tails pinched (causes stress), which induced eating. Stress-related eating was reduced by injecting naloxone, an opioid peptide antagonist.[39]
Mandenoff et al.[33] proposed that, although endogenous opioids are not necessary to maintain body weight and energy expenditure under predictable circumstances, they become activated under stressful conditions. They found that endogenous opioids, such as dynorphin, stimulate appetite and decrease energy expenditure. Taken together, the studies above suggest an important evolutionary mechanism in which more food is eaten, more nutrients are stored, and less energy is expended by an organism during times of stress.
# Temperature regulation
In addition to their role in weight control, dynorphins have been found to regulate body temperature. Opioid peptides were first investigated in hyperthermia, where it was found that MOR agonists stimulate this response when injected into the periaqueductal gray (PAG) region of the brain.[3] Xin et al.[40] showed that delivery of dynorphin A1-17 (a KOR agonist) through microdialysis into the PAG region induced hypothermia in rats. The authors found that the severity of hypothermia was proportional to the dose of dynorphin A1-17 administered. Hypothermia could be prevented by administering KOR antagonist norBNI to the rat.[40] Xin et al.[40] hypothesized that while MOR agonists mediate hyperthermia, KOR agonists, such as dynorphin, mediate hypothermia.
Sharma and Alm[41] found that subjecting rats to heat (38˚C) caused dynorphins to be upregulated in the cerebral cortex, hippocampus, cerebellum, and the brain stem. Further, authors found that administration of nitric oxide synthase (NOS) inhibitors reduced dynorphin A1-17 levels in the brain and attenuated symptoms related to heat stress. Sharma and Alm[41] concluded that hyperthermia increases dynorphin levels, which may cause damage and promote heat stress reaction. They further hypothesized that nitric oxide was part of this mechanism. Ansonoff et al.[42] found that hypothermic effects are mediated through K1 (κ-opioid receptor 1), but not K2. The authors applied a KOR agonist to K1 knockout mice, which eliminated hypothermic response. Thus, K2 does not appear to have a role in the hypothermic mechanism
# Clinical significance
Dynorphin derivatives are generally considered to be of little clinical use because of their very short duration of action.[43] | https://www.wikidoc.org/index.php/Dynorphin | |
49d6adb5c1778d5ee4a220706150fec4bb1d840b | wikidoc | Dysbindin | Dysbindin
Dysbindin, short for dystrobrevin-binding protein 1, is a protein constituent of the dystrophin-associated protein complex (DPC) of skeletal muscle cells. It is also a part of BLOC-1, or biogenesis of lysosome-related organelles complex 1. Dysbindin was discovered by the research group of Derek Blake via yeast two-hybrid screening for binding partners of α-dystrobrevin. In addition, dysbindin is found in neural tissue of the brain, particularly in axon bundles and especially in certain axon terminals, notably mossy fiber synaptic terminals in the cerebellum and hippocampus. In humans, dysbindin is encoded by the DTNBP1 gene.
# Clinical significance
Much interest in dysbindin has arisen through pedigree-based family-association studies of families with a history of schizophrenia, where a strong association was found between expression of a particular dysbindin allele and a clinical expression of schizophrenia. However, the genetic link between dysbindin and schizophrenia has not been established in all the case control samples tested and this implies that there are different genetic subtypes of schizophrenia with different disease allele frequencies in different populations. This phenomenon is called genetic locus heterogeneity and is typical of all common disorders with a strong genetic component. A further complication is that it is highly likely that there are several or many different mutations within the dysbindin gene that are responsible for schizophrenia. This complexity is called
disease allele heterogeneity and is a further reason that genetic associations are found with different markers in the dysbindin gene when different samples are studied.
Genetically caused dysbindin-related mechanisms causing brain dysfunction are not fully known, but in one study, schizophrenic patients carrying the high-risk haplotype demonstrated visual processing deficits. In another work, damping down the DTNBP1 expression led to an increase in cell surface dopamine D2-receptor levels.
Mutation in the DTNBP1 gene was also shown to cause Hermansky–Pudlak syndrome type 7.
In drosophila, dysbindin has been shown to be essential for neural plasticity.
# Interactions
Dysbindin has been shown to interact with SNAPAP, MUTED and PLDN. | Dysbindin
Dysbindin, short for dystrobrevin-binding protein 1, is a protein constituent of the dystrophin-associated protein complex (DPC) of skeletal muscle cells. It is also a part of BLOC-1, or biogenesis of lysosome-related organelles complex 1. Dysbindin was discovered by the research group of Derek Blake via yeast two-hybrid screening for binding partners of α-dystrobrevin.[1] In addition, dysbindin is found in neural tissue of the brain, particularly in axon bundles and especially in certain axon terminals, notably mossy fiber synaptic terminals in the cerebellum and hippocampus.[1] In humans, dysbindin is encoded by the DTNBP1 gene.[1]
# Clinical significance
Much interest in dysbindin has arisen through pedigree-based family-association studies of families with a history of schizophrenia, where a strong association was found between expression of a particular dysbindin allele and a clinical expression of schizophrenia.[2] However, the genetic link between dysbindin and schizophrenia has not been established in all the case control samples tested and this implies that there are different genetic subtypes of schizophrenia with different disease allele frequencies in different populations. This phenomenon is called genetic locus heterogeneity and is typical of all common disorders with a strong genetic component. A further complication is that it is highly likely that there are several or many different mutations within the dysbindin gene that are responsible for schizophrenia. This complexity is called
disease allele heterogeneity and is a further reason that genetic associations are found with different markers in the dysbindin gene when different samples are studied.
Genetically caused dysbindin-related mechanisms causing brain dysfunction are not fully known, but in one study, schizophrenic patients carrying the high-risk haplotype demonstrated visual processing deficits.[3] In another work, damping down the DTNBP1 expression led to an increase in cell surface dopamine D2-receptor levels.[4]
Mutation in the DTNBP1 gene was also shown to cause Hermansky–Pudlak syndrome type 7.[5]
In drosophila, dysbindin has been shown to be essential for neural plasticity.[6]
# Interactions
Dysbindin has been shown to interact with SNAPAP,[7] MUTED[7] and PLDN.[7] | https://www.wikidoc.org/index.php/Dysbindin | |
1f4451c9286f562089a575719d537b49b93e6836 | wikidoc | Dysferlin | Dysferlin
Dysferlin also known as dystrophy-associated fer-1-like protein is a protein that in humans is encoded by the DYSF gene.
Dysferlin is linked with skeletal muscle repair. A defect in the DYSF gene, located on chromosome 2p12-14, results in several types of muscular dystrophy; including Miyoshi myopathy (MM), Limb-girdle muscular dystrophy type 2B (LGMD2B) and Distal Myopathy (DM). A reduction or absence of dysferlin, termed dysferlinopathy, usually becomes apparent in the third or fourth decade of life and is characterised by weakness and wasting of various voluntary skeletal muscles.
# Structure
The human dysferlin protein is a 237 kilodalton type-II transmembrane protein. It contains a large intracellular cytoplasmic N-terminal domain, an extreme C-terminal transmembrane domain, and a short C-terminal extracellular domain. The cytosolic domain of dysferlin is composed of seven highly conserved C2 domains (C2A-G) which are conserved across several proteins within the ferlin family, including dysferlin homolog myoferlin. In fact, the C2 domain at any given position is more similar to the C2 domain at the corresponding position within other ferlin family members than the adjacent C2 domain within the same protein. This suggests that each individual C2 domain may in fact play a specific role in dysferlin function. A crystal structure of the C2A domain of human dysferlin has been solved, and reveals that the C2A domain changes conformation when interacting with calcium ions, which is consistent with a growing body of evidence suggesting that the C2A domain plays a role in calcium-dependent lipid binding. In addition to the C2 domains, dysferlin also contains "FerA" and "DysF" domains. Mutations in both FerA and DysF can cause muscular dystrophies. DysF domain has an interesting structure as in contains one DysF domain within another DysF domain, a result of gene duplication; however, the function of this domain is currently unknown. FerA domain is conserved among all members of ferlin protein family. There has been two single point mutations in dysferlin FerA domain that have been associated with muscular dystrophy. FerA domain is a four helix bundle and it can interact with membrane, usually in a calcium-dependent manner.
# Function
The most intensively studied role for dysferlin is in a cellular process called membrane repair. Membrane repair is a critical mechanism by which cells are able to seal dramatic wounds to the plasma membrane. Muscle is thought to be particularly prone to membrane wounds given that muscle cells transmit high force and undergo cycles of contraction. Dysferlin is highly expressed in muscle, and is homologous to the ferlin family of proteins, which are thought to regulate membrane fusion across a wide variety of species and cell types. Several lines of evidence suggest that dysferlin may be involved in membrane repair in muscle. First, dysferlin-deficient muscle fibers show accumulation of vesicles (which are critical for membrane repair in non-muscle cell types) near membrane lesions, indicating that dysferlin may be required for fusion of repair vesicles with the plasma membrane. Further, dysferlin-deficient muscle fibers take up extracellular dyes to a greater extent than wild-type muscle fibers following laser-induced wounding in-vitro. Dysferlin is also markedly enriched at membrane lesions with several additional proteins thought to be involved in membrane resealing, including annexin and MG53. Exactly how dysferlin contributes to membrane resealing is not clear, but biochemical evidence indicates that dysferlin may bind lipids in a calcium-dependent manner, consistent with a role for dysferlin in regulating fusion of repair vesicles with the sarcolemma during membrane repair. Furthermore, live-cell imaging of dysferlin-eGFP expressing myotubes indicates that dysferlin localizes to a cellular compartment that responds to injury by forming large dysferlin-containing vesicles, and formation of these vesicles may contribute to wound repair. Dysferlin may also be involved in Alzheimer's disease pathogenesis.
# Interactions
Dysferlin has been shown to interact with Caveolin 3 in skeletal muscle, and this interaction is thought to retain dysferlin within the plasma membrane. Dysferlin also interacts with MG53, and a functional interaction between dysferlin, caveolin-3 and MG53 is thought to be critical for membrane repair in skeletal muscle. | Dysferlin
Dysferlin also known as dystrophy-associated fer-1-like protein is a protein that in humans is encoded by the DYSF gene.[1]
Dysferlin is linked with skeletal muscle repair.[2] A defect in the DYSF gene, located on chromosome 2p12-14, results in several types of muscular dystrophy; including Miyoshi myopathy (MM), Limb-girdle muscular dystrophy type 2B (LGMD2B) and Distal Myopathy (DM). A reduction or absence of dysferlin, termed dysferlinopathy, usually becomes apparent in the third or fourth decade of life and is characterised by weakness and wasting of various voluntary skeletal muscles.[3]
# Structure
The human dysferlin protein is a 237 kilodalton type-II transmembrane protein.[4][5][6][7][8] It contains a large intracellular cytoplasmic N-terminal domain, an extreme C-terminal transmembrane domain, and a short C-terminal extracellular domain. The cytosolic domain of dysferlin is composed of seven highly conserved C2 domains (C2A-G) which are conserved across several proteins within the ferlin family, including dysferlin homolog myoferlin.[9][10][5] In fact, the C2 domain at any given position is more similar to the C2 domain at the corresponding position within other ferlin family members than the adjacent C2 domain within the same protein. This suggests that each individual C2 domain may in fact play a specific role in dysferlin function. A crystal structure of the C2A domain of human dysferlin has been solved, and reveals that the C2A domain changes conformation when interacting with calcium ions,[5] which is consistent with a growing body of evidence suggesting that the C2A domain plays a role in calcium-dependent lipid binding.[11] In addition to the C2 domains, dysferlin also contains "FerA" and "DysF" domains. Mutations in both FerA[12] and DysF[13] can cause muscular dystrophies. DysF domain has an interesting structure as in contains one DysF domain within another DysF domain, a result of gene duplication; however, the function of this domain is currently unknown.[13] FerA domain is conserved among all members of ferlin protein family. There has been two single point mutations in dysferlin FerA domain that have been associated with muscular dystrophy. FerA domain is a four helix bundle and it can interact with membrane, usually in a calcium-dependent manner.[12]
# Function
The most intensively studied role for dysferlin is in a cellular process called membrane repair. Membrane repair is a critical mechanism by which cells are able to seal dramatic wounds to the plasma membrane. Muscle is thought to be particularly prone to membrane wounds given that muscle cells transmit high force and undergo cycles of contraction. Dysferlin is highly expressed in muscle, and is homologous to the ferlin family of proteins, which are thought to regulate membrane fusion across a wide variety of species and cell types.[14] Several lines of evidence suggest that dysferlin may be involved in membrane repair in muscle. First, dysferlin-deficient muscle fibers show accumulation of vesicles (which are critical for membrane repair in non-muscle cell types) near membrane lesions, indicating that dysferlin may be required for fusion of repair vesicles with the plasma membrane. Further, dysferlin-deficient muscle fibers take up extracellular dyes to a greater extent than wild-type muscle fibers following laser-induced wounding in-vitro.[15] Dysferlin is also markedly enriched at membrane lesions with several additional proteins thought to be involved in membrane resealing, including annexin and MG53.[16] Exactly how dysferlin contributes to membrane resealing is not clear, but biochemical evidence indicates that dysferlin may bind lipids in a calcium-dependent manner, consistent with a role for dysferlin in regulating fusion of repair vesicles with the sarcolemma during membrane repair.[17] Furthermore, live-cell imaging of dysferlin-eGFP expressing myotubes indicates that dysferlin localizes to a cellular compartment that responds to injury by forming large dysferlin-containing vesicles, and formation of these vesicles may contribute to wound repair.[18] Dysferlin may also be involved in Alzheimer's disease pathogenesis.[19]
# Interactions
Dysferlin has been shown to interact with Caveolin 3 in skeletal muscle,[20] and this interaction is thought to retain dysferlin within the plasma membrane.[21] Dysferlin also interacts with MG53, and a functional interaction between dysferlin, caveolin-3 and MG53 is thought to be critical for membrane repair in skeletal muscle.[22] | https://www.wikidoc.org/index.php/Dysferlin | |
49b3497ed5d966cbea44012035c7654580daa50a | wikidoc | Dysmetria | Dysmetria
# Overview
Dysmetria (Greek: "difficult to measure") is a condition that describes a lack of coordination of movement typified by the undershoot and/or overshoot of intended position with the hand, arm, leg, or eye. It is sometimes described as an inability to judge distance or scale .
(From the Online Medical Dictionary) an aspect of ataxia, in which the ability to control the distance, power, and speed of an act is impaired. Usually used to describe abnormalities of movement caused by cerebellar disorders.
As dysmetria can refer to more than just a motor problem, an overlying definition that encompasses all forms of it is “the inability to receive and process information rapidly, to retrieve the relevant associated constructs, and to produce a well-modulated and fine-tuned response.”
Hypermetria describes undershooting intended position and hypometria describes overshooting intended position .
The cerebellum is the area of the brain that contributes to coordination and motor processes and is anatomically inferior to the cerebrum . Sensorimotor integration is the brain’s way of integrating the information received from the sensory (or proprioceptive) neurons from the body, including any visual information. To be more specific, information needed to perform a motor task comes from retinal information pertaining to the eyes’ position and has to be translated into spatial information . Sensorimotor integration is crucial for performing any motor task and takes place in the post parietal cortex . After the visual information has been translated into spatial information, the cerebellum must use this information to perform the motor task . If there is damage to any pathways that connect the pathways, dysmetria may result.
## Motor
Motor dysmetria is the customary term used when a person refers to dysmetria. Dysmetria of the extremities caused by hemispheric syndromes is manifested in multiple ways: dysrhythmic tapping of hands and feet and dysdiadochokinesis, which is the impairment of alternating movements .. Damage to the cerebellum makes a person slow to orient their extremities in space .
Motor Control as a Learning Process
Recent research has also shed light upon a specific process that if interrupted, may be the cause of ataxia and dysmetria. According to sources cited in this article, motor control is a learning process that occurs in the synapses of Purkinje dendrites . Research has shown that inhibitory synaptic connections are the primary way the learning occurs, as saturation would occur with excitatory synaptic transmission . There have been varying theories as to the makeup of the cerebellum, which controls this process . Some predicted that the cerebellum was an array of adjustable pattern generators (APGs), each of which generate a “burst command” with varying intensity and duration . Other models, which apply mostly in robotic applications, propose that the cerebellum acquires an “inverse model of the motor apparatus .” More recent research in electrophysiology has shown modular structures in the spinal cord known as “motor primitives .”
Based on the APG model, modules of APG are the features that control motor learning . The entire process is a positive feedback loop . Inhibitory input is transmitted and received from various components of the cortex, including the cerebellar nucleus, a motor cortical cell and Purkinje cells . Purkinje cells send the inhibitive information by obtaining learning information from parallel fibers of granule cells . This model of APGs is useful in that it effectively describes the motor learning process .
Motor primitives are another proposed module of motor learning . This information was found by electrical stimulation of the lumbar spinal cord in rats and frogs . Upon the stimulation, researchers found that motor primitives are found in the spinal cord and use patterns of muscle activation to generate a specific motor output . Different movements are learned from different levels of activation . These findings lead researchers to believe that these same motor primitives could be found in the cerebellum .
These two different models combined show that it is possible that motor primitives are in the cerebellum, because, “a set of parallel arrays of APG can drive each motor primitive module in the spinal cord .” The authors have generated a model of adjustable primitive pattern generator (APPG), which is basically a group of parallel APGs summed together .
The APPG model is a vector sum of all the inputs of the APG, which are units of position, velocity and time . Granule cells send information from the spinal cord and the motor cortex which in turn translates the information in a process called state mapping . The final model of the APPG becomes linear upon the vector summation of the information from the neurons and muscles . This model is consistent with the “virtual trajectory hypothesis” which states that the desired trajectory is sent to the spinal cord as a motor command .
## Saccadic
Saccadic eye movements are the very quick, simultaneous movements made by the eye to receive visual information and shift the line of vision from one position to another . A person depends profoundly on the ability of the accuracy of these movements .. The area of the brain that controls saccades is the superior colliculus, specifically the fastigial oculomotor region (FOR) .. The information is received from the retina, is translated into spatial information and is then transferred to motor centers for motor response. A person with saccadic dysmetria will constantly produce abnormal eye movements including microsaccades, ocular flutter, and square wave jerks even when the eye is at rest . During eye movements hypometric and hypermetric saccades will occur and interruption and slowing of normal saccadic movement is common .
## Cognitive
There have been many studies concerning the cerebellum’s role in cognitive processes. The cerebellum is connected to other higher-order areas of the brain and is therefore thought to take part in many cognitive processes . Previously there has been evidence that the cerebellum contributed to cognitive processes but with the development of functional magnetic resonance imaging (fMRI), researchers have proved that the cerebellum is associated with higher-order functions including attention, perception, and language . Some clinical studies have revealed that there is an association between the cerebellum and personality . Researchers have also been able to find correlations between cerebellar disorders and psychosis, especially schizophrenia . In particular, cerebellar cognitive affective syndrome (CCAS) is a cerebellar disorder that exhibits both motor dysfunction (including dysmetria: referred to as impaired spatial cognition), personality change, impairment of linguistic abilities, and disturbance of higher-order functions including reasoning and memory . It is believed that the there are specific pathways that link not only the prefrontal cortex, superior temporal regions, posterior parietal lobes, and hippocampus to the cerebellum, but there are also very specific pathways that link the cerebellum back to these areas of the brain . These loops may contribute to the cognitive properties of the cerebellum that have recently been discovered. A good definition of cognitive dysmetria, also referred to as dysmetria of thought, is “a difficulty in coordinating and monitoring the process of receiving, processing, and expressing information” . Cognitive dysmetria manifests itself in association with other cerebellar disorders .
# Causes
The actual cause of dysmetria is thought to be caused by lesions in the cerebellum or by lesions in the proprioceptive nerves that lead to the cerebellum that coordinate visual, spatial and other sensory information with motor control .. Damage to the proprioceptive nerves does not allow the cerebellum to accurately judge where the hand, arm, leg, or eye should move. These lesions are often caused by strokes, Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), or tumors .
According to the research article cited above, motor control is a learning process that utilizes APPGs . Disruption of APPGs is possibly the cause of ataxia and dysmetria and upon identification of the motor primitives, clinicians may be able to isolate the specific areas responsible for the cerebellar problems .
There are two types of cerebellar disorders that produce dysmetria, specifically midline cerebellar syndromes and hemispheric cerebellar syndromes . Midline cerebellar syndromes can cause ocular dysmetria, which is a condition in which the pupils of the eye overshoot . Ocular dysmetria makes it difficult to focus vision onto one object. Hemispheric cerebellar syndromes cause dysmetria in the typical motor sense that many think of when hearing the term dysmetria .
A common motor syndrome that causes dysmetria is cerebellar motor syndrome, which also marked by impairments in gait (also known as ataxia), disordered eye movements, tremor, difficulty swallowing and poor articulation . As stated above, cerebellar cognitive affective syndrome (CCAS) also causes dysmetria.
# Associated Diseases
Dysmetria is often found in individuals with Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and persons who have suffered from tumors or strokes. Persons who have been diagnosed with autosomal dominant spinocerebellar ataxia (SCAs) also exhibit dysmetria . SCAs are a type of cerebellar disease that is inherited. There are many types of SCAs and though many exhibit similar symptoms (one being dysmetria), they are considered to be heterogeneous . Freidrich’s ataxia is a well-known SCA in which children have dysmetria . It is also closely associated with schizophrenia and autism .
# Diagnosis
Diagnosis of any cerebellar disorder or syndrome should be made by a qualified neurologist. Prior to referring a patient to a neurologist, a general practitioner or MS nurse will perform a finger-to-nose test . The clinician will raise a finger in front of the patient and ask him to touch it with his finger and then touch his nose with his forefinger several times. This shows a patient’s ability to judge the position of a target. Other tests that could be performed are similar in nature and include a heel to shin test in which proximal overshoot characterizes dysmetria and an inability to draw an imaginary circle with the arms or legs without any decomposition of movement . After a positive result in the finger-to-nose test, a neurologist will do a magnetic resonance image (MRI) to determine any damage to the cerebellum .
# Treatments
Currently there is no cure for dysmetria itself as it is actually a symptom of an underlying disorder. However, Isoniazid and Clonazepam have been used to treat dysmetria . Cannabis has been used in trials in the U.K. and displayed some success, though it is not legal to use in the U.S. at this time .
## Research
Researchers now are testing different possibilities for treating dysmetria and ataxia. One opportunity for treatment is called rehearsal by eye movement . It is believed that visually guided movements require both lower- and higher-order visual functioning by first identifying a target location and then moving to acquire what is sought after . In one study, researchers used visually guided stepping which is parallel to visually guided arm movements to test this treatment . The patients suffered from saccadic dysmetria which in turn caused them to overshoot their movements 3. The patients first walked normally and were then told to twice review the area that was to be walked through 3. After rehearsal with eye movements, the patients improved their motor performance . Researchers believe that prior rehearsal with the eyes might be enough for a patient that suffers from motor dysmetria as a result of saccadic dysmetria to complete a motor task with enhanced spatial awareness .
Research has also been done for those patients that suffer from Multiple Sclerosis (MS) . Deep brain stimulation (DBS) remains a viable possibility for some MS patients though the long term effects of this treatment are currently under review . The subjects that have undergone this treatment had had no major relapse for 6 months and disabling motor function problems . Most subjects benefited from the implantation of the electrodes and some reported that their movement disorder was gone after surgery . However, these results are limiting at this time because of the small range of subjects that were used for the experiment and it is unknown whether this is a viable option for all MS patients that suffer from motor control problems . | Dysmetria
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dysmetria (Greek: "difficult to measure") is a condition that describes a lack of coordination of movement typified by the undershoot and/or overshoot of intended position with the hand, arm, leg, or eye. It is sometimes described as an inability to judge distance or scale [1].
(From the Online Medical Dictionary) an aspect of ataxia, in which the ability to control the distance, power, and speed of an act is impaired. Usually used to describe abnormalities of movement caused by cerebellar disorders.
As dysmetria can refer to more than just a motor problem, an overlying definition that encompasses all forms of it is “the inability to receive and process information rapidly, to retrieve the relevant associated constructs, and to produce a well-modulated and fine-tuned response.”[2]
Hypermetria describes undershooting intended position and hypometria describes overshooting intended position [3].
The cerebellum is the area of the brain that contributes to coordination and motor processes and is anatomically inferior to the cerebrum [2] [4]. Sensorimotor integration is the brain’s way of integrating the information received from the sensory (or proprioceptive) neurons from the body, including any visual information. To be more specific, information needed to perform a motor task comes from retinal information pertaining to the eyes’ position and has to be translated into spatial information . Sensorimotor integration is crucial for performing any motor task and takes place in the post parietal cortex [3] [4]. After the visual information has been translated into spatial information, the cerebellum must use this information to perform the motor task [2][5]. If there is damage to any pathways that connect the pathways, dysmetria may result.
## Motor
Motor dysmetria is the customary term used when a person refers to dysmetria. Dysmetria of the extremities caused by hemispheric syndromes is manifested in multiple ways: dysrhythmic tapping of hands and feet and dysdiadochokinesis, which is the impairment of alternating movements [5].. Damage to the cerebellum makes a person slow to orient their extremities in space [4].
Motor Control as a Learning Process
Recent research has also shed light upon a specific process that if interrupted, may be the cause of ataxia and dysmetria. According to sources cited in this article, motor control is a learning process that occurs in the synapses of Purkinje dendrites [6]. Research has shown that inhibitory synaptic connections are the primary way the learning occurs, as saturation would occur with excitatory synaptic transmission [6]. There have been varying theories as to the makeup of the cerebellum, which controls this process [6]. Some predicted that the cerebellum was an array of adjustable pattern generators (APGs), each of which generate a “burst command” with varying intensity and duration [6]. Other models, which apply mostly in robotic applications, propose that the cerebellum acquires an “inverse model of the motor apparatus [6].” More recent research in electrophysiology has shown modular structures in the spinal cord known as “motor primitives [6].”
Based on the APG model, modules of APG are the features that control motor learning [6]. The entire process is a positive feedback loop [6]. Inhibitory input is transmitted and received from various components of the cortex, including the cerebellar nucleus, a motor cortical cell and Purkinje cells [6]. Purkinje cells send the inhibitive information by obtaining learning information from parallel fibers of granule cells [6]. This model of APGs is useful in that it effectively describes the motor learning process [6].
Motor primitives are another proposed module of motor learning [6]. This information was found by electrical stimulation of the lumbar spinal cord in rats and frogs [6]. Upon the stimulation, researchers found that motor primitives are found in the spinal cord and use patterns of muscle activation to generate a specific motor output [6]. Different movements are learned from different levels of activation [6]. These findings lead researchers to believe that these same motor primitives could be found in the cerebellum [6].
These two different models combined show that it is possible that motor primitives are in the cerebellum, because, “a set of parallel arrays of APG can drive each motor primitive module in the spinal cord [6].” The authors have generated a model of adjustable primitive pattern generator (APPG), which is basically a group of parallel APGs summed together [6].
The APPG model is a vector sum of all the inputs of the APG, which are units of position, velocity and time [6]. Granule cells send information from the spinal cord and the motor cortex which in turn translates the information in a process called state mapping [6]. The final model of the APPG becomes linear upon the vector summation of the information from the neurons and muscles [6]. This model is consistent with the “virtual trajectory hypothesis” which states that the desired trajectory is sent to the spinal cord as a motor command [6].
## Saccadic
Saccadic eye movements are the very quick, simultaneous movements made by the eye to receive visual information and shift the line of vision from one position to another [7]. A person depends profoundly on the ability of the accuracy of these movements [7].. The area of the brain that controls saccades is the superior colliculus, specifically the fastigial oculomotor region (FOR) [7].. The information is received from the retina, is translated into spatial information and is then transferred to motor centers for motor response. A person with saccadic dysmetria will constantly produce abnormal eye movements including microsaccades, ocular flutter, and square wave jerks even when the eye is at rest [5]. During eye movements hypometric and hypermetric saccades will occur and interruption and slowing of normal saccadic movement is common [5].
## Cognitive
There have been many studies concerning the cerebellum’s role in cognitive processes. The cerebellum is connected to other higher-order areas of the brain and is therefore thought to take part in many cognitive processes [2]. Previously there has been evidence that the cerebellum contributed to cognitive processes but with the development of functional magnetic resonance imaging (fMRI), researchers have proved that the cerebellum is associated with higher-order functions including attention, perception, and language [8] [4]. Some clinical studies have revealed that there is an association between the cerebellum and personality [5]. Researchers have also been able to find correlations between cerebellar disorders and psychosis, especially schizophrenia [5]. In particular, cerebellar cognitive affective syndrome (CCAS) is a cerebellar disorder that exhibits both motor dysfunction (including dysmetria: referred to as impaired spatial cognition), personality change, impairment of linguistic abilities, and disturbance of higher-order functions including reasoning and memory [5]. It is believed that the there are specific pathways that link not only the prefrontal cortex, superior temporal regions, posterior parietal lobes, and hippocampus to the cerebellum, but there are also very specific pathways that link the cerebellum back to these areas of the brain [5]. These loops may contribute to the cognitive properties of the cerebellum that have recently been discovered. A good definition of cognitive dysmetria, also referred to as dysmetria of thought, is “a difficulty in coordinating and monitoring the process of receiving, processing, and expressing information” [2]. Cognitive dysmetria manifests itself in association with other cerebellar disorders [5].
# Causes
The actual cause of dysmetria is thought to be caused by lesions in the cerebellum or by lesions in the proprioceptive nerves that lead to the cerebellum that coordinate visual, spatial and other sensory information with motor control [4].. Damage to the proprioceptive nerves does not allow the cerebellum to accurately judge where the hand, arm, leg, or eye should move. These lesions are often caused by strokes, Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), or tumors [9].
According to the research article cited above, motor control is a learning process that utilizes APPGs [6]. Disruption of APPGs is possibly the cause of ataxia and dysmetria and upon identification of the motor primitives, clinicians may be able to isolate the specific areas responsible for the cerebellar problems [6].
There are two types of cerebellar disorders that produce dysmetria, specifically midline cerebellar syndromes and hemispheric cerebellar syndromes [9]. Midline cerebellar syndromes can cause ocular dysmetria, which is a condition in which the pupils of the eye overshoot [9]. Ocular dysmetria makes it difficult to focus vision onto one object. Hemispheric cerebellar syndromes cause dysmetria in the typical motor sense that many think of when hearing the term dysmetria [9].
A common motor syndrome that causes dysmetria is cerebellar motor syndrome, which also marked by impairments in gait (also known as ataxia), disordered eye movements, tremor, difficulty swallowing and poor articulation [5]. As stated above, cerebellar cognitive affective syndrome (CCAS) also causes dysmetria.
# Associated Diseases
Dysmetria is often found in individuals with Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and persons who have suffered from tumors or strokes. Persons who have been diagnosed with autosomal dominant spinocerebellar ataxia (SCAs) also exhibit dysmetria [10]. SCAs are a type of cerebellar disease that is inherited. There are many types of SCAs and though many exhibit similar symptoms (one being dysmetria), they are considered to be heterogeneous [10]. Freidrich’s ataxia is a well-known SCA in which children have dysmetria [5]. It is also closely associated with schizophrenia and autism [8].
# Diagnosis
Diagnosis of any cerebellar disorder or syndrome should be made by a qualified neurologist. Prior to referring a patient to a neurologist, a general practitioner or MS nurse will perform a finger-to-nose test [5]. The clinician will raise a finger in front of the patient and ask him to touch it with his finger and then touch his nose with his forefinger several times. This shows a patient’s ability to judge the position of a target. Other tests that could be performed are similar in nature and include a heel to shin test in which proximal overshoot characterizes dysmetria and an inability to draw an imaginary circle with the arms or legs without any decomposition of movement [5]. After a positive result in the finger-to-nose test, a neurologist will do a magnetic resonance image (MRI) to determine any damage to the cerebellum [5].
# Treatments
Currently there is no cure for dysmetria itself as it is actually a symptom of an underlying disorder. However, Isoniazid and Clonazepam have been used to treat dysmetria [1]. Cannabis has been used in trials in the U.K. and displayed some success, though it is not legal to use in the U.S. at this time [1].
## Research
Researchers now are testing different possibilities for treating dysmetria and ataxia. One opportunity for treatment is called rehearsal by eye movement [11]. It is believed that visually guided movements require both lower- and higher-order visual functioning by first identifying a target location and then moving to acquire what is sought after [10]. In one study, researchers used visually guided stepping which is parallel to visually guided arm movements to test this treatment [11]. The patients suffered from saccadic dysmetria which in turn caused them to overshoot their movements 3. The patients first walked normally and were then told to twice review the area that was to be walked through 3. After rehearsal with eye movements, the patients improved their motor performance [11]. Researchers believe that prior rehearsal with the eyes might be enough for a patient that suffers from motor dysmetria as a result of saccadic dysmetria to complete a motor task with enhanced spatial awareness [11].
Research has also been done for those patients that suffer from Multiple Sclerosis (MS) [12]. Deep brain stimulation (DBS) remains a viable possibility for some MS patients though the long term effects of this treatment are currently under review [12]. The subjects that have undergone this treatment had had no major relapse for 6 months and disabling motor function problems [12]. Most subjects benefited from the implantation of the electrodes and some reported that their movement disorder was gone after surgery [12]. However, these results are limiting at this time because of the small range of subjects that were used for the experiment and it is unknown whether this is a viable option for all MS patients that suffer from motor control problems [12]. | https://www.wikidoc.org/index.php/Dysmetria | |
3b83af48b4dc31afd0cbcf5f067613c085f9502b | wikidoc | Dyssomnia | Dyssomnia
# Overview
Dyssomnias are a broad classification of sleeping disorder that make it difficult to get to sleep, or to stay sleeping.
Dyssomnias are primary disorders of initiating or maintaining sleep or of excessive sleepiness and are characterized by a disturbance in the amount, quality, or timing of sleep.
Patients may complain of difficulty getting to sleep or staying asleep, intermittent wakefulness during the night, early morning awakening, or combinations of any of these. Transient episodes are usually of little significance. Stress, caffeine, physical discomfort, daytime napping, and early bedtimes are common factors.
# Major types of dyssomnias
There are over 30 recognized kinds of dyssomnias. Major groups of dyssomnias include:
- Intrinsic sleep disorders - 12 disorders recognized, including
hypersomnia,
narcolepsy,
periodic limb movement disorder,
restless legs syndrome,
sleep apnea.
- hypersomnia,
- narcolepsy,
- periodic limb movement disorder,
- restless legs syndrome,
- sleep apnea.
- Extrinsic sleep disorders - 13 disorders recognized, including
alcohol-dependent sleep disorder,
food allergy insomnia,
inadequate sleep routine.
- alcohol-dependent sleep disorder,
- food allergy insomnia,
- inadequate sleep routine.
- Circadian rhythm sleep disorders - 6 disorders recognized, including
advanced sleep phase syndrome,
delayed sleep phase syndrome,
jet lag,
shift work sleep disorder.
- advanced sleep phase syndrome,
- delayed sleep phase syndrome,
- jet lag,
- shift work sleep disorder.
# Causeas
## Life Threatening Causes
## Common Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Treatment
In general, there are two broad classes of treatment, and the two may be combined: psychological (cognitive-behavioral) and pharmacologic. In situations of acute distress, such as a grief reaction, pharmacologic measures may be most appropriate. With primary insomnia, however, initial efforts should be psychologically based. | Dyssomnia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dyssomnias are a broad classification of sleeping disorder that make it difficult to get to sleep, or to stay sleeping.
Dyssomnias are primary disorders of initiating or maintaining sleep or of excessive sleepiness and are characterized by a disturbance in the amount, quality, or timing of sleep.
Patients may complain of difficulty getting to sleep or staying asleep, intermittent wakefulness during the night, early morning awakening, or combinations of any of these. Transient episodes are usually of little significance. Stress, caffeine, physical discomfort, daytime napping, and early bedtimes are common factors.
# Major types of dyssomnias
There are over 30 recognized kinds of dyssomnias. Major groups of dyssomnias include:
- Intrinsic sleep disorders - 12 disorders recognized, including
hypersomnia,
narcolepsy,
periodic limb movement disorder,
restless legs syndrome,
sleep apnea.
- hypersomnia,
- narcolepsy,
- periodic limb movement disorder,
- restless legs syndrome,
- sleep apnea.
- Extrinsic sleep disorders - 13 disorders recognized, including
alcohol-dependent sleep disorder,
food allergy insomnia,
inadequate sleep routine.
- alcohol-dependent sleep disorder,
- food allergy insomnia,
- inadequate sleep routine.
- Circadian rhythm sleep disorders - 6 disorders recognized, including
advanced sleep phase syndrome,
delayed sleep phase syndrome,
jet lag,
shift work sleep disorder.
- advanced sleep phase syndrome,
- delayed sleep phase syndrome,
- jet lag,
- shift work sleep disorder.
# Causeas
## Life Threatening Causes
## Common Causes
## Causes by Organ System
## Causes in Alphabetical Order
# Treatment
In general, there are two broad classes of treatment, and the two may be combined: psychological (cognitive-behavioral) and pharmacologic. In situations of acute distress, such as a grief reaction, pharmacologic measures may be most appropriate. With primary insomnia, however, initial efforts should be psychologically based. | https://www.wikidoc.org/index.php/Dysomnia | |
a96cc72890077cafd4e4466af2b92c5bf2bfa793 | wikidoc | Dysphoria | Dysphoria
# Overview
Dysphoria (from Greek δύσφορος (dysphoros), from δυσ-, difficult, and φέρω, to bear) is generally characterized as an unpleasant or uncomfortable mood, such as sadness (depressed mood), anxiety, irritability, or restlessness. Etymologically, it is the opposite of euphoria.
Dysphoria refers only to a condition of mood and may be experienced in response to ordinary life events, such as illness or grief. Additionally, it is a feature of many psychiatric disorders, including anxiety disorders and mood disorders. Dysphoria is usually experienced during depressive episodes, but in people with bipolar disorder, it may also be experienced during manic or hypomanic episodes. Dysphoria in the context of a mood disorder indicates a heightened risk of suicide.
Dysphoria can be chemically induced by substances including mu-opioid antagonists and selective kappa-opioid agonists.
Dysphoria is also one of the symptoms of hypoglycemia.
# Causes
- Drug side effect: Butorphanol, Hydrocodone bitartrate and acetaminophen
# Conditions related to dysphoria
The following conditions may include dysphoria as a major component or symptom.
- Clinical depression (unipolar) and dysthymia
- Premenstrual Syndrome
- Bipolar disorder
- General anxiety disorder
- Gender identity disorder, sometimes called gender dysphoria
- Personality disorders such as borderline personality disorder and avoidant personality disorder
- Substance withdrawal
- Body dysmorphic disorder
- Hypoglycemia
"Dysphoria" is also the name of an alternative-rock band based in Alexandria, Virginia. Band members include Kyle Lynn and Blair Hicks.
# Notes
- ↑ Abbess; Alleydog.com.
- ↑ Jump up to: 2.0 2.1 2.2 Read, 2006.
- ↑ Metcalf & Coop, 2005. | Dysphoria
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dysphoria (from Greek δύσφορος (dysphoros), from δυσ-, difficult, and φέρω, to bear) is generally characterized as an unpleasant or uncomfortable mood, such as sadness (depressed mood), anxiety, irritability, or restlessness.[1] Etymologically, it is the opposite of euphoria.
Dysphoria refers only to a condition of mood and may be experienced in response to ordinary life events, such as illness or grief. Additionally, it is a feature of many psychiatric disorders, including anxiety disorders and mood disorders. Dysphoria is usually experienced during depressive episodes, but in people with bipolar disorder, it may also be experienced during manic or hypomanic episodes.[2] Dysphoria in the context of a mood disorder indicates a heightened risk of suicide.[2]
Dysphoria can be chemically induced by substances including mu-opioid antagonists[3] and selective kappa-opioid agonists.[4]
Dysphoria is also one of the symptoms of hypoglycemia.[citation needed]
# Causes
- Drug side effect: Butorphanol, Hydrocodone bitartrate and acetaminophen
# Conditions related to dysphoria
The following conditions may include dysphoria as a major component or symptom.
- Clinical depression (unipolar) and dysthymia
- Premenstrual Syndrome
- Bipolar disorder[2]
- General anxiety disorder
- Gender identity disorder, sometimes called gender dysphoria
- Personality disorders such as borderline personality disorder and avoidant personality disorder
- Substance withdrawal
- Body dysmorphic disorder
- Hypoglycemia
"Dysphoria" is also the name of an alternative-rock band based in Alexandria, Virginia. Band members include Kyle Lynn and Blair Hicks.
# Notes
- ↑ Abbess; Alleydog.com.
- ↑ Jump up to: 2.0 2.1 2.2 Read, 2006.
- ↑ http://www.drugs.com/pro/nalbuphine.html
- ↑ Metcalf & Coop, 2005. | https://www.wikidoc.org/index.php/Dysphoria | |
d7ac04f3e32e33019c3c14884caa8d23fd947bf4 | wikidoc | Dysplasia | Dysplasia
# Overview
Dysplasia (from Greek, roughly: "bad form") is a term used in pathology to refer to an abnormality in maturation of cells within a tissue. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process. The term dysplasia is typically used when the cellular abnormality is restricted to the originating tissue, as in the case of an early, in-situ neoplasm. For example, epithelial dysplasia of the cervix (cervical intraepithelial neoplasia - a disorder commonly detected by an abnormal pap smear) consists of an increased population of immature (basal-like) cells which are restricted to the mucosal surface, and have not invaded through the basement membrane to the deeper soft tissues. Myelodysplastic syndromes, or dysplasia of blood-forming cells, show increased numbers of immature cells in the bone marrow, and a decrease in mature, functional cells in the blood.
Dysplasia, in which cell maturation and differentiation are delayed, can be contrasted with metaplasia, in which cells of one mature, differentiated type are replaced by cells of another mature, differentiated type.
# Dysplasia vs. carcinoma in situ vs. invasive carcinoma
These terms are related since they represent the three steps in the progression of many malignant neoplasms (cancers) of epithelial tissues.
- Dysplasia is the earliest form of pre-cancerous lesion recognizable in a pap smear or in a biopsy by a pathologist. Dysplasia can be low grade or high grade (see "Carcinoma in situ", below). The risk of low grade dysplasia transforming into high grade dysplasia and, eventually, cancer is low. Treatment is usually straightforward. High grade dysplasia represents a more advanced progression towards malignant transformation.
- Carcinoma in situ , meaning 'cancer in place', represents the transformation of a neoplastic lesion to one in which cells undergo essentially no maturation, and thus may be considered cancer-like. In this state, cells have lost their tissue identity and have reverted back to a primitive cell form that grows rapidly and without regulation. However, this form of cancer remains localized, and has not invaded into tissues below the surface.
- Invasive carcinoma is the final step in this sequence. It is a cancer which has invaded beyond the original tissue layer and may be able to spread to other parts of the body (metastasize). Invasive cancer can usually be treated, but not always successfully. However, if left untreated it is almost always fatal. | Dysplasia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Dysplasia (from Greek, roughly: "bad form") is a term used in pathology to refer to an abnormality in maturation of cells within a tissue. This generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells. Dysplasia is often indicative of an early neoplastic process. The term dysplasia is typically used when the cellular abnormality is restricted to the originating tissue, as in the case of an early, in-situ neoplasm. For example, epithelial dysplasia of the cervix (cervical intraepithelial neoplasia - a disorder commonly detected by an abnormal pap smear) consists of an increased population of immature (basal-like) cells which are restricted to the mucosal surface, and have not invaded through the basement membrane to the deeper soft tissues. Myelodysplastic syndromes, or dysplasia of blood-forming cells, show increased numbers of immature cells in the bone marrow, and a decrease in mature, functional cells in the blood.
Dysplasia, in which cell maturation and differentiation are delayed, can be contrasted with metaplasia, in which cells of one mature, differentiated type are replaced by cells of another mature, differentiated type.
# Dysplasia vs. carcinoma in situ vs. invasive carcinoma
These terms are related since they represent the three steps in the progression of many malignant neoplasms (cancers) of epithelial tissues.
- Dysplasia is the earliest form of pre-cancerous lesion recognizable in a pap smear or in a biopsy by a pathologist. Dysplasia can be low grade or high grade (see "Carcinoma in situ", below). The risk of low grade dysplasia transforming into high grade dysplasia and, eventually, cancer is low. Treatment is usually straightforward. High grade dysplasia represents a more advanced progression towards malignant transformation.
- Carcinoma in situ , meaning 'cancer in place', represents the transformation of a neoplastic lesion to one in which cells undergo essentially no maturation, and thus may be considered cancer-like. In this state, cells have lost their tissue identity and have reverted back to a primitive cell form that grows rapidly and without regulation. However, this form of cancer remains localized, and has not invaded into tissues below the surface.
- Invasive carcinoma is the final step in this sequence. It is a cancer which has invaded beyond the original tissue layer and may be able to spread to other parts of the body (metastasize). Invasive cancer can usually be treated, but not always successfully. However, if left untreated it is almost always fatal. | https://www.wikidoc.org/index.php/Dysplasia | |
203d9210cd2e41d084383582669b68392d3fbdc3 | wikidoc | Dysthymia | Dysthymia
Synonyms and keywords: Dysthymic disorder; persistent depressive disorder; double depression
# Overview
Dysthymia is a mood disorder that falls on the depression spectrum. It is characterized by the lack of enjoyment or pleasure, clinically referred to as anhedonia, that continues for an extended period. Dysthymia differs from major depression in that it is both longer-lasting and not as distressing. The symptoms of dysthymia are often underestimated by the patients and misdiagnosed by clinicians. Dysthymia can have a substantial impact on an individual's life by preventing effective functioning, disrupting sleep patterns, and interfering with activities of daily living (ADLs). It usually presents with mild symptoms on a day-to-day basis. Progressively, the disorder may take a more severe form, resulting in work impairment, social isolation, and high rates of suicide. Due to its chronicity and lesser severity, most of the patients suffering from dysthymia believe that it is a part of their character and do not seek treatment until it gets extremely disabling.
# Historical Perspective
- The historical origin of the term 'dysthymia' is Greek.
- In 1844, dysthymia was used first in psychiatry by C.F. Flemming.
- In 1882, dysthymia was further described by Kahlbaum, and he differentiated it from the fluctuating mood of cyclothymia.
- In the Diagnostic and Statistical Manual of Mental Disorders (DSM), dysthymia as a clinical entity has undergone complex evolution from being considered a personality disorder to an affective disorder.
# Classification
- The Diagnostic and Statistical Manual of Mental Disorders (DSM-II) described chronic depression as a personality disorder.
- 'Dysthymic disorder' was the term used in DSM-III to describe depression present for more than two years.
- From the personality disorder of DSM-II, DSM-III-R placed it under the affective category.
- DSM-IV has classified chronic depression into dysthymic disorder and major depressive disorder, chronic type.
- Based on the age of onset, DSM-IV has divided dysthymic disorders into early (before 21 years) and late-onset (after 21 years) subtypes.
- Early-onset dysthymic disorder is related to a higher familial burden of mood disorders and childhood adverse conditions. On the other hand, late-onset has an association with health issues and major losses.
- In DSM-IV, individuals having underlying dysthymic disorder who develop major depressive episodes are diagnosed as having both dysthymic disorder and major depressive disorder. So, DSM-IV has categorized dysthymic disorder and major depressive episodes as separate diagnoses instead of phases of a single disorder that fluctuates in severity over time.
- In spite of minor differences in the definitions of dysthymic disorder in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) and International Classification of Diseases Tenth Edition (ICD-l0), both the systems are competent to establish the diagnosis.
- Dysthymia and chronic major depression are both included under the new term 'persistent depressive disorder' in DSM-5.
- Since the introduction in DSM-III, the diagnostic validity of dysthymia is questioned. It is a heterogeneous diagnosis including various depressive and anxiety conditions. As persistent depressive disorder includes dysthymia as a component, the former is more likely to represent a heterogeneous domain diagnosis. It limits the identification of the preferred treatment options.
# Pathophysiology
- Brain-derived neurotrophic factor (BDNF) has been found to play a major role in the long-term potentiation, functioning of neurons and therefore, affecting neuroplasticity.
- Compared to controls, BDNF is significantly lower in individuals with dysthymia.
- Interleukin-6 (IL-6) levels are higher in dysthymic patients as compared to controls. Individuals with major depressive disorder also have higher levels of IL-6.
- The expression of cytokines has also been found to have a role in the pathophysiology of dysthymia. Macrophage inflammatory protein-1α and Interferon-γ-induced protein10 have a correlation with the response to treatment.
- The elevated Interleukin-1β associated with dysthymia fails to reach the normal range even after symptom resolution. It further suggests that IL-1β can be the trait marker of dysthymia and can help in early detection of the illness.
# Clinical Features
- The main features of dysthymia are
Low or irritable mood
Lack of interest in previously enjoyed activities
Loss of energy or easy fatigability
Increased or decreased appetite
Weight gain or loss
Excessive sleepiness or insomnia
Difficulty concentrating
Indecisiveness and having pessimistic thoughts
Negative self-image
- Low or irritable mood
- Lack of interest in previously enjoyed activities
- Loss of energy or easy fatigability
- Increased or decreased appetite
- Weight gain or loss
- Excessive sleepiness or insomnia
- Difficulty concentrating
- Indecisiveness and having pessimistic thoughts
- Negative self-image
- Dysthymia as compared to major depression, tends to be less intense and persists for a longer duration.
- Other than the variation in magnitude of severity, both these conditions exhibit similar symptomatology.
- To diagnose major depressive disorder, the symptoms should be present for a minimum duration of 14 days (2 weeks) whereas, dysthymia symptoms should be present for at least 2 years.
- The symptoms of dysthymia can grow into a full-blown episode of major depression. The intense episode often exists with the underlying feelings of low mood and this resulting condition is called "double depression"
- As compared to the general population, the people with dysthymia have a greater-than-average chance of developing major depression.
- While major depressive disorder mostly occurs in episodes, dysthymia lasts for longer periods, is consistent, and sometimes begins in childhood. Therefore, persons with dysthymia tend to consider depression as a part of their character.
- Dysthymia and major depression, both are inheritable.
- Some individuals describe dysthymia as being under chronic stress.
- When treating cases, it is often difficult to distinguish if these people are actually under unusually high environmental stress or if the dysthymia causes them to be more psychologically stressed in a standard environment.
# Differential Diagnosis
The differential diagnosis of dysthymia includes the following:
- Mood disorder secondary to general medical condition
- Major depressive disorder
- Recurrent depressive disorder
- Personality disorders
- Generalized Anxiety Disorder
- Mixed anxiety and depressive disorder
- Substance-induced mood disorder
- Neurasthenia
- Adjustment disorder
- Psychotic disorders
# Epidemiology and Demographics
## Prevalence
- The 12-month prevalence of dysthymia is approximately 500 per 100,000 (0.5%) of the overall population.
## Age
- Individuals of all age groups may develop dysthymia.
- Based on the age of onset, the etiology of dysthymia varies.
- The individuals with early onset dysthymia often have a history of physical or sexual abuse. They have also been found to have poor relationships with both the parents.
- Compared to adolescents, children display lesser variability in the symptoms of dysthymia.
- 'Anhedonia' is a common characteristic in adolescents with dysthymia.
- In younger adults, dysthymia is related to the abnormalities of personality whereas, the elderly have a strong association with losses in life and other health-related issues.
## Gender
- Dysthymia affects both men and women.
- The prevalence of dysthymia is more in women compared to men.
- The symptomatic profile is similar in males and females of the adolescent population. While comparing the symptoms of dysthymia in both genders, no specific symptom predominance has been noticed.
- Gender differences have been noted in the elderly population.
- In elderly men, dysthymia is more related to lower educational levels and in those receiving nursing home/ institutional care. No relation has been found based on occupation or marital status.
- As opposed to this, in elderly females, dysthymia is predominant in older individuals (70 years +), married, and in those with higher education levels. It is not related to marital status, occupation, or form of health care received.
## Race
- Dysthymia has a higher lifetime prevalence in individuals of Mexican American and African American backgrounds. This can be explained by a number of factors dominating these populations:
Lower education level
Poverty
Hesitancy in seeking help
Lesser utilization of mental health services
Failure to comply with treatment
Various cultural beliefs
- Lower education level
- Poverty
- Hesitancy in seeking help
- Lesser utilization of mental health services
- Failure to comply with treatment
- Various cultural beliefs
# Risk Factors
Common risk factors in the development of dysthymia are:
- Genetic predisposition
- First-degree relatives with persistent depressive disorder
- Major depressive disorder in first-degree relatives
- Family history of other mood disorders
- Lower social integration
- Co-morbid substance use disorder
- Parental loss or separation
- Physical or sexual abuse
- Lower educational levels
- Polysomnographic abnormalities
# Natural History, Complications, and Prognosis
- Individuals with dysthymia have a higher risk of developing major depressive disorder in the future.
- Similar to adults, children and adolescents with dysthymia are also more likely to develop depression.
- These children have a poor scholastic performance and deteriorating quality of life.
- Dysthymia has an impact on personal relationships, financial state as well as physical and mental well-being.
- Dysthymia is associated with higher suicide rates and significant disability.
## Prognosis
Overall, dysthymia has a worse prognosis than major depressive disorder.
Poor prognostic factors related to dysthymia are:
- Anxiety disorders
- Less education
- Conduct disorder
- Familial loading for chronic depression
- History of poor maternal relationship in childhood
- History of childhood sexual abuse
- Longer duration of symptoms
- Comorbid personality disorder
- Increased severity of the symptoms
- Higher levels of neuroticism
- Poorer global functioning
# Diagnostic Criteria
## DSM-5 Diagnostic Criteria for Dysthymia
- Persistent Depressive Disorder (Dysthymia) is diagnosed using DSM-5 Criteria.
# Treatment
## Medications
### Selective Serotonin Reuptake Inhibitors (SSRI)
- The most commonly prescribed anti-depressants for dysthymia are the selective serotonin reuptake inhibitors (SSRI), which include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and citalopram (Celexa).
- SSRIs have a very high affinity for Serotonin (5-HT) receptors whereas low affinity for noradrenaline uptake receptors. They act by inhibiting the reuptake of 5-HT from the synaptic cleft, increasing its concentration and contributing to the therapeutic effect.
- The different SSRIs have variability in efficacy and side-effect profile, which requires thorough clinical consideration before prescribing them.
- SSRIs are easy to take and relatively safer compared with the other older forms of anti-depressants.
### Side Effects of SSRI
- SSRI are associated with some side effects like sleep disturbances, nausea, vomiting, sexual dysfunction, weight gain, cognitive disturbances and SSRI discontinuation syndrome.
- The sleep disturbances are more prominent initially in the treatment course. These are in the form of earlier onset of rapid eye movement (REM) sleep, increased duration of REM sleep, and lesser slow-wave sleep.
- The immediate adverse effects of SSRIs are due to increased concentration of serotonin at particular receptor subtypes in various parts of the brain. The post-synaptic receptor desensitization in these regions leads to tolerance to these side effects after some time.
### Other medications
- Some patients do not respond to SSRIs or have to discontinue them due to inability to tolerate the adverse effects.
- Older antidepressants, such as a tricyclic antidepressant (TCA) or a monoamine oxidase inhibitor (MAOI) can be prescribed in such cases.
- TCAs have anticholinergic side-effects like weight gain, dry mouth, urinary retention, constipation, and blurry vision.
- Some individuals on TCA also develop sexual dysfunction, cardiac side-effects and orthostatic hypotension.
- These medications should be avoided in elderly patients.
- MAOIs can predispose to serotonin syndrome if used with SSRIs as an adjuvant therapy or if insufficient time is given for washout of SSRIs before switching to MAOIs.
- A considerable approach to deal with this problem is to give at least a washout period of 14 days while switching from SSRIs to MAOIs or vice-versa.
- Fluoxetine has a longer half-life as compared to other SSRIs, therefore a longer washout period (a minimum of 5 weeks) is required to switch from Fluoxetine to another MAOI.
- Other antidepressants that can be used for treating dysthymia are bupropion (Wellbutrin), venlafaxine (Effexor), mirtazapine (Remeron), and duloxetine (Cymbalta).
## Psychotherapy
- Evidence suggests the combination of pharmacotherapy and psychotherapy provides the greatest improvement in dysthymia.
- On the contrary, some studies point towards the inferiority of psychotherapy in treating dysthymia.
- There are different types of psychotherapies. The type of therapy chosen depends upon a number of factors like the nature of any stressful events, the availability of family and other social support, and personal preference.
- Psychotherapy focuses mainly on education about the disease model, correcting the underlying cognitive distortions, and building up support.
- Cognitive-behavioral therapy is designed to examine and help correct the faulty, self-critical thought patterns and correct the cognitive distortions that persons with mood disorders commonly experience.
- Psychodynamic, insight-oriented, or interpersonal psychotherapy (IPT) can find out the origin of the symptoms, address them appropriately, and explore the conflicts in important relationships which are further deteriorating the illness.
- IPT emphasizes resolving the conflict in current relationships that are exacerbating the depressive symptoms.
- Both CBT and IPT are effective for adolescents. Psychoeducation and psychosocial support provided to the parents of adolescents with dysthymia plays a very important role in the early and satisfactory response to these therapies.
- An adapted version for IPT is used for adolescents because they are in conflict with their parents as well as peers, limiting the outlet options for their emotional burden. | Dysthymia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vatsala Sharma; M.B.B.S[2]
Synonyms and keywords: Dysthymic disorder; persistent depressive disorder; double depression
# Overview
Dysthymia is a mood disorder that falls on the depression spectrum. It is characterized by the lack of enjoyment or pleasure, clinically referred to as anhedonia, that continues for an extended period. Dysthymia differs from major depression in that it is both longer-lasting and not as distressing. The symptoms of dysthymia are often underestimated by the patients and misdiagnosed by clinicians. Dysthymia can have a substantial impact on an individual's life by preventing effective functioning, disrupting sleep patterns, and interfering with activities of daily living (ADLs). It usually presents with mild symptoms on a day-to-day basis. Progressively, the disorder may take a more severe form, resulting in work impairment, social isolation, and high rates of suicide. Due to its chronicity and lesser severity, most of the patients suffering from dysthymia believe that it is a part of their character and do not seek treatment until it gets extremely disabling.
# Historical Perspective
- The historical origin of the term 'dysthymia' is Greek.
- In 1844, dysthymia was used first in psychiatry by C.F. Flemming. [1]
- In 1882, dysthymia was further described by Kahlbaum, and he differentiated it from the fluctuating mood of cyclothymia.[2]
- In the Diagnostic and Statistical Manual of Mental Disorders (DSM), dysthymia as a clinical entity has undergone complex evolution from being considered a personality disorder to an affective disorder.
# Classification
- The Diagnostic and Statistical Manual of Mental Disorders (DSM-II) described chronic depression as a personality disorder.[3]
- 'Dysthymic disorder' was the term used in DSM-III to describe depression present for more than two years.
- From the personality disorder of DSM-II, DSM-III-R placed it under the affective category. [4]
- DSM-IV has classified chronic depression into dysthymic disorder and major depressive disorder, chronic type.
- Based on the age of onset, DSM-IV has divided dysthymic disorders into early (before 21 years) and late-onset (after 21 years) subtypes. [5]
- Early-onset dysthymic disorder is related to a higher familial burden of mood disorders and childhood adverse conditions. On the other hand, late-onset has an association with health issues and major losses.[5]
- In DSM-IV, individuals having underlying dysthymic disorder who develop major depressive episodes are diagnosed as having both dysthymic disorder and major depressive disorder. So, DSM-IV has categorized dysthymic disorder and major depressive episodes as separate diagnoses instead of phases of a single disorder that fluctuates in severity over time.[6]
- In spite of minor differences in the definitions of dysthymic disorder in the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) and International Classification of Diseases Tenth Edition (ICD-l0), both the systems are competent to establish the diagnosis.[7]
- Dysthymia and chronic major depression are both included under the new term 'persistent depressive disorder' in DSM-5.[8]
- Since the introduction in DSM-III, the diagnostic validity of dysthymia is questioned. It is a heterogeneous diagnosis including various depressive and anxiety conditions. As persistent depressive disorder includes dysthymia as a component, the former is more likely to represent a heterogeneous domain diagnosis. It limits the identification of the preferred treatment options. [9]
# Pathophysiology
- Brain-derived neurotrophic factor (BDNF) has been found to play a major role in the long-term potentiation, functioning of neurons and therefore, affecting neuroplasticity. [10]
- Compared to controls, BDNF is significantly lower in individuals with dysthymia. [11]
- Interleukin-6 (IL-6) levels are higher in dysthymic patients as compared to controls. Individuals with major depressive disorder also have higher levels of IL-6. [12]
- The expression of cytokines has also been found to have a role in the pathophysiology of dysthymia. Macrophage inflammatory protein-1α and Interferon-γ-induced protein10 have a correlation with the response to treatment.[13]
- The elevated Interleukin-1β associated with dysthymia fails to reach the normal range even after symptom resolution. It further suggests that IL-1β can be the trait marker of dysthymia and can help in early detection of the illness.[14]
# Clinical Features
- The main features of dysthymia are
Low or irritable mood
Lack of interest in previously enjoyed activities
Loss of energy or easy fatigability
Increased or decreased appetite
Weight gain or loss
Excessive sleepiness or insomnia
Difficulty concentrating
Indecisiveness and having pessimistic thoughts
Negative self-image
- Low or irritable mood
- Lack of interest in previously enjoyed activities
- Loss of energy or easy fatigability
- Increased or decreased appetite
- Weight gain or loss
- Excessive sleepiness or insomnia
- Difficulty concentrating
- Indecisiveness and having pessimistic thoughts
- Negative self-image
- Dysthymia as compared to major depression, tends to be less intense and persists for a longer duration.
- Other than the variation in magnitude of severity, both these conditions exhibit similar symptomatology.
- To diagnose major depressive disorder, the symptoms should be present for a minimum duration of 14 days (2 weeks) whereas, dysthymia symptoms should be present for at least 2 years.
- The symptoms of dysthymia can grow into a full-blown episode of major depression. The intense episode often exists with the underlying feelings of low mood and this resulting condition is called "double depression"[15]
- As compared to the general population, the people with dysthymia have a greater-than-average chance of developing major depression.
- While major depressive disorder mostly occurs in episodes, dysthymia lasts for longer periods, is consistent, and sometimes begins in childhood. Therefore, persons with dysthymia tend to consider depression as a part of their character.
- Dysthymia and major depression, both are inheritable.
- Some individuals describe dysthymia as being under chronic stress.
- When treating cases, it is often difficult to distinguish if these people are actually under unusually high environmental stress or if the dysthymia causes them to be more psychologically stressed in a standard environment.
# Differential Diagnosis
The differential diagnosis of dysthymia includes the following: [16]
- Mood disorder secondary to general medical condition
- Major depressive disorder
- Recurrent depressive disorder
- Personality disorders
- Generalized Anxiety Disorder
- Mixed anxiety and depressive disorder
- Substance-induced mood disorder
- Neurasthenia
- Adjustment disorder
- Psychotic disorders
# Epidemiology and Demographics
## Prevalence
- The 12-month prevalence of dysthymia is approximately 500 per 100,000 (0.5%) of the overall population.[17]
## Age
- Individuals of all age groups may develop dysthymia.
- Based on the age of onset, the etiology of dysthymia varies.
- The individuals with early onset dysthymia often have a history of physical or sexual abuse. They have also been found to have poor relationships with both the parents.[18]
- Compared to adolescents, children display lesser variability in the symptoms of dysthymia.
- 'Anhedonia' is a common characteristic in adolescents with dysthymia. [19]
- In younger adults, dysthymia is related to the abnormalities of personality whereas, the elderly have a strong association with losses in life and other health-related issues. [20]
## Gender
- Dysthymia affects both men and women.
- The prevalence of dysthymia is more in women compared to men.[21]
- The symptomatic profile is similar in males and females of the adolescent population. While comparing the symptoms of dysthymia in both genders, no specific symptom predominance has been noticed. [22]
- Gender differences have been noted in the elderly population.
- In elderly men, dysthymia is more related to lower educational levels and in those receiving nursing home/ institutional care. No relation has been found based on occupation or marital status.[23]
- As opposed to this, in elderly females, dysthymia is predominant in older individuals (70 years +), married, and in those with higher education levels. It is not related to marital status, occupation, or form of health care received. [24]
## Race
- Dysthymia has a higher lifetime prevalence in individuals of Mexican American and African American backgrounds. This can be explained by a number of factors dominating these populations: [25]
Lower education level
Poverty
Hesitancy in seeking help
Lesser utilization of mental health services
Failure to comply with treatment
Various cultural beliefs
- Lower education level
- Poverty
- Hesitancy in seeking help
- Lesser utilization of mental health services
- Failure to comply with treatment
- Various cultural beliefs
# Risk Factors
Common risk factors in the development of dysthymia are:[17][26]
- Genetic predisposition
- First-degree relatives with persistent depressive disorder
- Major depressive disorder in first-degree relatives
- Family history of other mood disorders
- Lower social integration
- Co-morbid substance use disorder
- Parental loss or separation
- Physical or sexual abuse
- Lower educational levels
- Polysomnographic abnormalities
# Natural History, Complications, and Prognosis
- Individuals with dysthymia have a higher risk of developing major depressive disorder in the future.
- Similar to adults, children and adolescents with dysthymia are also more likely to develop depression. [27]
- These children have a poor scholastic performance and deteriorating quality of life.[28]
- Dysthymia has an impact on personal relationships, financial state as well as physical and mental well-being.[29]
- Dysthymia is associated with higher suicide rates and significant disability.[30]
## Prognosis
Overall, dysthymia has a worse prognosis than major depressive disorder. [31]
Poor prognostic factors related to dysthymia are: [17][32]
- Anxiety disorders
- Less education
- Conduct disorder
- Familial loading for chronic depression
- History of poor maternal relationship in childhood
- History of childhood sexual abuse
- Longer duration of symptoms
- Comorbid personality disorder
- Increased severity of the symptoms
- Higher levels of neuroticism
- Poorer global functioning
# Diagnostic Criteria
## DSM-5 Diagnostic Criteria for Dysthymia
- Persistent Depressive Disorder (Dysthymia) is diagnosed using DSM-5 Criteria.[17]
# Treatment
## Medications
### Selective Serotonin Reuptake Inhibitors (SSRI)
- The most commonly prescribed anti-depressants for dysthymia are the selective serotonin reuptake inhibitors (SSRI), which include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and citalopram (Celexa).
- SSRIs have a very high affinity for Serotonin (5-HT) receptors whereas low affinity for noradrenaline uptake receptors. They act by inhibiting the reuptake of 5-HT from the synaptic cleft, increasing its concentration and contributing to the therapeutic effect.[33]
- The different SSRIs have variability in efficacy and side-effect profile, which requires thorough clinical consideration before prescribing them.[34]
- SSRIs are easy to take and relatively safer compared with the other older forms of anti-depressants.[35]
### Side Effects of SSRI
- SSRI are associated with some side effects like sleep disturbances, nausea, vomiting, sexual dysfunction, weight gain, cognitive disturbances and SSRI discontinuation syndrome.[36]
- The sleep disturbances are more prominent initially in the treatment course. These are in the form of earlier onset of rapid eye movement (REM) sleep, increased duration of REM sleep, and lesser slow-wave sleep.[37]
- The immediate adverse effects of SSRIs are due to increased concentration of serotonin at particular receptor subtypes in various parts of the brain. The post-synaptic receptor desensitization in these regions leads to tolerance to these side effects after some time. [38]
### Other medications
- Some patients do not respond to SSRIs or have to discontinue them due to inability to tolerate the adverse effects.
- Older antidepressants, such as a tricyclic antidepressant (TCA) or a monoamine oxidase inhibitor (MAOI) can be prescribed in such cases.
- TCAs have anticholinergic side-effects like weight gain, dry mouth, urinary retention, constipation, and blurry vision.
- Some individuals on TCA also develop sexual dysfunction, cardiac side-effects and orthostatic hypotension.
- These medications should be avoided in elderly patients.
- MAOIs can predispose to serotonin syndrome if used with SSRIs as an adjuvant therapy or if insufficient time is given for washout of SSRIs before switching to MAOIs. [39]
- A considerable approach to deal with this problem is to give at least a washout period of 14 days while switching from SSRIs to MAOIs or vice-versa.[40]
- Fluoxetine has a longer half-life as compared to other SSRIs, therefore a longer washout period (a minimum of 5 weeks) is required to switch from Fluoxetine to another MAOI.[41]
- Other antidepressants that can be used for treating dysthymia are bupropion (Wellbutrin), venlafaxine (Effexor), mirtazapine (Remeron), and duloxetine (Cymbalta).
## Psychotherapy
- Evidence suggests the combination of pharmacotherapy and psychotherapy provides the greatest improvement in dysthymia. [42]
- On the contrary, some studies point towards the inferiority of psychotherapy in treating dysthymia.[43]
- There are different types of psychotherapies. The type of therapy chosen depends upon a number of factors like the nature of any stressful events, the availability of family and other social support, and personal preference.
- Psychotherapy focuses mainly on education about the disease model, correcting the underlying cognitive distortions, and building up support.
- Cognitive-behavioral therapy is designed to examine and help correct the faulty, self-critical thought patterns and correct the cognitive distortions that persons with mood disorders commonly experience.[44]
- Psychodynamic, insight-oriented, or interpersonal psychotherapy (IPT) can find out the origin of the symptoms, address them appropriately, and explore the conflicts in important relationships which are further deteriorating the illness.[45]
- IPT emphasizes resolving the conflict in current relationships that are exacerbating the depressive symptoms.[46]
- Both CBT and IPT are effective for adolescents. Psychoeducation and psychosocial support provided to the parents of adolescents with dysthymia plays a very important role in the early and satisfactory response to these therapies.[47]
- An adapted version for IPT is used for adolescents because they are in conflict with their parents as well as peers, limiting the outlet options for their emotional burden.[48] | https://www.wikidoc.org/index.php/Dysthymia | |
83387903108d332e36816dccb58bf26185e492d8 | wikidoc | E/a ratio | E/a ratio
# Overview
The E/A ratio is the ratio between early (E) and late (atrial - A) ventricular filling velocity.
The early (E) diastolic wave is caused by accumulation of blood in the atria during previous systole, and second, a late one created by atrial contraction (A).
In a young and compliant heart, early ventricular filling accounts for ~80% of ventricular end diastolic volume (with atrial systole pushing the last ~20% of blood into the ventricle). Thus, the 'E' component of the ratio is greater than the 'A' component. In an aging, less compliant heart, a greater proportion of this blood is pushed into the ventricles during atrial systole. In this scenario, the emphasis of ventricular filling during late diastole increases the 'A' component of the E/A ratio causing a reversal of the ratio.
The reversal of the E:A ratio is widely accepted as a clinical marker of diastolic heart failure.
It can be estimated by doppler echocardiography.
In diastolic dysfunction, a greater portion of end-diastolic volume results from late filling rather than early filling. Therefore, the E/A ratio is reduced in diastolic dysfunction.
The late phase is dependent upon atrial contraction and is therefore absent in patients with atrial fibrillation, making the E/A ratio very large.
The E:A ratio is a first generation test for diastolic performance of the heart.
Diastolic relaxation is divided into four distinct phases during the cardiac cycle:
- Isovolumetric relaxation (abbreviated as IVRT)
- Early filling
- Diastasis
- Atrial contraction.
In short, there are a number of factors that influence ventricular filling during each of these phases, but remember that the main factor is the driving gradient between the atrial and ventricular pressure.
The E/A ratio is measured by placing a pulse wave doppler across the mitral valve, and measuring the velocities across the valve. Hence the other names for the test - transmitral velocity profile or transmitral doppler waveforms.
Pulse wave doppler allows measurement of velocities at a specific point, but has the disadvantage of aliasing, so often has to be adjusted (baseline shifted etc.) to best fit the individual point of measurement.
IVRT is measured as the time between the closure of the aortic valve and the opening of the mitral valve.
The normal transmitral flow profile has two peaks - an E and an A wave.
The E peak arises due to early diastolic filling. Most filling (70-75%) of the ventricle occurs during this phase.
The A peak arises due to atrial contraction, forcing approximately 20-25% of stroke volume into the ventricle.
The deceleration time (DT) is the time taken from the maximum E point to baseline. Normally in adults it is less than 220 milliseconds.
Below is a transthoracic image - for those with TEE/TOE experience, simply invert the image mentally, but the concept is the same.
On the left is a heart with normal diastolic function, and on the right is a heart of impaired relaxation (note the different height of the E and A waves). Note the DT is prolonged - another hallmark of impaired relaxation.
Note too the timing according to the ECG - the waves are being measured prior to the commencement of the QRS complex (the start of systole). The A wave corresponds to the mechanical action of the electrical P wave on the ECG.
# Grading of ventricular diastolic dysfunction
From this, a number of grades of diastolic function can be determined:
1. Normal diastolic function (E > A)
2. Impaired relaxation (E:A reversal i.e. E is < A)
3. Pseudonormal (E:A ratio appears normal
4. Restrictive filling (E:A ratio often > 2)
Pseudonormalisation shows a transmitral profile that appears normal, however with the use of pulmonary vein pulse wave doppler, it can be shown that the relaxation pattern is abnormal (systolic blunting, a decrease in the height of the S wave). In addition, performance of a valsalva manouvre will result in unmasking of the pseudonormal state.
# Disadvantages
- Cursor position is important - if the PW sample window is incorrect, it will produce artifact. The cursor should be placed at the level of the open leaflets in diastole.
- Presence of mitral valve abormalities e.g. mitral stenosis will alter the pressure gradients and change loading conditions of the LV.
- Presence of AI - aortic incompetence will result in a rapid rise in LV diastolic pressure, limiting the gradient across the mitral valve during diastole.
- Heart rate & rhythm - loss of a normal atrial rhythm e.g. atrial fibrillation will cause loss of the A wave. The heigh of the E wave now becomes dependent on the length of the cardiac cycle (variable) rather than a true measure of diastolic function. Similarly, pacing and tachycardia can result in alterations, whereas bradycardia actually increases the E/A ratio.
These are some of the disadvantages of first generation testing methods.
Diastolic function should be assessed normally in addition to the twenty views. It is important in establishing a number of cardiac conditions - e.g. pericardial tamponade (where E/A ratios across the tricuspid valve are often more important), restrictive pericarditis vs constrictive cardiomyopathy etc. | E/a ratio
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
The E/A ratio is the ratio between early (E) and late (atrial - A) ventricular filling velocity.
The early (E) diastolic wave is caused by accumulation of blood in the atria during previous systole, and second, a late one created by atrial contraction (A).
In a young and compliant heart, early ventricular filling accounts for ~80% of ventricular end diastolic volume (with atrial systole pushing the last ~20% of blood into the ventricle). Thus, the 'E' component of the ratio is greater than the 'A' component. In an aging, less compliant heart, a greater proportion of this blood is pushed into the ventricles during atrial systole. In this scenario, the emphasis of ventricular filling during late diastole increases the 'A' component of the E/A ratio causing a reversal of the ratio.
The reversal of the E:A ratio is widely accepted as a clinical marker of diastolic heart failure.
It can be estimated by doppler echocardiography. [1]
In diastolic dysfunction, a greater portion of end-diastolic volume results from late filling rather than early filling. Therefore, the E/A ratio is reduced in diastolic dysfunction. [1]
The late phase is dependent upon atrial contraction and is therefore absent in patients with atrial fibrillation, making the E/A ratio very large.[1]
The E:A ratio is a first generation test for diastolic performance of the heart.
Diastolic relaxation is divided into four distinct phases during the cardiac cycle:
- Isovolumetric relaxation (abbreviated as IVRT)
- Early filling
- Diastasis
- Atrial contraction.
In short, there are a number of factors that influence ventricular filling during each of these phases, but remember that the main factor is the driving gradient between the atrial and ventricular pressure.
The E/A ratio is measured by placing a pulse wave doppler across the mitral valve, and measuring the velocities across the valve. Hence the other names for the test - transmitral velocity profile or transmitral doppler waveforms.
Pulse wave doppler allows measurement of velocities at a specific point, but has the disadvantage of aliasing, so often has to be adjusted (baseline shifted etc.) to best fit the individual point of measurement.
IVRT is measured as the time between the closure of the aortic valve and the opening of the mitral valve.
The normal transmitral flow profile has two peaks - an E and an A wave.
The E peak arises due to early diastolic filling. Most filling (70-75%) of the ventricle occurs during this phase.
The A peak arises due to atrial contraction, forcing approximately 20-25% of stroke volume into the ventricle.
The deceleration time (DT) is the time taken from the maximum E point to baseline. Normally in adults it is less than 220 milliseconds.
Below is a transthoracic image - for those with TEE/TOE experience, simply invert the image mentally, but the concept is the same.
On the left is a heart with normal diastolic function, and on the right is a heart of impaired relaxation (note the different height of the E and A waves). Note the DT is prolonged - another hallmark of impaired relaxation.
Note too the timing according to the ECG - the waves are being measured prior to the commencement of the QRS complex (the start of systole). The A wave corresponds to the mechanical action of the electrical P wave on the ECG.
# Grading of ventricular diastolic dysfunction
From this, a number of grades of diastolic function can be determined:
1. Normal diastolic function (E > A)
2. Impaired relaxation (E:A reversal i.e. E is < A)
3. Pseudonormal (E:A ratio appears normal
4. Restrictive filling (E:A ratio often > 2)
Pseudonormalisation shows a transmitral profile that appears normal, however with the use of pulmonary vein pulse wave doppler, it can be shown that the relaxation pattern is abnormal (systolic blunting, a decrease in the height of the S wave). In addition, performance of a valsalva manouvre will result in unmasking of the pseudonormal state.
# Disadvantages
- Cursor position is important - if the PW sample window is incorrect, it will produce artifact. The cursor should be placed at the level of the open leaflets in diastole.
- Presence of mitral valve abormalities e.g. mitral stenosis will alter the pressure gradients and change loading conditions of the LV.
- Presence of AI - aortic incompetence will result in a rapid rise in LV diastolic pressure, limiting the gradient across the mitral valve during diastole.
- Heart rate & rhythm - loss of a normal atrial rhythm e.g. atrial fibrillation will cause loss of the A wave. The heigh of the E wave now becomes dependent on the length of the cardiac cycle (variable) rather than a true measure of diastolic function. Similarly, pacing and tachycardia can result in alterations, whereas bradycardia actually increases the E/A ratio.
These are some of the disadvantages of first generation testing methods.
Diastolic function should be assessed normally in addition to the twenty views. It is important in establishing a number of cardiac conditions - e.g. pericardial tamponade (where E/A ratios across the tricuspid valve are often more important), restrictive pericarditis vs constrictive cardiomyopathy etc. | https://www.wikidoc.org/index.php/E/A_ratio | |
aac7ec891c7b4ad61f031125bcd2bc64d7dc1def | wikidoc | ECA stack | ECA stack
The ECA stack is a drug combination used as a stimulant and in weight loss. ECA is an acronym for ephedrine, caffeine, and aspirin.
# Mechanism of effect in weight loss
The effects of the ECA stack in weight loss are primarily due to the ephedrine component. Ephedrine acts both as a beta agonist and stimulates the release of norepinephrine. Increased circulating norepinephrine in the body then acts on white adipose tissue by increasing cAMP levels. This causes a thermogenic effect, raising body temperature and increasing the user's metabolism in conjunction with the rest of the stack.
However, the body's negative feedback system then activates to normalize the metabolism. This is done via the production of phosphodiesterase inside the cells, and prostaglandins outside the cell, which both lower cAMP levels within the cell.
Caffeine inhibits the production of phosphodiesterase inside the cell and therefore slows cAMP breakdown. It also binds with and competitively inhibits adenosine receptors in the brain, triggering the release of epinephrine and increasing cAMP levels further.
Aspirin inhibits prostaglandin production outside of the cells, which, in conjunction with caffeine, greatly prolongs the thermogenic effects and increased metabolism by substaining elevated cAMP levels.
Ephedrine also has an anorectic, or appetite-suppressing, effect. However, these effects only last for about two weeks if the stack is not cycled, as the body becomes tolerant to ephedrine to some degree. It is estimated that 60% – 75% of the weight loss from using the ECA stack comes from the anorectic effect, and the remainder from thermogenesis.
The final component in weight loss of the ECA stack is that of a simple stimulant; the higher epinephrine and norepinephrine levels result in increased aerobic exercise performance and less fatigue.
# Mechanisms of effect in energy gain
Ephedrine acts to increase energy by its actions as a sympathomimetic amine. It directly acts in the brain to increase the release of norepinephrine into the synaptic cleft, and also partially serves as a norepinephrine reuptake inhibitor, thereby also partially functioning as a dopamine reuptake inhibitor due to the shared action between the two terminals. Caffeine blocks adenosine receptors which lessens feelings of tiredness, and also increases dopamine levels, resulting in greater concentration, focus, and memory. The effects of caffeine on dopamine levels are usually short lived, but ephedrine's partial action as a dopamine reuptake inhibitor lengthens the duration.
# Dosage
Typically the ECA stack is consumed two or three times per day in a 1:10:10 or 1:10:15 ratio of ephedrine:caffeine:aspirin. These ratios vary across studies and across users but despite variance they all seem to be effective. Usually, no more than 25 mg of ephedrine, 200 mg of caffeine and 325 mg of aspirin is consumed in a single dose. It is not recommended that the stack be taken past late afternoon as this may contribute to insomnia.
# Addiction
While aspirin is not physically addictive, caffeine is, and users develop a tolerance to lowered adenosine levels, leading to withdrawal symptoms from adenosine sensitivity if caffeine use is discontinued too quickly. Psychological addiction to ephedrine and caffeine are also possible.
# Risks
The primary risk of the ECA stack is in the effect of ephedrine on the heart. Ephedrine has been linked to deaths in people with valve damage, heart problems and heart disease, but also in previously healthy young adults when taken in high doses. It is not recommended that stimulants be taken in users with a pre-existing heart condition. Additionally, there is some evidence that the long term use of amphetamines can lead to heart damage, but this has not been shown for ephedrine use.
Caffeine and ephedrine also act to raise blood pressure by approximately 4 – 7 mmHg on average, so users with existing hypertension must be careful that the stack does not increase their blood pressure to dangerous levels — especially during exercise (for example, by lifting exceptionally heavy weights).
Other risks include insomnia, dry mouth, irritability, stress, euphoria, headache, anxiety, dizziness, nausea, irregular heartbeat, interaction with MAO inhibitors, trembling hands, increased need for water and potassium, and psychosis resulting from the long-term use of ephedrine.
# Controversy and legality
Due to deaths linked to ephedrine and its potential use as a precursor in illegal methamphetamine manufacture, many countries have taken steps to regulate ephedrine. If ephedrine cannot be obtained, pseudoephedrine, ephedrine's optical isomer, can be substituted, but many countries are restricting sales of over the counter pseudoephedrine as well, because it is likewise used as a precursor in methamphetamine manufacture. Contrary to popular belief studies have shown pseudoephedrine to have a thermogenic effect; approximately three times less than L-ephedrine.
Many people have felt that ephedrine is not worth the risks, and have tried "ephedrine free" stack formulas. However, there is no proof that any of these formulations are actually effective, whereas a great deal of evidence exists to support the effectiveness of the ECA stack, albeit with apparent risks.
Currently in the United States, ephedrine is legal, but the FDA bars marketing any supplements containing ephedrine as weightloss or bodybuilding supplements. To be legal, ephedrine must be marketed for medical conditions such as asthma. In addition, the FDA recently barred the sale of herbal supplements containing ephedra (a herb which contains both ephedrine and pseudoephedrine) under any circumstances. Ephedrine is still commonly available as a bronchodilator in several over the counter asthma medications from companies such as Biotek and Vasopro as well as in Primatine tablets.
As of 4/14/2005, U.S. District Judge Tena Campbell struck down the FDA's ban of weight loss supplements containing ephedrine alkaloids in the US, which may pave the way for its reintroduction as a weight loss supplement in the US. The ban on marketing ephedrine as a weightloss supplement at the moment is being challenged by several companies. A judge in Utah has ruled in favor of a pharmaceutical company that challenged the FDA's ban and the company may once again release products containing ephedrine back into the market. | ECA stack
Template:Disputed
The ECA stack is a drug combination used as a stimulant and in weight loss. ECA is an acronym for ephedrine, caffeine, and aspirin.
# Mechanism of effect in weight loss
The effects of the ECA stack in weight loss are primarily due to the ephedrine component. Ephedrine acts both as a beta agonist and stimulates the release of norepinephrine. Increased circulating norepinephrine in the body then acts on white adipose tissue by increasing cAMP levels. This causes a thermogenic effect, raising body temperature and increasing the user's metabolism in conjunction with the rest of the stack.[citation needed]
However, the body's negative feedback system then activates to normalize the metabolism. This is done via the production of phosphodiesterase inside the cells, and prostaglandins outside the cell, which both lower cAMP levels within the cell.
Caffeine inhibits the production of phosphodiesterase inside the cell and therefore slows cAMP breakdown. It also binds with and competitively inhibits adenosine receptors in the brain, triggering the release of epinephrine and increasing cAMP levels further.
Aspirin inhibits prostaglandin production outside of the cells, which, in conjunction with caffeine, greatly prolongs the thermogenic effects and increased metabolism by substaining elevated cAMP levels.
Ephedrine also has an anorectic, or appetite-suppressing, effect. However, these effects only last for about two weeks if the stack is not cycled, as the body becomes tolerant to ephedrine to some degree.[citation needed] It is estimated that 60% – 75% of the weight loss from using the ECA stack comes from the anorectic effect, and the remainder from thermogenesis.[citation needed]
The final component in weight loss of the ECA stack is that of a simple stimulant; the higher epinephrine and norepinephrine levels result in increased aerobic exercise performance and less fatigue.[citation needed]
# Mechanisms of effect in energy gain
Ephedrine acts to increase energy by its actions as a sympathomimetic amine. It directly acts in the brain to increase the release of norepinephrine into the synaptic cleft, and also partially serves as a norepinephrine reuptake inhibitor, thereby also partially functioning as a dopamine reuptake inhibitor due to the shared action between the two terminals. Caffeine blocks adenosine receptors which lessens feelings of tiredness, and also increases dopamine levels, resulting in greater concentration, focus, and memory. The effects of caffeine on dopamine levels are usually short lived, but ephedrine's partial action as a dopamine reuptake inhibitor lengthens the duration.[citation needed]
# Dosage
Typically the ECA stack is consumed two or three times per day in a 1:10:10 or 1:10:15 ratio of ephedrine:caffeine:aspirin. These ratios vary across studies and across users but despite variance they all seem to be effective.[citation needed] Usually, no more than 25 mg of ephedrine, 200 mg of caffeine and 325 mg of aspirin is consumed in a single dose. It is not recommended that the stack be taken past late afternoon as this may contribute to insomnia.
# Addiction
While aspirin is not physically addictive, caffeine is, and users develop a tolerance to lowered adenosine levels, leading to withdrawal symptoms from adenosine sensitivity if caffeine use is discontinued too quickly. Psychological addiction to ephedrine and caffeine are also possible.
# Risks
The primary risk of the ECA stack is in the effect of ephedrine on the heart. Ephedrine has been linked to deaths in people with valve damage, heart problems and heart disease, but also in previously healthy young adults when taken in high doses. It is not recommended that stimulants be taken in users with a pre-existing heart condition. Additionally, there is some evidence that the long term use of amphetamines can lead to heart damage, but this has not been shown for ephedrine use.
Caffeine and ephedrine also act to raise blood pressure by approximately 4 – 7 mmHg on average,[citation needed] so users with existing hypertension must be careful that the stack does not increase their blood pressure to dangerous levels — especially during exercise (for example, by lifting exceptionally heavy weights).
Other risks include insomnia, dry mouth, irritability, stress, euphoria, headache, anxiety, dizziness, nausea, irregular heartbeat, interaction with MAO inhibitors, trembling hands, increased need for water and potassium, and psychosis resulting from the long-term use of ephedrine.
# Controversy and legality
Due to deaths linked to ephedrine and its potential use as a precursor in illegal methamphetamine manufacture, many countries have taken steps to regulate ephedrine. If ephedrine cannot be obtained, pseudoephedrine, ephedrine's optical isomer, can be substituted, but many countries are restricting sales of over the counter pseudoephedrine as well, because it is likewise used as a precursor in methamphetamine manufacture. Contrary to popular belief studies have shown pseudoephedrine to have a thermogenic effect; approximately three times less than L-ephedrine.[citation needed]
Many people have felt that ephedrine is not worth the risks, and have tried "ephedrine free" stack formulas. However, there is no proof that any of these formulations are actually effective, whereas a great deal of evidence exists to support the effectiveness of the ECA stack,[dubious – discuss] albeit with apparent risks.
Currently in the United States, ephedrine is legal, but the FDA bars marketing any supplements containing ephedrine as weightloss or bodybuilding supplements. To be legal, ephedrine must be marketed for medical conditions such as asthma. In addition, the FDA recently barred the sale of herbal supplements containing ephedra (a herb which contains both ephedrine and pseudoephedrine) under any circumstances. Ephedrine is still commonly available as a bronchodilator in several over the counter asthma medications from companies such as Biotek and Vasopro as well as in Primatine tablets.
As of 4/14/2005, U.S. District Judge Tena Campbell struck down the FDA's ban of weight loss supplements containing ephedrine alkaloids in the US, which may pave the way for its reintroduction as a weight loss supplement in the US. The ban on marketing ephedrine as a weightloss supplement at the moment is being challenged by several companies. A judge in Utah has ruled in favor of a pharmaceutical company that challenged the FDA's ban and the company may once again release products containing ephedrine back into the market.[citation needed] | https://www.wikidoc.org/index.php/ECA_stack | |
0b4d77bffcf6f0c88ef84fd45b125cc4990dbacb | wikidoc | Echovirus | Echovirus
# Overview
An echovirus is a type of RNA virus that belongs to the genus Enterovirus of the Picornaviridae family. Echoviruses are found in the gastrointestinal tract (hence it being part of the enterovirus genus) and exposure to the virus causes other opportunistic infections and diseases.
# Historical Perspective
The first isolation of echoviruses occurred from the feces of asymptomatic children early in the 1950s, just after cell culturing had been developed. The echo– part of the name was originally an acronym for "enteric cytopathic human orphan" virus: Orphan virus means a virus that is not associated with any known disease. Even though Echoviruses have since been identified with various diseases, the original name is still used.
# Microbiology
## Viral Structure
An echovirus measures 24-30 nanometres (nm), and is similar to other viruses, since it has a naked protein capsid, which makes up 75% of the virus particle that encloses a dense central core of single-stranded RNA. This RNA has a length of approximately 7.5 kilobase (kb), contains an RNA replicase, viral-coded proteins, and a single polyprotein that is responsible for the formation of structural proteins and other proteins necessary for cellular replication. The structural proteins determine host range and play a very important role in delivering the RNA genome into the cytoplasm of new host cells.
## Replication
Some viral replication of an echovirus occurs in the nasopharynx after infection and then spreads to regional lymph nodes. However, most viral particles are swallowed and they reach the lower gut tract, where the virus is presumed to bind to specific receptors. The virus then spreads to the lower intestinal tract, replicating but not causing any major cellular effects along the way. Next, the virus spreads to many secondary sites in the body such as the central nervous system, liver, spleen, bone marrow, heart and finally the lungs. Additional replication of the virus will occur, causing symptoms 4 to 6 days after infection. The most deadly part however is delayed when symptoms of a central nervous system disease start to appear. Enteroviruses are capable of infecting any cell in the body. These viruses are highly infectious. They can spread through the air to other hosts 1-3 weeks after infection and can spread through feces to other hosts eight weeks after infection.
## Manifestation
Echovirus is a highly infectious, and its primary target is children. The echovirus is among the leading causes of acute febrile illness in infants and young children, and is the most common cause of aseptic meningitis.
Infection of an infant with this virus following birth may cause severe systemic diseases, and is associated with high infant mortality rates. The echovirus can mimic symptoms caused by other common bacterial and viral infections, so echovirus infections are often treated with therapies aimed for other infections. This can lead to the evolution of antibiotic-resistant bacteria.
# Causes of Infection
Causes of echovirus infections can be placed in several categories. Main causes of infection are from overcrowded conditions such as the poor districts of a city and poor hygiene. Echoviruses are transmitted person-to-person; the fecal-oral route is the predominant mode, although transmission sometimes occurs via respiration of oral secretions such as saliva. Indirect transmission occurs through numerous routes, including via contaminated water, food, and fomites (inanimate objects). Contaminated swimming and wading pools can also transmit the virus. Also, there are well-documented reports of transmission via the contaminated hands of hospital personnel.
# Diagnosis
## Symptoms
Echovirus disease occurs disproportionately in males. Infection within the first two weeks of birth can cause devastating and potentially fatal disease. In this population, death usually results from overwhelming liver failure or myocarditis, rather than infection of the central nervous system. Older children and adults have a better prognosis. Myocarditis is the most frequent complication in adults.
Echovirus infections can occur in people of all age groups. However, with increasing age, there is increased production of specific antibodies to the echovirus. Several studies performed during epidemics show that infants become infected at notably higher rates than older children and adults.
# Treatment
No specific treatment for echovirus infection is currently available. Care is directed at relief of symptoms. The anti-viral drug pleconaril interferes with the binding of the echovirus particle to the cell membrane and the drug also hinders the uncoating of virions by attaching itself to the viral protein capsid. The pharmaceutical company, ViroPharma Incorporated, ended development of pleconaril in 2004. | Echovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
An echovirus is a type of RNA virus that belongs to the genus Enterovirus of the Picornaviridae family.[1] Echoviruses are found in the gastrointestinal tract (hence it being part of the enterovirus genus) and exposure to the virus causes other opportunistic infections and diseases.
# Historical Perspective
The first isolation of echoviruses occurred from the feces of asymptomatic children early in the 1950s, just after cell culturing had been developed. The echo– part of the name was originally an acronym for "enteric cytopathic human orphan" virus: Orphan virus means a virus that is not associated with any known disease. Even though Echoviruses have since been identified with various diseases, the original name is still used.[2]
# Microbiology
## Viral Structure
An echovirus measures 24-30 nanometres (nm), and is similar to other viruses, since it has a naked protein capsid, which makes up 75% of the virus particle that encloses a dense central core of single-stranded RNA. This RNA has a length of approximately 7.5 kilobase (kb), contains an RNA replicase, viral-coded proteins, and a single polyprotein that is responsible for the formation of structural proteins and other proteins necessary for cellular replication. The structural proteins determine host range and play a very important role in delivering the RNA genome into the cytoplasm of new host cells.
## Replication
Some viral replication of an echovirus occurs in the nasopharynx after infection and then spreads to regional lymph nodes. However, most viral particles are swallowed and they reach the lower gut tract, where the virus is presumed to bind to specific receptors. The virus then spreads to the lower intestinal tract, replicating but not causing any major cellular effects along the way. Next, the virus spreads to many secondary sites in the body such as the central nervous system, liver, spleen, bone marrow, heart and finally the lungs. Additional replication of the virus will occur, causing symptoms 4 to 6 days after infection. The most deadly part however is delayed when symptoms of a central nervous system disease start to appear. Enteroviruses are capable of infecting any cell in the body. These viruses are highly infectious. They can spread through the air to other hosts 1-3 weeks after infection and can spread through feces to other hosts eight weeks after infection.
## Manifestation
Echovirus is a highly infectious, and its primary target is children. The echovirus is among the leading causes of acute febrile illness in infants and young children, and is the most common cause of aseptic meningitis.
Infection of an infant with this virus following birth may cause severe systemic diseases, and is associated with high infant mortality rates. The echovirus can mimic symptoms caused by other common bacterial and viral infections, so echovirus infections are often treated with therapies aimed for other infections. This can lead to the evolution of antibiotic-resistant bacteria.
# Causes of Infection
Causes of echovirus infections can be placed in several categories. Main causes of infection are from overcrowded conditions such as the poor districts of a city and poor hygiene. Echoviruses are transmitted person-to-person; the fecal-oral route is the predominant mode, although transmission sometimes occurs via respiration of oral secretions such as saliva. Indirect transmission occurs through numerous routes, including via contaminated water, food, and fomites (inanimate objects). Contaminated swimming and wading pools can also transmit the virus. Also, there are well-documented reports of transmission via the contaminated hands of hospital personnel.
# Diagnosis
## Symptoms
Echovirus disease occurs disproportionately in males. Infection within the first two weeks of birth can cause devastating and potentially fatal disease. In this population, death usually results from overwhelming liver failure or myocarditis, rather than infection of the central nervous system. Older children and adults have a better prognosis. Myocarditis is the most frequent complication in adults.
Echovirus infections can occur in people of all age groups. However, with increasing age, there is increased production of specific antibodies to the echovirus. Several studies performed during epidemics show that infants become infected at notably higher rates than older children and adults.
# Treatment
No specific treatment for echovirus infection is currently available. Care is directed at relief of symptoms. The anti-viral drug pleconaril interferes with the binding of the echovirus particle to the cell membrane and the drug also hinders the uncoating of virions by attaching itself to the viral protein capsid. The pharmaceutical company, ViroPharma Incorporated, ended development of pleconaril in 2004. | https://www.wikidoc.org/index.php/ECHO_virus | |
e64a613950a049dd96eed83b3675b04f8c4183d1 | wikidoc | EC number | EC number
# Overview
The Enzyme Commission number (EC number) is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze.
As a system of enzyme nomenclature, every EC number is associated with a recommended name for the respective enzyme.
Strictly speaking, EC numbers do not specify enzymes, but enzyme-catalyzed reactions. If different enzymes (for instance from different organisms) catalyze the same reaction, then they receive the same EC number. By contrast, UniProt identifiers uniquely specify a protein by its amino acid sequence.
# Format of number
Every enzyme code consists of the letters "EC" followed by four numbers separated by periods. Those numbers represent a progressively finer classification of the enzyme.
For example, the tripeptide aminopeptidases have the code "EC 3.4.11.4", whose components indicate the following groups of enzymes:
- EC 3 enzymes are hydrolases (enzymes that use water to break up some other molecule)
- EC 3.4 are hydrolases that act on peptide bonds
- EC 3.4.11 are those hydrolases that cleave off the amino-terminal amino acid from a polypeptide
- EC 3.4.11.4 are those that cleave off the amino-terminal end from a tripeptide
# Top level codes
# History
The enzyme nomenclature scheme was developed starting in 1955, when the International Congress of Biochemistry in Brussels set up an Enzyme Commission.
The first version was published in 1961.
The current sixth edition, published by the International Union of Biochemistry and Molecular Biology in 1992, contains 3196 different enzymes. | EC number
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Enzyme Commission number (EC number) is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze.
As a system of enzyme nomenclature, every EC number is associated with a recommended name for the respective enzyme.
Strictly speaking, EC numbers do not specify enzymes, but enzyme-catalyzed reactions. If different enzymes (for instance from different organisms) catalyze the same reaction, then they receive the same EC number. By contrast, UniProt identifiers uniquely specify a protein by its amino acid sequence.[1]
# Format of number
Every enzyme code consists of the letters "EC" followed by four numbers separated by periods. Those numbers represent a progressively finer classification of the enzyme.
For example, the tripeptide aminopeptidases have the code "EC 3.4.11.4", whose components indicate the following groups of enzymes:
- EC 3 enzymes are hydrolases (enzymes that use water to break up some other molecule)
- EC 3.4 are hydrolases that act on peptide bonds
- EC 3.4.11 are those hydrolases that cleave off the amino-terminal amino acid from a polypeptide
- EC 3.4.11.4 are those that cleave off the amino-terminal end from a tripeptide
# Top level codes
# History
The enzyme nomenclature scheme was developed starting in 1955, when the International Congress of Biochemistry in Brussels set up an Enzyme Commission.
The first version was published in 1961.
The current sixth edition, published by the International Union of Biochemistry and Molecular Biology in 1992, contains 3196 different enzymes. | https://www.wikidoc.org/index.php/EC_number | |
0bac933e57c26e6e342fe50623d613c5091e50cf | wikidoc | Enolase 2 | Enolase 2
Gamma-enolase, also known as enolase 2 (ENO2) or neuron specific enolase (NSE), is an enzyme that in humans is encoded by the ENO2 gene. Gamma-enolase is a phosphopyruvate hydratase.
Gamma-enolase is one of the three enolase isoenzymes found in mammals. This isoenzyme, a homodimer, is found in mature neurons and cells of neuronal origin. A switch from alpha enolase to gamma enolase occurs in neural tissue during development in rats and primates.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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}
# Utility
Detection of NSE with antibodies can be used to identify neuronal cells and cells with neuroendocrine differentiation. NSE is produced by small cell carcinomas which are neuroendocrine in origin. NSE is therefore a useful tumor marker for lung cancer patients. | Enolase 2
Gamma-enolase, also known as enolase 2 (ENO2) or neuron specific enolase (NSE), is an enzyme that in humans is encoded by the ENO2 gene.[1][2] Gamma-enolase is a phosphopyruvate hydratase.
Gamma-enolase is one of the three enolase isoenzymes found in mammals. This isoenzyme, a homodimer, is found in mature neurons and cells of neuronal origin. A switch from alpha enolase to gamma enolase occurs in neural tissue during development in rats and primates.[1]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..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}
# Utility
Detection of NSE with antibodies can be used to identify neuronal cells and cells with neuroendocrine differentiation. NSE is produced by small cell carcinomas which are neuroendocrine in origin. NSE is therefore a useful tumor marker for lung cancer patients.[3] | https://www.wikidoc.org/index.php/ENO2 | |
c7b1fd19669b20743cfcca6fdefc0469732c21fb | wikidoc | Eagle III | Eagle III
Eagle III is an emergency air and ground transportation program operated by County Rescue Services, in partnership with Bellin Hospital, and St. Vincient Hospital, all in Green Bay, Wisconsin. Services are provided via ground ambulance, helicopter, turboprop or jet aircraft to and from medical facilities or accident scenes.
The Eagle III rescue helicopter service performs an average of 400 transports a year
# Objectives
The primary mission for Eagle III is emergency air medical services to include scene flights and transport of critically ill or injured patients to facilities with specialized or greater levels of care. In addition to this, Eagle III also provides air support to local law enforcement agencies upon request due to its prime location and ability to rapidly deploy aircraft. Eagle III also flies support missions for the U.S. Secret Service during presidential visits.
# Aircraft
Eagle III’s primary aircraft is a Eurocopter EC 135 (N135CR) with a Bell 206 (N396JS) serving as secondary. In the past the Eagle III program has operated a Bell 407 (N407CR) which has been retired, and a Messerschmitt-Bölkow-Blohm Bo 105 (N202LF) which was lost in the 2006 Eagle III accident on April 13 2006. That was the first accident for County Rescue's air ambulance service. The program began in May 1998 with the purchase of the $1.8 million Bell 407 aircraft and construction of a $200,000 hangar and helipad at the Bellevue headquarters. | Eagle III
Eagle III is an emergency air and ground transportation program operated by County Rescue Services, in partnership with Bellin Hospital, and St. Vincient Hospital, all in Green Bay, Wisconsin. Services are provided via ground ambulance, helicopter, turboprop or jet aircraft to and from medical facilities or accident scenes.[1]
The Eagle III rescue helicopter service performs an average of 400 transports a year[2]
# Objectives
The primary mission for Eagle III is emergency air medical services to include scene flights and transport of critically ill or injured patients to facilities with specialized or greater levels of care. In addition to this, Eagle III also provides air support to local law enforcement agencies upon request due to its prime location and ability to rapidly deploy aircraft. Eagle III also flies support missions for the U.S. Secret Service during presidential visits.[citation needed]
# Aircraft
Eagle III’s primary aircraft is a Eurocopter EC 135 (N135CR) with a Bell 206 (N396JS) serving as secondary. In the past the Eagle III program has operated a Bell 407 (N407CR) which has been retired, and a Messerschmitt-Bölkow-Blohm Bo 105 (N202LF) which was lost in the 2006 Eagle III accident on April 13 2006. That was the first accident for County Rescue's air ambulance service. The program began in May 1998 with the purchase of the $1.8 million Bell 407 aircraft and construction of a $200,000 hangar and helipad at the Bellevue headquarters.
[3] | https://www.wikidoc.org/index.php/Eagle_III | |
d185e3f2f0bbf2b5f86feaee9b88a91063959637 | wikidoc | Ear canal | Ear canal
# Overview
The ear canal (external auditory meatus, external acoustic meatus), is a tube running from the outer ear to the middle ear. The human ear canal extends from the pinna to the eardrum and is about 26 mm in length and 7 mm in diameter.
# Size and shape
The human ear canal is approximately 26 mm long and 7 mm in diameter. Size and shape of the canal vary among individuals. This is an important factor to consider when fitting hearing protectors.
# Disorders
The ear canal, because of its relative exposure to the outside world, is a common victim of diseases and other disorders. Some disorders include:
- Otitis externa (swimmer's ear), bacteria-caused inflammation of the ear canal
- Contact dermatitis of the ear canal
- Ear fungus
- Ear myiasis, an extremely rare infestation of maggots
- Bone exposure, caused by the wearing away of skin in the canal
- Granuloma, a scar usually caused by tympanostomy tubes
- Stenosis, a gradual closing of the canal
- Foreign body in ear
- Ear mites in animals.
- Cysts of the external auditory meatus
- Epidermal cyst of the external auditory meatus.
- Same cyst of external auditory meatus, magnified.
- Large cyst of the external auditory meatus.
# Earwax
Earwax, also known as cerumen, is a yellowish, waxy substance secreted in the ear canals. It plays an important role in the human ear canal, assisting in cleaning and lubrication, and also provides some protection from bacteria, fungi, and insects. Excess or impacted cerumen can press against the eardrum and/or occlude the external auditory canal and impair hearing. | Ear canal
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The ear canal (external auditory meatus, external acoustic meatus), is a tube running from the outer ear to the middle ear. The human ear canal extends from the pinna to the eardrum and is about 26 mm in length and 7 mm in diameter.
# Size and shape
The human ear canal is approximately 26 mm long and 7 mm in diameter. Size and shape of the canal vary among individuals. This is an important factor to consider when fitting hearing protectors.
# Disorders
The ear canal, because of its relative exposure to the outside world, is a common victim of diseases and other disorders. Some disorders include:
- Otitis externa (swimmer's ear), bacteria-caused inflammation of the ear canal
- Contact dermatitis of the ear canal
- Ear fungus
- Ear myiasis, an extremely rare infestation of maggots
- Bone exposure, caused by the wearing away of skin in the canal
- Granuloma, a scar usually caused by tympanostomy tubes
- Stenosis, a gradual closing of the canal
- Foreign body in ear
- Ear mites in animals.
- Cysts of the external auditory meatus
- Epidermal cyst of the external auditory meatus.[1]
- Same cyst of external auditory meatus, magnified.[2]
- Large cyst of the external auditory meatus. [3]
# Earwax
Earwax, also known as cerumen, is a yellowish, waxy substance secreted in the ear canals. It plays an important role in the human ear canal, assisting in cleaning and lubrication, and also provides some protection from bacteria, fungi, and insects. Excess or impacted cerumen can press against the eardrum and/or occlude the external auditory canal and impair hearing. | https://www.wikidoc.org/index.php/Ear_canal | |
97bc7588669af9066cd26e52b11a72ff302a6aa9 | wikidoc | Otoplasty | Otoplasty
# Overview
Otoplasty, is a cosmetic surgery to change the appearance of a person's external ears. Otoplasty can take many forms, such as bringing the ears closer to the head (often called ear pinning), reducing the size of very big ears, or reshaping various bends in the cartilage. Other reconstructive procedures deal with the deformed, or abscent-microtic ears. Otoplasty surgery can involve a combination of moving, reshaping, adding, or removing structural ear elements. This procedure is usually performed by either an oral and maxillofacial surgeon, plastic surgeon, or ENT surgeon.
The external ear is made of a thin structural cartilage cover over with thin skin. Each of the various folds and structures of the pinna (external ear) is named. Ear deformity results from distorted, damaged, or missing ear elements. Many otoplasties are performed not because of actual deformity, but because the individual is displeased with the shape of their ears.
# History
Otoplasty was first developed by Sushruta, a physician often regarded as the "father of surgery". He lived in ancient India circa 600 BC, which he first described in his text Susrutha Samhita. He and his later students and disciples used otoplasty to reconstruct ears that were amputated as a punishment for crimes. The techniques of otoplasty he developed form the basis of surgical procedures that are practiced to this day. This knowledge of plastic surgery existed in India up to the late 18th century.
# How otoplasty ear surgery is performed
Anesthetic options depend on the problem to be treated and ability of the patient to cooperate and can include local anesthesia alone, local anesthesia with sedation, and under general anesthesia (which is generally the case for children). Most otoplasty surgery is performed as a outpatient surgery, some requires a hospital stay. The procedure can take from two to five hours depending on the problem.
Incising one side of a flat cartilage piece leaves unopposed elastic forces on the other side and permits the shape to evolve over time. Thus, incising one side of the lop-ear cartilage along the new anti-helical fold may be one element of the surgery. This can be done through a small incision, or without an incision: an "Incisionless Otoplasty," where a needle is placed through the skin to model the cartilage and also to place the retention sutures.
For many ear operations, one or more incisions give access to the structures to be sculpted. The main, and often only incision, is behind the ear. Other possible incisions depend on what needs to be done. Through the incision behind the ear, the concha bowl can be moved closer to the head, a small tunnel created along the front of a poorly folded antihelix to weaken this cartilage, sutures placed to reshape the anti-helix fold, and to balance the ear lobe with the rest of the ear.
Ear reduction otoplasty may involve reducing one or more components of the ear. Incisions are typically hidden near folds in the front when a part of this surgery.
Addressing Microtia (small ear deformity) or Anotia (missing ear deformity) involve augmentation or adding elements to replace deformed or missing structures. Cartilage from the ear or rib are the most common for these more extensive reconstructions. Other ear shapes may be changed through moving, adding, and weakening ear structures.
Internal sutures often are permanent. The wound(s) are then closed with either dissolvable sutures or ones that are removed by a doctor after the wounds have healed. A bulky ear dressing protects the ear after surgery. | Otoplasty
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2]
# Overview
Otoplasty, is a cosmetic surgery to change the appearance of a person's external ears. Otoplasty can take many forms, such as bringing the ears closer to the head (often called ear pinning), reducing the size of very big ears, or reshaping various bends in the cartilage. Other reconstructive procedures deal with the deformed, or abscent-microtic ears. Otoplasty surgery can involve a combination of moving, reshaping, adding, or removing structural ear elements. This procedure is usually performed by either an oral and maxillofacial surgeon, plastic surgeon, or ENT surgeon.
The external ear is made of a thin structural cartilage cover over with thin skin. Each of the various folds and structures of the pinna (external ear) is named. Ear deformity results from distorted, damaged, or missing ear elements. Many otoplasties are performed not because of actual deformity, but because the individual is displeased with the shape of their ears.
# History
Otoplasty was first developed by Sushruta, a physician often regarded as the "father of surgery". He lived in ancient India circa 600 BC, which he first described in his text Susrutha Samhita. He and his later students and disciples used otoplasty to reconstruct ears that were amputated as a punishment for crimes. The techniques of otoplasty he developed form the basis of surgical procedures that are practiced to this day. This knowledge of plastic surgery existed in India up to the late 18th century.
# How otoplasty ear surgery is performed
Anesthetic options depend on the problem to be treated and ability of the patient to cooperate and can include local anesthesia alone, local anesthesia with sedation, and under general anesthesia (which is generally the case for children). Most otoplasty surgery is performed as a outpatient surgery, some requires a hospital stay. The procedure can take from two to five hours depending on the problem.
Incising one side of a flat cartilage piece leaves unopposed elastic forces on the other side and permits the shape to evolve over time. Thus, incising one side of the lop-ear cartilage along the new anti-helical fold may be one element of the surgery. This can be done through a small incision, or without an incision: an "Incisionless Otoplasty," where a needle is placed through the skin to model the cartilage and also to place the retention sutures.
For many ear operations, one or more incisions give access to the structures to be sculpted. The main, and often only incision, is behind the ear. Other possible incisions depend on what needs to be done. Through the incision behind the ear, the concha bowl can be moved closer to the head, a small tunnel created along the front of a poorly folded antihelix to weaken this cartilage, sutures placed to reshape the anti-helix fold, and to balance the ear lobe with the rest of the ear.
Ear reduction otoplasty may involve reducing one or more components of the ear. Incisions are typically hidden near folds in the front when a part of this surgery.
Addressing Microtia (small ear deformity) or Anotia (missing ear deformity) involve augmentation or adding elements to replace deformed or missing structures. Cartilage from the ear or rib are the most common for these more extensive reconstructions. Other ear shapes may be changed through moving, adding, and weakening ear structures.
Internal sutures often are permanent. The wound(s) are then closed with either dissolvable sutures or ones that are removed by a doctor after the wounds have healed. A bulky ear dressing protects the ear after surgery. | https://www.wikidoc.org/index.php/Ear_pinning | |
0178f2b732377ea9aaefd648c264347c09fc70eb | wikidoc | Early ACS | Early ACS
Tracking Information
First Received Date †
August 17, 2004
Last Updated Date
December 17, 2008
Start Date †
November 2004
Current Primary Outcome Measures †
(submitted: January 3, 2008)
Incidence of the composite of death, myocardial infarction (MI), recurrent ischemia requiring urgent revascularization (RI-UR), and thrombotic bail-out.
Original Primary Outcome Measures †
Same as current
Change History
Complete list of historical versions of study NCT00089895 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures †
(submitted: January 3, 2008)
Key secondary outcome is incidence of the composite of death/MI.
Incidences of (1) MI and (2) the composite of death/MI.
Incidence of the composite of death/MI/RI-UR
Incidence of death.
Original Secondary Outcome Measures †
Same as current
Descriptive Information
Brief Title †
EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (Study P03684AM2)(COMPLETED)
Official Title †
Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome: A Randomized, Placebo-Controlled Trial Evaluating the Clinical Benefits of Early Front-Loaded Eptifibatide in the Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS)
Brief Summary
The purpose of this study is to see if early INTEGRILIN® (eptifibatide) therapy in patients with non-ST-segment elevation acute coronary syndrome (ACS) reduces the occurence of death, heart attack and urgent cardiac intervention (surgery) compared to placebo.
Detailed Description
This study will enroll patients who experience symptoms of acute coronary syndrome (experiencing chest pain at rest with episodes lasting at least 10 minutes) and who are planned to undergo invasive surgical procedures after being given study drug for 12 to 96 hours. There are two different treatment groups in this study; approximately half of the patients will go to each group and the likelihood of receiving study drug vs. placebo is 50/50 (like tossing a coin). Medications that are standard of care will be provided to the patients (all patients will be given aspirin and standard hospital doses of one of two other blood thinning drugs - unfractionated heparin (UFH) or low-molecular-weight heparin). Which one patients receive is at the discretion of the Investigator.
Study Phase
Phase III
Study Type †
Interventional
Study Design †
Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study
Condition †
Myocardial Ischemia
Acute Coronary Syndrome
Intervention †
Drug: Eptifibatide (Integrilin)
Drug: Placebo
Study Arms / Comparison Groups
Experimental: Eptifibatide in addition to standard of care.
Placebo Comparator: Placebo in addition to standard of care.
Publications *
- Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status †
Completed
Estimated Enrollment †
Completion Date
November 2008
Primary Completion Date
November 2008 (final data collection date for primary outcome measure)
Eligibility Criteria †
Inclusion Criteria:
Willing and able to give informed consent and comply with study procedures and follow-up through 1 year.
Plan to undergo an invasive strategy after receiving study drug for 12 to 96 hours.
Able to be randomized into the trial within 12 hours of having symptoms of acute coronary syndrome.
Experiencing symptoms of cardiac ischemia at rest (angina or anginal equivalent) with episode(s) lasting at least 10 minutes and have at least 2 of the following:
60 years of age or more
Electrocardiogram changes (ECG)
Elevated troponin (protein released in the blood stream in people suffering from acute coronary syndrome) or CK-MB levels
Or have all 3 of the following:
Prior history of cardiovascular disease
Elevated troponin or CK-MB levels
50-59 years of age
Exclusion Criteria:
pregnancy (known or suspected)
renal dialysis within 30 days prior to randomizing in study
-ther serious illnesses or any condition that the investigator feels would pose a significant hazard to the patient if the investigational therapy was to be initiated
Stroke (hemorrhagic stroke at any time or non-hemorrhagic stroke within previous 7 days), central nervous system damage (such as neoplasm, aneurysm, intracranial surgery), bleeding disorders (including gastrointestinal bleeding), or recent major surgery or major trauma.
History of certain hematologic problems following treatment with heparin or eptifibatide.
Therapy with certain related drugs within a short time before randomization into the trial.
Gender
Both
Ages
18 Years and older
Accepts Healthy Volunteers
No
Contacts ††
Location Countries †
Expanded Access Status
Administrative Information
NCT ID †
NCT00089895
Responsible Party
Head, Clinical Trials Registry & Results Disclosure Group, Schering-Plough
Secondary IDs ††
Study Sponsor †
Schering-Plough
Collaborators ††
Duke University
Investigators †
Information Provided By
Schering-Plough
Verification Date
December 2008
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists. | Early ACS
Tracking Information
First Received Date †
August 17, 2004
Last Updated Date
December 17, 2008
Start Date †
November 2004
Current Primary Outcome Measures †
(submitted: January 3, 2008)
Incidence of the composite of death, myocardial infarction (MI), recurrent ischemia requiring urgent revascularization (RI-UR), and thrombotic bail-out. [Time Frame: 96 hours after randomization] [Designated as safety issue: No]
Original Primary Outcome Measures †
Same as current
Change History
Complete list of historical versions of study NCT00089895 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures †
(submitted: January 3, 2008)
Key secondary outcome is incidence of the composite of death/MI. [Time Frame: 30 days after randomization] [Designated as safety issue: No]
Incidences of (1) MI and (2) the composite of death/MI. [Time Frame: 96 hours after randomization] [Designated as safety issue: No]
Incidence of the composite of death/MI/RI-UR [Time Frame: 30 days after randomization] [Designated as safety issue: No]
Incidence of death. [Time Frame: 30 days, 6 months, and 1 year after randomization] [Designated as safety issue: No]
Original Secondary Outcome Measures †
Same as current
Descriptive Information
Brief Title †
EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (Study P03684AM2)(COMPLETED)
Official Title †
Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome: A Randomized, Placebo-Controlled Trial Evaluating the Clinical Benefits of Early Front-Loaded Eptifibatide in the Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS)
Brief Summary
The purpose of this study is to see if early INTEGRILIN® (eptifibatide) therapy in patients with non-ST-segment elevation acute coronary syndrome (ACS) reduces the occurence of death, heart attack and urgent cardiac intervention (surgery) compared to placebo.
Detailed Description
This study will enroll patients who experience symptoms of acute coronary syndrome (experiencing chest pain at rest with episodes lasting at least 10 minutes) and who are planned to undergo invasive surgical procedures after being given study drug for 12 to 96 hours. There are two different treatment groups in this study; approximately half of the patients will go to each group and the likelihood of receiving study drug vs. placebo is 50/50 (like tossing a coin). Medications that are standard of care will be provided to the patients (all patients will be given aspirin and standard hospital doses of one of two other blood thinning drugs - unfractionated heparin (UFH) or low-molecular-weight heparin). Which one patients receive is at the discretion of the Investigator.
Study Phase
Phase III
Study Type †
Interventional
Study Design †
Treatment, Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study
Condition †
Myocardial Ischemia
Acute Coronary Syndrome
Intervention †
Drug: Eptifibatide (Integrilin)
Drug: Placebo
Study Arms / Comparison Groups
Experimental: Eptifibatide in addition to standard of care.
Placebo Comparator: Placebo in addition to standard of care.
Publications *
- Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status †
Completed
Estimated Enrollment †
9500
Completion Date
November 2008
Primary Completion Date
November 2008 (final data collection date for primary outcome measure)
Eligibility Criteria †
Inclusion Criteria:
Willing and able to give informed consent and comply with study procedures and follow-up through 1 year.
Plan to undergo an invasive strategy after receiving study drug for 12 to 96 hours.
Able to be randomized into the trial within 12 hours of having symptoms of acute coronary syndrome.
Experiencing symptoms of cardiac ischemia at rest (angina or anginal equivalent) with episode(s) lasting at least 10 minutes and have at least 2 of the following:
60 years of age or more
Electrocardiogram changes (ECG)
Elevated troponin (protein released in the blood stream in people suffering from acute coronary syndrome) or CK-MB levels
Or have all 3 of the following:
Prior history of cardiovascular disease
Elevated troponin or CK-MB levels
50-59 years of age
Exclusion Criteria:
pregnancy (known or suspected)
renal dialysis within 30 days prior to randomizing in study
other serious illnesses or any condition that the investigator feels would pose a significant hazard to the patient if the investigational therapy was to be initiated
Stroke (hemorrhagic stroke at any time or non-hemorrhagic stroke within previous 7 days), central nervous system damage (such as neoplasm, aneurysm, intracranial surgery), bleeding disorders (including gastrointestinal bleeding), or recent major surgery or major trauma.
History of certain hematologic problems following treatment with heparin or eptifibatide.
Therapy with certain related drugs within a short time before randomization into the trial.
Gender
Both
Ages
18 Years and older
Accepts Healthy Volunteers
No
Contacts ††
Location Countries †
Expanded Access Status
Administrative Information
NCT ID †
NCT00089895
Responsible Party
Head, Clinical Trials Registry & Results Disclosure Group, Schering-Plough
Secondary IDs ††
Study Sponsor †
Schering-Plough
Collaborators ††
Duke University
Investigators †
Information Provided By
Schering-Plough
Verification Date
December 2008
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists. | https://www.wikidoc.org/index.php/Early_ACS | |
c441989feef698954951d601f375215f69d24357 | wikidoc | Echenacia | Echenacia
Echinacea is a herbal supplement that is supposed to boost the immune system and help calm mood.
The primary constituent responsible for its activity are large sugar molecules called polysaccharides.
Echinacea is a popular natural product all over the world, especially used to treat colds. | Echenacia
Template:Mergeto
Echinacea is a herbal supplement that is supposed to boost the immune system and help calm mood.
The primary constituent responsible for its activity are large sugar molecules called polysaccharides.
Echinacea is a popular natural product all over the world, especially used to treat colds.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Echenacia | |
1b556931129c5821b08b2550c1e05559f12446e5 | wikidoc | Echinacea | Echinacea
Echinacea commonly called the Purple coneflowers, is a genus of nine species of herbaceous plants in the Family Asteraceae. All are strictly native to eastern and central North America. The plants have large showy heads of composite flowers, blooming from early to late summer. Some species are used in herbal medicines.
The genus name is from the Greek echino, meaning "spiny", due to the spiny central disk. They are herbaceous, drought-tolerant perennial plants growing to 1 or 2 m in height. The leaves are lanceolate to elliptic, 10–20 cm long and 1.5–10 cm broad. Like all Asteraceae, the flowers are a composite inflorescence, with purple (rarely yellow or white) florets arranged in a prominent, somewhat cone-shaped head; "cone-shaped" because the petals of the outer ray florets tend to point downward (are reflexed) once the flower head opens, thus forming a cone.
# Species
The species of Echinacea are:
- Echinacea angustifolia - Narrow-leaf Coneflower
- Echinacea atrorubens - Topeka Purple Coneflower
- Echinacea laevigata - Smooth Coneflower, Smooth Purple Coneflower
- Echinacea pallida - Pale Purple Coneflower
- Echinacea paradoxa - Yellow Coneflower, Bush's Purple Coneflower
- Echinacea purpurea - Purple Coneflower, Eastern Purple Coneflower
- Echinacea sanguinea - Sanguine purple coneflower
- Echinacea simulata - Wavyleaf Purple Coneflower
- Echinacea tennesseensis - Tennessee Coneflower
# Health effects
Echinacea is popularly believed to stimulate the body's immune system and ward off infections, particularly the common cold. However, its clinical efficacy has not been established.
## History
Echinacea angustifolia rhizome was used by North American Plains Indians, perhaps more than most other plants, for various herbal remedies. Echinacea was one of the basic antimicrobial herbs of Eclectic medicine in the mid 1800s through the early 1900s and its use was documented for snakebite and anthrax. In the 1930s "Echinacea" became popular in both Europe and America as a herbal medicine.
## Active substances
The full spectrum of echinacea's chemical components responsible for its health effects are not well understood. Like most crude drugs from plant or animal origin, the constituent base is complex and some parts may be directly antimicrobial while others work at stimulating or modulating different parts of the immune system. All species have chemical compounds called phenols, which are common to many other plants. Both the phenol compounds Cichoric and caftaric are present in E. purpurea, other phenols include echinacoside, which is found in greater levels within E. angustifolia and E. pallida roots than in other species. When making herbal remedies, these phenols can serve as markers to evaluate the quantity of echinacea in the product. Other chemical constituents that may be important in echinacea health effects include alcamides and polysaccharides.
### Root or whole plant
A medical study (Taylor et al. 2003.) found that when echinacea products made from the entire plant (not just the root) were taken after the second cold symptom appeared they provided no measurable beneficial effect for children in treating the severity or duration of symptoms caused by the common cold virus. Dosage however was about a third of what clinical herbalists routinely use, and the leaves and stems are not known to be clinically effective. Studies by the University of Virginia School of Medicine (Turner, 2005 ) confirmed these results, and added that Echinacea had no clinically significant effects on the common cold even if taken immediately upon infection, or as a prophylaxis starting a week prior to symptoms of infection. However, a University of Maryland review of available studies concluded that Echinacea, when taken at first sign of a cold, reduced cold symptoms or shortened their duration. This conclusion was based on 13 European studies. The University of Maryland study also found that three of four studies concluded that taking Echinacea to prevent a cold was ineffective, although including studies that use subclinical doses, the wrong part or unassayed material will bias such conclusions. Another scientific review, however, of 14 published studies found that the incidence of colds was reduced by 58% and the duration by a day and half.
### Alcohol-based or dry
Leading herbalists claim that many studies do not distinguish between alcohol-based echinacea tinctures, which retain potency for up to seven years after production, and capsules containing the dried herb, which lose their efficacy over time. Capsules not only lose strength, but must be digested in the stomach while alcohol tinctures enter the lymphatic system through the tongue.
### Frequency of administration
Proponents of echinacea assert that it is not a "one-dose" treatment, and that in order to work effectively, a dose should be taken at the very first sign of a cold symptom. Subsequent doses must be taken every two to four hours after the first dose, including every two to four hours during the overnight sleeping period, until the cold symptoms have disappeared (generally within 24 hours.) The scientific studies stated above appear to disagree with these claims as ad hoc rationalising; if the cold doesn't go away when expected, the patient can always be blamed for not following the strict regimen, and the product is never to blame. This is known as subjective validation.
### Species
Not all species of Echinacea are equally effective. A Cochrane review of the published studies has found that there is some evidence of benefit in the treatment (but not prevention) of the common cold by the aerial parts of Echinacea purpurea; other formulations of the plant did not show the same effect, and no formulation was effective for prevention.
## Contraindications
Echinacea herbals should not be taken by persons with progressive systemic and auto-immune disorders such as tuberculosis, leicosis, connective tissue disorders, collagenosis, and related diseases such as lupus erythematosus, according to the German Kommission E. Its use in AIDS or against opportunistic infections in AIDS patients is controversial: the Kommission E recommend against it. . It should not be used with other known hepatotoxic drugs such as anabolic steroids, amiodarone (Pacerone® or Cordarone®), methotrexate, or ketoconazole (Nizoral®) .
# Other uses
## Medical
Echinacea may, in addition to common cold, be useful when treating Athlete's foot with Econazole, or in cancer treatment.
## Others
Some species of Echinacea, notably P. purpurea, E. angustifolia, and E. pallida, are grown as ornamental plants in gardens They tolerate a wide variety of conditions, maintain attractive foliage throughout the season, and multiply rapidly. Appropriate species are used in prairie restorations. | Echinacea
Echinacea commonly called the Purple coneflowers, is a genus of nine species of herbaceous plants in the Family Asteraceae. All are strictly native to eastern and central North America. The plants have large showy heads of composite flowers, blooming from early to late summer. Some species are used in herbal medicines.
The genus name is from the Greek echino, meaning "spiny", due to the spiny central disk. They are herbaceous, drought-tolerant perennial plants growing to 1 or 2 m in height. The leaves are lanceolate to elliptic, 10–20 cm long and 1.5–10 cm broad. Like all Asteraceae, the flowers are a composite inflorescence, with purple (rarely yellow or white) florets arranged in a prominent, somewhat cone-shaped head; "cone-shaped" because the petals of the outer ray florets tend to point downward (are reflexed) once the flower head opens, thus forming a cone.
# Species
The species of Echinacea are:
- Echinacea angustifolia - Narrow-leaf Coneflower
- Echinacea atrorubens - Topeka Purple Coneflower
- Echinacea laevigata - Smooth Coneflower, Smooth Purple Coneflower
- Echinacea pallida - Pale Purple Coneflower
- Echinacea paradoxa - Yellow Coneflower, Bush's Purple Coneflower
- Echinacea purpurea - Purple Coneflower, Eastern Purple Coneflower
- Echinacea sanguinea - Sanguine purple coneflower
- Echinacea simulata - Wavyleaf Purple Coneflower
- Echinacea tennesseensis - Tennessee Coneflower
# Health effects
Echinacea is popularly believed to stimulate the body's immune system and ward off infections, particularly the common cold. However, its clinical efficacy has not been established.[1]
## History
Echinacea angustifolia rhizome was used by North American Plains Indians, perhaps more than most other plants, for various herbal remedies. Echinacea was one of the basic antimicrobial herbs of Eclectic medicine in the mid 1800s through the early 1900s and its use was documented for snakebite and anthrax. In the 1930s "Echinacea" became popular in both Europe and America as a herbal medicine.
## Active substances
The full spectrum of echinacea's chemical components responsible for its health effects are not well understood. Like most crude drugs from plant or animal origin, the constituent base is complex and some parts may be directly antimicrobial while others work at stimulating or modulating different parts of the immune system. All species have chemical compounds called phenols, which are common to many other plants. Both the phenol compounds Cichoric and caftaric are present in E. purpurea, other phenols include echinacoside, which is found in greater levels within E. angustifolia and E. pallida roots than in other species. When making herbal remedies, these phenols can serve as markers to evaluate the quantity of echinacea in the product. Other chemical constituents that may be important in echinacea health effects include alcamides and polysaccharides.
### Root or whole plant
A medical study (Taylor et al. 2003[2].) found that when echinacea products made from the entire plant (not just the root) were taken after the second cold symptom appeared they provided no measurable beneficial effect for children in treating the severity or duration of symptoms caused by the common cold virus. Dosage however was about a third of what clinical herbalists routinely use, and the leaves and stems are not known to be clinically effective. Studies by the University of Virginia School of Medicine (Turner, 2005 [3]) confirmed these results, and added that Echinacea had no clinically significant effects on the common cold even if taken immediately upon infection, or as a prophylaxis starting a week prior to symptoms of infection. However, a University of Maryland review of available studies concluded that Echinacea, when taken at first sign of a cold, reduced cold symptoms or shortened their duration. This conclusion was based on 13 European studies.[4] The University of Maryland study also found that three of four studies concluded that taking Echinacea to prevent a cold was ineffective, although including studies that use subclinical doses, the wrong part or unassayed material will bias such conclusions. Another scientific review, however, of 14 published studies found that the incidence of colds was reduced by 58% and the duration by a day and half.[5]
### Alcohol-based or dry
Leading herbalists claim that many studies do not distinguish between alcohol-based echinacea tinctures, which retain potency for up to seven years after production, and capsules containing the dried herb, which lose their efficacy over time.[citation needed] Capsules not only lose strength, but must be digested in the stomach while alcohol tinctures enter the lymphatic system through the tongue.
### Frequency of administration
Proponents of echinacea assert that it is not a "one-dose" treatment, and that in order to work effectively, a dose should be taken at the very first sign of a cold symptom. Subsequent doses must be taken every two to four hours after the first dose, including every two to four hours during the overnight sleeping period, until the cold symptoms have disappeared (generally within 24 hours.) The scientific studies stated above appear to disagree with these claims as ad hoc rationalising; if the cold doesn't go away when expected, the patient can always be blamed for not following the strict regimen, and the product is never to blame. This is known as subjective validation.
### Species
Not all species of Echinacea are equally effective. A Cochrane review of the published studies [6] has found that there is some evidence of benefit in the treatment (but not prevention) of the common cold by the aerial parts of Echinacea purpurea; other formulations of the plant did not show the same effect, and no formulation was effective for prevention.
## Contraindications
Echinacea herbals should not be taken by persons with progressive systemic and auto-immune disorders such as tuberculosis, leicosis, connective tissue disorders, collagenosis, and related diseases such as lupus erythematosus, according to the German Kommission E. Its use in AIDS or against opportunistic infections in AIDS patients is controversial: the Kommission E recommend against it. [7]. It should not be used with other known hepatotoxic drugs such as anabolic steroids, amiodarone (Pacerone® or Cordarone®), methotrexate, or ketoconazole (Nizoral®) [8].
# Other uses
## Medical
Echinacea may, in addition to common cold, be useful when treating Athlete's foot with Econazole, or in cancer treatment[9].
## Others
Some species of Echinacea, notably P. purpurea, E. angustifolia, and E. pallida, are grown as ornamental plants in gardens[10] They tolerate a wide variety of conditions, maintain attractive foliage throughout the season, and multiply rapidly. Appropriate species are used in prairie restorations. | https://www.wikidoc.org/index.php/Echinacea | |
0ffb85fad5c2114d718204b3078c6b685926fd57 | wikidoc | Echolalia | Echolalia
# Overview
Echolalia is the repetition of vocalizations made by another person. Echolalia is present in autism, Tourette syndrome, developmental disability, schizophrenia and, occasionally, other forms of psychopathology. When done involuntarily, it is considered a tic.
The word "echolalia" is derived from the Greek language|Greek]] Template:Polytonic meaning echo or "to repeat", and Template:Polytonic (laliá) meaning "babbling, meaningless talk" (of onomatopoeic origin from the verb Template:Polytonic (laleín) meaning "to talk").
# Immediate echolalia
Immediate echolalia is when a word or phrase is immediately repeated. In some autistic and Asperger's cases it may be a method of buying time to help process language. In an instance a child with autism is asked, "Do you want dinner?" The child echoes back "Do you want dinner?" followed by a pause and then a response, "Yes. What's for dinner?"
# Delayed echolalia
Delayed echolalia has been defined as the "echoing of a phrase after some delay or lapse of time". Persons with autism who repeat TV commercials, favorite movie scripts, or parental reprimands are examples used in describing this phenomenon. It may or may not be communicative.
This condition appears to tap into long-term auditory memory, and for this reason, may be a different phenomenon from immediate echolalia. As it can involve the recitation of entire scripts, delayed echolalia is often mistaken as evidence for higher-than-average intellect. | Echolalia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Echolalia is the repetition of vocalizations made by another person. Echolalia is present in autism, Tourette syndrome, developmental disability, schizophrenia and, occasionally, other forms of psychopathology. When done involuntarily, it is considered a tic.
The word "echolalia" is derived from the Greek language|Greek]] Template:Polytonic meaning echo or "to repeat",[1] and Template:Polytonic (laliá) meaning "babbling, meaningless talk"[2] (of onomatopoeic origin from the verb Template:Polytonic (laleín) meaning "to talk").
# Immediate echolalia
Immediate echolalia is when a word or phrase is immediately repeated. In some autistic and Asperger's cases it may be a method of buying time to help process language. In an instance a child with autism is asked, "Do you want dinner?" The child echoes back "Do you want dinner?" followed by a pause and then a response, "Yes. What's for dinner?"[3]
# Delayed echolalia
Delayed echolalia has been defined as the "echoing of a phrase after some delay or lapse of time". Persons with autism who repeat TV commercials, favorite movie scripts, or parental reprimands are examples used in describing this phenomenon. It may or may not be communicative.
This condition appears to tap into long-term auditory memory, and for this reason, may be a different phenomenon from immediate echolalia. As it can involve the recitation of entire scripts, delayed echolalia is often mistaken as evidence for higher-than-average intellect. | https://www.wikidoc.org/index.php/Echolalia | |
35fa5920423ab8dd28f5afed87d6e0e1f0840ac0 | wikidoc | Econazole | Econazole
# 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
Econazole is a antifungal, imidazole that is FDA approved for the treatment of tinea pedis, tinea cruris, and tinea corporis, cutaneous candidiasis, and in the treatment of tinea versicolor. Common adverse reactions include application site reaction, burning sensation, erythema, pruritus, stinging of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Econazole Nitrate Cream, 1% is indicated for topical application in the treatment of:
- Tinea pedis, Tinea cruris, Tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Microsporum canis, Microsporum audouini, Microsporum gypseum, and Epidermophyton floccosum.
- In the treatment of cutaneous candidiasis, and
- In the treatment of tinea versicolor.
### Dosing Information
- Sufficient Econazole Nitrate Cream, 1% should be applied to cover affected areas once daily in patients with tinea pedis, tinea cruris, tinea corporis, and tinea versicolor, and twice daily (morning and evening) in patients with cutaneous candidiasis.
- Early relief of symptoms is experienced by the majority of patients and clinical improvement may be seen fairly soon after treatment is begun; however, candidal infections and tinea cruris and corporis should be treated for two weeks and tinea pedis for one month in order to reduce the possibility of recurrence. If a patient shows no clinical improvement after the treatment period, 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 Econazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Econazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- 12 years or older
- Apply topically to affected areas once daily for 1 month
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Econazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Econazole in pediatric patients.
# Contraindications
- Econazole Nitrate Cream, 1% is contraindicated in individuals who have shown hypersensitivity to any of its ingredients.
# Warnings
- Econazole Nitrate Cream, 1% is not for ophthalmic use.
### PRECAUTIONS
- If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued.
- For external use only. Avoid introduction of Econazole Nitrate Cream into the eyes.
# Adverse Reactions
## Clinical Trials Experience
During clinical trials, approximately 3% of patients treated with econazole nitrate 1% cream reported side effects thought possibly to be due to the drug, consisting mainly of burning, itching, stinging, and erythema. One case of pruritic rash has also been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Econazole in the drug label.
# Drug Interactions
- Concomitant administration of econazole and warfarin has resulted in enhancement of anticoagulation effect. Most cases reported product application with use under occlusion, genital application, or application to large body surface area which may increase the systemic absorption of econazole nitrate. Monitoring of International Normalized Ratio (INR) and/or prothrombin time may be indicated especially for patients who apply econazole to large body surface areas, in the genital area, or under occlusion.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Econazole nitrate has not been shown to be teratogenic when administered orally to mice, rabbits or rats. Fetotoxic or embryotoxic effects were observed in Segment I oral studies with rats receiving 10 to 40 times the human dermal dose. Similar effects were observed in Segment II or Segment III studies with mice, rabbits and/or rats receiving oral doses 80 or 40 times the human dermal dose.
- Econazole nitrate should be used in the first trimester of pregnancy only when the physician considers it essential to the welfare of the patient. The drug should be used during the second and third trimesters of 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 Econazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Econazole during labor and delivery.
### Nursing Mothers
- It is not know whether econazole nitrate is excreted in human milk. Following oral administration of econazole nitrate to lactating rats, econazole and/or metabolites were excreted in milk and were found in nursing pups. Also, in lactating rats receiving large oral doses (40 or 80 times the human dermal dose), there was a reduction in post partum viability of pups and survival to weaning; however, at these high doses, maternal toxicity was present and may have been a contributing factor. Caution should be exercised when econazole nitrate is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Econazole with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Econazole with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Econazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Econazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Econazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Econazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Oral administration of econazole nitrate in rats has been reported to produce prolonged gestation. Intravaginal administration in humans has not shown prolonged gestation or other adverse reproductive effects attributable to econazole nitrate therapy.
### Immunocompromised Patients
There is no FDA guidance one the use of Econazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
- Concomitant administration of econazole and warfarin has resulted in enhancement of anticoagulation effect. Most cases reported product application with use under occlusion, genital application, or application to large body surface area which may increase the systemic absorption of econazole nitrate. Monitoring of International Normalized Ratio (INR) and/or prothrombin time may be indicated especially for patients who apply econazole to large body surface areas, in the genital area, or under occlusion.
# IV Compatibility
There is limited information regarding IV Compatibility of Econazole in the drug label.
# Overdosage
- Overdosage of econazole nitrate in humans has not been reported to date. In mice, rats, guinea pigs and dogs, the oral LD 50 values were found to be 462, 668, 272, and >160 mg/kg, respectively.
# Pharmacology
## Mechanism of Action
- Econazole nitrate is an azole antifungal agent, inhibits fungal CYP450-mediated conversion of lanosterol to ergosterol. Loss of ergosterol in the fungal cell wall may antifungal activity.
## Structure
- Econazole Nitrate Cream, 1% contains the antifungal agent, Econazole Nitrate USP 1%, in a water-miscible base consisting of pegoxyl 7 stearate, peglicol 5 oleate, mineral oil, benzoic acid, butylated hydroxyanisole, and purified water. The white to off-white soft cream is for topical use only.
## Pharmacodynamics
- Econazole nitrate has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections.
## Pharmacokinetics
- After topical application to the skin of normal subjects, systemic absorption of econazole nitrate is extremely low. Although most of the applied drug remains on the skin surface, drug concentrations were found in the stratum corneum which, by far, exceeded the minimum inhibitory concentration for dermatophytes. Inhibitory concentrations were achieved in the epidermis and as deep as the middle region of the dermis. Less than 1% of the applied dose was recovered in the urine and feces.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Econazole in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Econazole in the drug label.
# How Supplied
Econazole Nitrate Cream, 1% is supplied as follows:
NDC 0168-0312-15 15 gram tube
NDC 0168-0312-30 30 gram tube
NDC 0168-0312-85 85 gram tube
E. FOUGERA & CO.
A division of
Fougera
PHARMACEUTICALS INC.
Melville, New York 11747
I2312C
R09/14
## Storage
- Store Econazole Nitrate Cream, 1% below 86°F.
# Images
## Drug Images
## Package and Label Display Panel
NDC 0168-0312-15
Fougera ®
ECONAZOLE
NITRATE CREAM, 1%
Rx only
FOR TOPICAL USE ONLY .
KEEP OUT OF THE
REACH OF CHILDREN.
NET WT 15 grams
NDC 0168-0312-15
Rx only
Fougera ®
ECONAZOLE
NITRATE CREAM, 1%
FOR TOPICAL USE ONLY.
KEEP OUT OF THE
REACH OF CHILDREN.
NET WT 15 grams
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Econazole in the drug label.
# Precautions with Alcohol
- Alcohol-Econazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Spectazole®
- Ecoza®
# Look-Alike Drug Names
There is limited information regarding Econazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Econazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, 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
Econazole is a antifungal, imidazole that is FDA approved for the treatment of tinea pedis, tinea cruris, and tinea corporis, cutaneous candidiasis, and in the treatment of tinea versicolor. Common adverse reactions include application site reaction, burning sensation, erythema, pruritus, stinging of skin.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Econazole Nitrate Cream, 1% is indicated for topical application in the treatment of:
- Tinea pedis, Tinea cruris, Tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Microsporum canis, Microsporum audouini, Microsporum gypseum, and Epidermophyton floccosum.
- In the treatment of cutaneous candidiasis, and
- In the treatment of tinea versicolor.
### Dosing Information
- Sufficient Econazole Nitrate Cream, 1% should be applied to cover affected areas once daily in patients with tinea pedis, tinea cruris, tinea corporis, and tinea versicolor, and twice daily (morning and evening) in patients with cutaneous candidiasis.
- Early relief of symptoms is experienced by the majority of patients and clinical improvement may be seen fairly soon after treatment is begun; however, candidal infections and tinea cruris and corporis should be treated for two weeks and tinea pedis for one month in order to reduce the possibility of recurrence. If a patient shows no clinical improvement after the treatment period, 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 Econazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Econazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- 12 years or older
- Apply topically to affected areas once daily for 1 month
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Econazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Econazole in pediatric patients.
# Contraindications
- Econazole Nitrate Cream, 1% is contraindicated in individuals who have shown hypersensitivity to any of its ingredients.
# Warnings
- Econazole Nitrate Cream, 1% is not for ophthalmic use.
### PRECAUTIONS
- If a reaction suggesting sensitivity or chemical irritation should occur, use of the medication should be discontinued.
- For external use only. Avoid introduction of Econazole Nitrate Cream into the eyes.
# Adverse Reactions
## Clinical Trials Experience
During clinical trials, approximately 3% of patients treated with econazole nitrate 1% cream reported side effects thought possibly to be due to the drug, consisting mainly of burning, itching, stinging, and erythema. One case of pruritic rash has also been reported.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Econazole in the drug label.
# Drug Interactions
- Concomitant administration of econazole and warfarin has resulted in enhancement of anticoagulation effect. Most cases reported product application with use under occlusion, genital application, or application to large body surface area which may increase the systemic absorption of econazole nitrate. Monitoring of International Normalized Ratio (INR) and/or prothrombin time may be indicated especially for patients who apply econazole to large body surface areas, in the genital area, or under occlusion.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Econazole nitrate has not been shown to be teratogenic when administered orally to mice, rabbits or rats. Fetotoxic or embryotoxic effects were observed in Segment I oral studies with rats receiving 10 to 40 times the human dermal dose. Similar effects were observed in Segment II or Segment III studies with mice, rabbits and/or rats receiving oral doses 80 or 40 times the human dermal dose.
- Econazole nitrate should be used in the first trimester of pregnancy only when the physician considers it essential to the welfare of the patient. The drug should be used during the second and third trimesters of 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 Econazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Econazole during labor and delivery.
### Nursing Mothers
- It is not know whether econazole nitrate is excreted in human milk. Following oral administration of econazole nitrate to lactating rats, econazole and/or metabolites were excreted in milk and were found in nursing pups. Also, in lactating rats receiving large oral doses (40 or 80 times the human dermal dose), there was a reduction in post partum viability of pups and survival to weaning; however, at these high doses, maternal toxicity was present and may have been a contributing factor. Caution should be exercised when econazole nitrate is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Econazole with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Econazole with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Econazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Econazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Econazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Econazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Oral administration of econazole nitrate in rats has been reported to produce prolonged gestation. Intravaginal administration in humans has not shown prolonged gestation or other adverse reproductive effects attributable to econazole nitrate therapy.
### Immunocompromised Patients
There is no FDA guidance one the use of Econazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
- Concomitant administration of econazole and warfarin has resulted in enhancement of anticoagulation effect. Most cases reported product application with use under occlusion, genital application, or application to large body surface area which may increase the systemic absorption of econazole nitrate. Monitoring of International Normalized Ratio (INR) and/or prothrombin time may be indicated especially for patients who apply econazole to large body surface areas, in the genital area, or under occlusion.
# IV Compatibility
There is limited information regarding IV Compatibility of Econazole in the drug label.
# Overdosage
- Overdosage of econazole nitrate in humans has not been reported to date. In mice, rats, guinea pigs and dogs, the oral LD 50 values were found to be 462, 668, 272, and >160 mg/kg, respectively.
# Pharmacology
## Mechanism of Action
- Econazole nitrate is an azole antifungal agent, inhibits fungal CYP450-mediated conversion of lanosterol to ergosterol. Loss of ergosterol in the fungal cell wall may antifungal activity.
## Structure
- Econazole Nitrate Cream, 1% contains the antifungal agent, Econazole Nitrate USP 1%, in a water-miscible base consisting of pegoxyl 7 stearate, peglicol 5 oleate, mineral oil, benzoic acid, butylated hydroxyanisole, and purified water. The white to off-white soft cream is for topical use only.
## Pharmacodynamics
- Econazole nitrate has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections.
## Pharmacokinetics
- After topical application to the skin of normal subjects, systemic absorption of econazole nitrate is extremely low. Although most of the applied drug remains on the skin surface, drug concentrations were found in the stratum corneum which, by far, exceeded the minimum inhibitory concentration for dermatophytes. Inhibitory concentrations were achieved in the epidermis and as deep as the middle region of the dermis. Less than 1% of the applied dose was recovered in the urine and feces.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Econazole in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Econazole in the drug label.
# How Supplied
Econazole Nitrate Cream, 1% is supplied as follows:
NDC 0168-0312-15 15 gram tube
NDC 0168-0312-30 30 gram tube
NDC 0168-0312-85 85 gram tube
E. FOUGERA & CO.
A division of
Fougera
PHARMACEUTICALS INC.
Melville, New York 11747
I2312C
R09/14
- 20
## Storage
- Store Econazole Nitrate Cream, 1% below 86°F.
# Images
## Drug Images
## Package and Label Display Panel
NDC 0168-0312-15
Fougera ®
ECONAZOLE
NITRATE CREAM, 1%
Rx only
FOR TOPICAL USE ONLY .
KEEP OUT OF THE
REACH OF CHILDREN.
NET WT 15 grams
NDC 0168-0312-15
Rx only
Fougera ®
ECONAZOLE
NITRATE CREAM, 1%
FOR TOPICAL USE ONLY.
KEEP OUT OF THE
REACH OF CHILDREN.
NET WT 15 grams
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Econazole in the drug label.
# Precautions with Alcohol
- Alcohol-Econazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Spectazole®
- Ecoza®
# Look-Alike Drug Names
There is limited information regarding Econazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Econazole | |
97bb7ae2829f5e8387493ee4e59d9b14d6f03ba3 | wikidoc | Edaravone | Edaravone
# 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
Edaravone is a a member of the substituted 2-pyrazolin-5-one class that is FDA approved for the treatment of amyotrophic lateral sclerosis (ALS). Common adverse reactions include contusion, gait disturbance, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Edaravone is indicated for the treatment of amyotrophic lateral sclerosis (ALS).
- The recommended dosage of edaravone is an intravenous infusion of 60 mg administered over a 60-minute period according to the following schedule:
- An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period.
- Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods.
- Edaravone is supplied for intravenous infusion in a single-dose polypropylene bag containing 30 mg of edaravone in 100 mL of clear, colorless aqueous solution
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding edaravone Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding edaravone Off-Label 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 Edaravone FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding edaravone Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding edaravone Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Edaravone is contraindicated in patients with a history of hypersensitivity to edaravone or any of the inactive ingredients of this product. Hypersensitivity reactions and anaphylactic reactions have occurred.
# Warnings
- Hypersensitivity reactions (redness, wheals, and erythema multiforme) and cases of anaphylaxis (urticaria, decreased blood pressure, and dyspnea) have been reported in spontaneous postmarketing reports with edaravone.
- Patients should be monitored carefully for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue edaravone, treat per standard of care, and monitor until the condition resolves.
- Edaravone contains sodium bisulfite, a sulfite that may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity occurs more frequently in asthmatic people.
# 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.
- In randomized, placebo-controlled trials, 184 ALS patients were administered edaravone 60 mg in treatment cycles for 6 months. The population consisted of Japanese patients who had a median age of 60 years (range 29-75) and were 59% male. Most (93%) of these patients were living independently at the time of screening.
- Table 1 lists the adverse reactions that occurred in ≥ 2% of patients in the edaravone-treated group and that occurred at least 2% more frequently than in the placebo-treated group in randomized placebo-controlled ALS trials. The most common adverse reactions that occurred in ≥10% of edaravone-treated patients were contusion, gait disturbance, and headache.
- A Pooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of edaravone outside of the United States. 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.
- Skin and subcutaneous tissue disorders: Hypersensitivity reactions and anaphylaxis.
# Drug Interactions
There is limited information regarding Edaravone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no adequate data on the developmental risk associated with the use of edaravone in pregnant women. In animal studies, administration of edaravone to pregnant rats and rabbits resulted in adverse developmental effects (increased mortality, decreased growth, delayed sexual development, and altered behavior) at clinically relevant doses. Most of these effects occurred at doses that were also associated with maternal toxicity.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk for major birth defects and miscarriage in patients with ALS is unknown.
- In rats, intravenous administration of edaravone (0, 3, 30, or 300 mg/kg/day) throughout the period of organogenesis resulted in reduced fetal weight at all doses. In dams allowed to deliver naturally, offspring weight was reduced at the highest dose tested. Maternal toxicity was also observed at the highest dose tested. There were no adverse effects on reproductive function in the offspring. A no-effect dose for embryofetal developmental toxicity was not identified; the low dose is less than the recommended human dose of 60 mg, on a body surface area (mg/m2) basis.
- In rabbits, intravenous administration of edaravone (0, 3, 20, or 100 mg/kg/day) throughout the period of organogenesis resulted in embryofetal death at the highest dose tested, which was associated with maternal toxicity. The higher no-effect dose for embryofetal developmental toxicity is approximately 6 times the recommended human dose (RHD) on a body surface area (mg/m2) basis.
- The effects on offspring of edaravone (0, 3, 20, or 200 mg/kg/day), administered by intravenous injection to rats from GD 17 throughout lactation, were assessed in two studies. In the first study, offspring mortality was observed at the high dose and increased activity was observed at the mid and high doses. In the second study, there was an increase in stillbirths, offspring mortality, and delayed physical development (vaginal opening) at the highest dose tested. Reproduction function in offspring was not affected in either study. Maternal toxicity was evident in both studies at all but the lowest dose tested. The no-effect dose for developmental toxicity (3 mg/kg/day) is less than the RHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Edaravone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Edaravone during labor and delivery.
### Nursing Mothers
- There are no data on the presence of edaravone in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Edaravone and its metabolites are excreted in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for edaravone and any potential adverse effects on the breastfed infant from edaravone or from the underlying maternal condition.
### Pediatric Use
- Safety and effectiveness of edaravone in pediatric patients have not been established.
### Geriatic Use
- Of the 184 patients with ALS who received edaravone in 3 placebo-controlled clinical trials, a total of 53 patients were 65 years of age and older, including 2 patients 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Edaravone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Edaravone with respect to specific racial populations.
### Renal Impairment
- The effect of renal impairment on the pharmacokinetics of edaravone has not been studied. However, renal impairment is not expected to significantly affect the exposure to edaravone. No dose adjustment is needed in these patients.
### Hepatic Impairment
- The effect of hepatic impairment on the pharmacokinetics of edaravone has not been studied. No dose adjustment is needed for patients with mild or moderate hepatic impairment. No specific dosing recommendation can be provided for patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Edaravone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Edaravone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Edaravone is for intravenous infusion only.
- Do not use if the oxygen indicator has turned blue or purple before opening the package. Once the overwrap package is opened, use within 24 hours.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Administer each 60 mg dose of edaravone injection as two consecutive 30 mg intravenous infusion bags over a total of 60 minutes (infusion rate approximately 1 mg per minute ).
- Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction.
- Other medications should not be injected into the infusion bag or mixed with edaravone.
### Monitoring
- Lack of disability progression or maintained functional ability in amyotrophic lateral sclerosis indicates efficacy.
- Hypersensitivity reaction.
# IV Compatibility
There is limited information regarding the compatibility of Edaravone and IV administrations.
# Overdosage
There is limited information regarding Edaravone overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- The mechanism by which edaravone exerts its therapeutic effect in patients with ALS is unknown.
## Structure
## Pharmacodynamics
There is limited information regarding Edaravone Pharmacodynamics in the drug label.
## Pharmacokinetics
- Edaravone is administered by IV infusion. The maximum plasma concentration (Cmax) of edaravone was reached by the end of infusion. There was a trend of more than dose-proportional increase in area under the concentration-time curve (AUC) and Cmax of edaravone. With multiple-dose administration, edaravone does not accumulate in plasma.
- Edaravone is bound to human serum proteins (92%), mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L.
- The mean terminal elimination half-life of edaravone is 4.5 to 6 hours. The half-lives of its metabolites are 2 to 2.8 hours.
- Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A6, UGT1A9, UGT2B7, and UGT2B17) in the liver and kidney. In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases.
- In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate form (70-90% of the dose). Approximately 5-10% of the dose was recovered in the urine as sulfate conjugate, and only 1% of the dose or less was recovered in the urine as unchanged form. In vitro studies suggest that sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine.
Geriatric Patients
- No age effect on edaravone pharmacokinetics has been found.
Patients with Renal and Hepatic Impairment
- No pharmacokinetic data are available in patients with renal impairment or hepatic impairment.
Male and Female Patients
- No gender effect on edaravone pharmacokinetics has been found.
Racial or Ethnic Groups
- There were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.
- The pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of CYP enzymes, UGTs, or major transporters.
- In vitro studies demonstrated that, at clinical dose, edaravone and its metabolites are not expected to significantly inhibit cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4), UGT1A1, UGT2B7, or transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, CYP2B6, or CYP3A4 at the clinical dose level of edaravone.
## Nonclinical Toxicology
Carcinogenesis
- The carcinogenic potential of edaravone has not been adequately assessed.
Mutagenesis
- Edaravone was negative in in vitro (bacterial reverse mutation and Chinese hamster lung chromosomal aberration) and in vivo (mouse micronucleus) assays.
Impairment of Fertility
- Intravenous administration of edaravone (0, 3, 20, or 200 mg/kg) prior to and throughout mating in males and females and continuing in females to gestation day 7 had no effect on fertility; however, disruption of the estrus cycle and mating behavior was observed at the highest dose tested. No effects on reproductive function were observed at the lower doses, which are up to 3 times the RHD of 60 mg, on a body surface area (mg/m2) basis.
# Clinical Studies
- The efficacy of edaravone for the treatment of ALS was established in a 6-month, randomized, placebo-controlled, double-blind study conducted in Japanese patients with ALS who were living independently and met the following criteria at screening:
- Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised )
- Normal respiratory function (defined as percent-predicted forced vital capacity values of ≥ 80%)
- Definite or Probable ALS based on El Escorial revised criteria
- Disease duration of 2 years or less
- The study enrolled 69 patients in the edaravone arm and 68 in the placebo arm. Baseline characteristics were similar between these groups, with over 90% of patients in each group being treated with riluzole.
- Edaravone was administered as an intravenous infusion of 60 mg given over a 60 minute period according to the following schedule:
- An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period (Cycle 1)
- Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (Cycles 2-6).
- The primary efficacy endpoint was a comparison of the change between treatment arms in the ALSFRS-R total scores from baseline to Week 24. The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency). Each item is scored from 0-4, with higher scores representing greater functional ability. The decline in ALSFRS-R scores from baseline was significantly less in the edaravone-treated patients as compared to placebo (see Table 2). The distribution of change in ALSFRS-R scores from baseline to Week 24 by percent of patients is shown in Figure 1.
# How Supplied
- Edaravone injection is supplied as a 30 mg/100 mL (0.3 mg/mL) clear, colorless, sterile solution for intravenous infusion in single-dose polypropylene bags, each overwrapped with polyvinyl alcohol (PVA) secondary packaging containing an oxygen absorber and oxygen indicator, which should be pink to reflect appropriate oxygen levels. These are supplied in cartons as listed below.
- NDC 70510-2171-1 30 mg/100 mL (0.3 mg/mL) single-dose bag
- NDC 70510-2171-2 2 bags per carton
## Storage
- Store at up to 25°C (77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F). Protect from light. Store in overwrapped package to protect from oxygen degradation until time of use. The oxygen indicator will turn blue or purple if the oxygen has exceeded acceptable levels. Once the overwrap package is opened, use within 24 hours.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patients to read the FDA-approved patient labeling.
- Advise patients to seek immediate medical care if they experience signs or symptoms of a hypersensitivity reaction.
- Advise patients about potential for sulfite sensitivity. Inform patients that edaravone contains sodium bisulfite, which may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, and to seek immediate medical care if they experience these signs or symptoms.
- Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during edaravone therapy.
- Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant.
# Precautions with Alcohol
Alcohol-Edaravone interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Radicava
# Look-Alike Drug Names
There is limited information regarding Edaravone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Edaravone
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]
# 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
Edaravone is a a member of the substituted 2-pyrazolin-5-one class that is FDA approved for the treatment of amyotrophic lateral sclerosis (ALS). Common adverse reactions include contusion, gait disturbance, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Edaravone is indicated for the treatment of amyotrophic lateral sclerosis (ALS).
- The recommended dosage of edaravone is an intravenous infusion of 60 mg administered over a 60-minute period according to the following schedule:
- An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period.
- Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods.
- Edaravone is supplied for intravenous infusion in a single-dose polypropylene bag containing 30 mg of edaravone in 100 mL of clear, colorless aqueous solution
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding edaravone Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding edaravone Off-Label 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 Edaravone FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding edaravone Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding edaravone Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Edaravone is contraindicated in patients with a history of hypersensitivity to edaravone or any of the inactive ingredients of this product. Hypersensitivity reactions and anaphylactic reactions have occurred.
# Warnings
- Hypersensitivity reactions (redness, wheals, and erythema multiforme) and cases of anaphylaxis (urticaria, decreased blood pressure, and dyspnea) have been reported in spontaneous postmarketing reports with edaravone.
- Patients should be monitored carefully for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue edaravone, treat per standard of care, and monitor until the condition resolves.
- Edaravone contains sodium bisulfite, a sulfite that may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity occurs more frequently in asthmatic people.
# 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.
- In randomized, placebo-controlled trials, 184 ALS patients were administered edaravone 60 mg in treatment cycles for 6 months. The population consisted of Japanese patients who had a median age of 60 years (range 29-75) and were 59% male. Most (93%) of these patients were living independently at the time of screening.
- Table 1 lists the adverse reactions that occurred in ≥ 2% of patients in the edaravone-treated group and that occurred at least 2% more frequently than in the placebo-treated group in randomized placebo-controlled ALS trials. The most common adverse reactions that occurred in ≥10% of edaravone-treated patients were contusion, gait disturbance, and headache.
- A Pooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of edaravone outside of the United States. 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.
- Skin and subcutaneous tissue disorders: Hypersensitivity reactions and anaphylaxis.
# Drug Interactions
There is limited information regarding Edaravone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There are no adequate data on the developmental risk associated with the use of edaravone in pregnant women. In animal studies, administration of edaravone to pregnant rats and rabbits resulted in adverse developmental effects (increased mortality, decreased growth, delayed sexual development, and altered behavior) at clinically relevant doses. Most of these effects occurred at doses that were also associated with maternal toxicity.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk for major birth defects and miscarriage in patients with ALS is unknown.
- In rats, intravenous administration of edaravone (0, 3, 30, or 300 mg/kg/day) throughout the period of organogenesis resulted in reduced fetal weight at all doses. In dams allowed to deliver naturally, offspring weight was reduced at the highest dose tested. Maternal toxicity was also observed at the highest dose tested. There were no adverse effects on reproductive function in the offspring. A no-effect dose for embryofetal developmental toxicity was not identified; the low dose is less than the recommended human dose of 60 mg, on a body surface area (mg/m2) basis.
- In rabbits, intravenous administration of edaravone (0, 3, 20, or 100 mg/kg/day) throughout the period of organogenesis resulted in embryofetal death at the highest dose tested, which was associated with maternal toxicity. The higher no-effect dose for embryofetal developmental toxicity is approximately 6 times the recommended human dose (RHD) on a body surface area (mg/m2) basis.
- The effects on offspring of edaravone (0, 3, 20, or 200 mg/kg/day), administered by intravenous injection to rats from GD 17 throughout lactation, were assessed in two studies. In the first study, offspring mortality was observed at the high dose and increased activity was observed at the mid and high doses. In the second study, there was an increase in stillbirths, offspring mortality, and delayed physical development (vaginal opening) at the highest dose tested. Reproduction function in offspring was not affected in either study. Maternal toxicity was evident in both studies at all but the lowest dose tested. The no-effect dose for developmental toxicity (3 mg/kg/day) is less than the RHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Edaravone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Edaravone during labor and delivery.
### Nursing Mothers
- There are no data on the presence of edaravone in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Edaravone and its metabolites are excreted in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for edaravone and any potential adverse effects on the breastfed infant from edaravone or from the underlying maternal condition.
### Pediatric Use
- Safety and effectiveness of edaravone in pediatric patients have not been established.
### Geriatic Use
- Of the 184 patients with ALS who received edaravone in 3 placebo-controlled clinical trials, a total of 53 patients were 65 years of age and older, including 2 patients 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Edaravone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Edaravone with respect to specific racial populations.
### Renal Impairment
- The effect of renal impairment on the pharmacokinetics of edaravone has not been studied. However, renal impairment is not expected to significantly affect the exposure to edaravone. No dose adjustment is needed in these patients.
### Hepatic Impairment
- The effect of hepatic impairment on the pharmacokinetics of edaravone has not been studied. No dose adjustment is needed for patients with mild or moderate hepatic impairment. No specific dosing recommendation can be provided for patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Edaravone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Edaravone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Edaravone is for intravenous infusion only.
- Do not use if the oxygen indicator has turned blue or purple before opening the package. Once the overwrap package is opened, use within 24 hours.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Administer each 60 mg dose of edaravone injection as two consecutive 30 mg intravenous infusion bags over a total of 60 minutes (infusion rate approximately 1 mg per minute [3.33 mL per minute]).
- Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction.
- Other medications should not be injected into the infusion bag or mixed with edaravone.
### Monitoring
- Lack of disability progression or maintained functional ability in amyotrophic lateral sclerosis indicates efficacy.
- Hypersensitivity reaction.
# IV Compatibility
There is limited information regarding the compatibility of Edaravone and IV administrations.
# Overdosage
There is limited information regarding Edaravone overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- The mechanism by which edaravone exerts its therapeutic effect in patients with ALS is unknown.
## Structure
## Pharmacodynamics
There is limited information regarding Edaravone Pharmacodynamics in the drug label.
## Pharmacokinetics
- Edaravone is administered by IV infusion. The maximum plasma concentration (Cmax) of edaravone was reached by the end of infusion. There was a trend of more than dose-proportional increase in area under the concentration-time curve (AUC) and Cmax of edaravone. With multiple-dose administration, edaravone does not accumulate in plasma.
- Edaravone is bound to human serum proteins (92%), mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L.
- The mean terminal elimination half-life of edaravone is 4.5 to 6 hours. The half-lives of its metabolites are 2 to 2.8 hours.
- Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A6, UGT1A9, UGT2B7, and UGT2B17) in the liver and kidney. In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases.
- In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate form (70-90% of the dose). Approximately 5-10% of the dose was recovered in the urine as sulfate conjugate, and only 1% of the dose or less was recovered in the urine as unchanged form. In vitro studies suggest that sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine.
Geriatric Patients
- No age effect on edaravone pharmacokinetics has been found.
Patients with Renal and Hepatic Impairment
- No pharmacokinetic data are available in patients with renal impairment or hepatic impairment.
Male and Female Patients
- No gender effect on edaravone pharmacokinetics has been found.
Racial or Ethnic Groups
- There were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.
- The pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of CYP enzymes, UGTs, or major transporters.
- In vitro studies demonstrated that, at clinical dose, edaravone and its metabolites are not expected to significantly inhibit cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4), UGT1A1, UGT2B7, or transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, CYP2B6, or CYP3A4 at the clinical dose level of edaravone.
## Nonclinical Toxicology
Carcinogenesis
- The carcinogenic potential of edaravone has not been adequately assessed.
Mutagenesis
- Edaravone was negative in in vitro (bacterial reverse mutation and Chinese hamster lung chromosomal aberration) and in vivo (mouse micronucleus) assays.
Impairment of Fertility
- Intravenous administration of edaravone (0, 3, 20, or 200 mg/kg) prior to and throughout mating in males and females and continuing in females to gestation day 7 had no effect on fertility; however, disruption of the estrus cycle and mating behavior was observed at the highest dose tested. No effects on reproductive function were observed at the lower doses, which are up to 3 times the RHD of 60 mg, on a body surface area (mg/m2) basis.
# Clinical Studies
- The efficacy of edaravone for the treatment of ALS was established in a 6-month, randomized, placebo-controlled, double-blind study conducted in Japanese patients with ALS who were living independently and met the following criteria at screening:
- Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised [ALSFRS-R; described below])
- Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] ≥ 80%)
- Definite or Probable ALS based on El Escorial revised criteria
- Disease duration of 2 years or less
- The study enrolled 69 patients in the edaravone arm and 68 in the placebo arm. Baseline characteristics were similar between these groups, with over 90% of patients in each group being treated with riluzole.
- Edaravone was administered as an intravenous infusion of 60 mg given over a 60 minute period according to the following schedule:
- An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period (Cycle 1)
- Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (Cycles 2-6).
- The primary efficacy endpoint was a comparison of the change between treatment arms in the ALSFRS-R total scores from baseline to Week 24. The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency). Each item is scored from 0-4, with higher scores representing greater functional ability. The decline in ALSFRS-R scores from baseline was significantly less in the edaravone-treated patients as compared to placebo (see Table 2). The distribution of change in ALSFRS-R scores from baseline to Week 24 by percent of patients is shown in Figure 1.
# How Supplied
- Edaravone injection is supplied as a 30 mg/100 mL (0.3 mg/mL) clear, colorless, sterile solution for intravenous infusion in single-dose polypropylene bags, each overwrapped with polyvinyl alcohol (PVA) secondary packaging containing an oxygen absorber and oxygen indicator, which should be pink to reflect appropriate oxygen levels. These are supplied in cartons as listed below.
- NDC 70510-2171-1 30 mg/100 mL (0.3 mg/mL) single-dose bag
- NDC 70510-2171-2 2 bags per carton
## Storage
- Store at up to 25°C (77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F). Protect from light. Store in overwrapped package to protect from oxygen degradation until time of use. The oxygen indicator will turn blue or purple if the oxygen has exceeded acceptable levels. Once the overwrap package is opened, use within 24 hours.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patients to read the FDA-approved patient labeling.
- Advise patients to seek immediate medical care if they experience signs or symptoms of a hypersensitivity reaction.
- Advise patients about potential for sulfite sensitivity. Inform patients that edaravone contains sodium bisulfite, which may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, and to seek immediate medical care if they experience these signs or symptoms.
- Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during edaravone therapy.
- Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant.
# Precautions with Alcohol
Alcohol-Edaravone interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Radicava
# Look-Alike Drug Names
There is limited information regarding Edaravone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Edaravone | |
1aa64f997a1a53f9fe6fa56561702341b3ad59a7 | wikidoc | Ediacaran | Ediacaran
The Ediacaran Period (Template:IPAEng, named after the Ediacara Hills of South Australia) is the last geological period of the Neoproterozoic Era, just preceding the Cambrian Period of the Paleozoic Era. Its status as an official geological period was ratified in March 2004 by the International Union of Geological Sciences (IUGS) and announced on May 13 2004, the first new geological period declared in 120 years. The type section is in the Flinders Ranges in South Australia. It overlaps, but is shorter than the Vendian period, a name that was earlier proposed in Russia.
# Base of the Ediacaran
Although the Ediacaran Period does contain soft bodied fossils, it is unusual in comparison to later periods because its beginning is not defined by a change in the fossil record. Rather, the beginning is defined at the base of a chemically distinctive carbonate layer, referred to as a "cap carbonate", because it caps glacial deposits and indicates a sudden climatic change at the end of an ice age. This bed is characterized by an unusual depletion of 13C, and is considered by many scientists to be of global extent, although this is controversial.
# Dating
No dating has been possible at the type section of the Ediacaran Period in South Australia. Therefore the age range of 635 to 542 million years before the present is based on correlations to other countries where dating has been possible. The base age of approximately 635 million years ago is based on U-Pb (uranium-lead) isochron dating from Namibia. Applying this age to the base of the Ediacaran assumes that individual cap carbonates are synchronous around the world and that the correct cap carbonate layers have been correlated between Australian and Namibia. This is controversial because an age of about 580 million years has been obtained in association with glacial rocks in Tasmania which some scientists tentatively correlate with those just beneath the Ediacaran rocks of the Flinders Ranges. The age of the top is the same as the widely recognised age for the base of the Cambrian Period.
# Biota
The animal fossil record from this period is sparse, possibly because animals had yet to evolve hard shells, which make for easier fossilization. The Ediacaran biota include the oldest definite multicellular organisms, and the most common types resemble segmented worms, fronds, disks, or immobile bags. They bear little resemblance to modern lifeforms, and their relationship even with the later lifeforms of the Cambrian explosion is difficult to interpret. More than 100 genera have been described, and well known forms include Arkarua, Charnia, Dickinsonia, Ediacaria, Marywadea, Onega, Pteridinium, and Yorgia. | Ediacaran
Template:Ediacaran biota timeline
The Ediacaran Period (Template:IPAEng, named after the Ediacara Hills of South Australia) is the last geological period of the Neoproterozoic Era, just preceding the Cambrian Period of the Paleozoic Era. Its status as an official geological period was ratified in March 2004 by the International Union of Geological Sciences (IUGS) and announced on May 13 2004, the first new geological period declared in 120 years.[1][2] The type section is in the Flinders Ranges in South Australia. It overlaps, but is shorter than the Vendian period, a name that was earlier proposed in Russia.
# Base of the Ediacaran
Although the Ediacaran Period does contain soft bodied fossils, it is unusual in comparison to later periods because its beginning is not defined by a change in the fossil record. Rather, the beginning is defined at the base of a chemically distinctive carbonate layer, referred to as a "cap carbonate", because it caps glacial deposits and indicates a sudden climatic change at the end of an ice age. This bed is characterized by an unusual depletion of 13C, and is considered by many scientists to be of global extent, although this is controversial.
# Dating
No dating has been possible at the type section of the Ediacaran Period in South Australia. Therefore the age range of 635 to 542 million years before the present is based on correlations to other countries where dating has been possible. The base age of approximately 635 million years ago is based on U-Pb (uranium-lead) isochron dating from Namibia.[3] Applying this age to the base of the Ediacaran assumes that individual cap carbonates are synchronous around the world and that the correct cap carbonate layers have been correlated between Australian and Namibia. This is controversial because an age of about 580 million years has been obtained in association with glacial rocks in Tasmania which some scientists tentatively correlate with those just beneath the Ediacaran rocks of the Flinders Ranges.[4] The age of the top is the same as the widely recognised age for the base of the Cambrian Period.[2]
# Biota
The animal fossil record from this period is sparse, possibly because animals had yet to evolve hard shells, which make for easier fossilization. The Ediacaran biota include the oldest definite multicellular organisms, and the most common types resemble segmented worms, fronds, disks, or immobile bags. They bear little resemblance to modern lifeforms, and their relationship even with the later lifeforms of the Cambrian explosion is difficult to interpret. More than 100 genera have been described, and well known forms include Arkarua, Charnia, Dickinsonia, Ediacaria, Marywadea, Onega, Pteridinium, and Yorgia. | https://www.wikidoc.org/index.php/Ediacaran | |
e2d2bffc087d761936aeac61cd0c7f2adcd96a61 | wikidoc | Education | Education
# Overview
Education encompasses both the teaching and learning of knowledge, proper conduct, and technical competency. It thus focuses on the cultivation of skills, trades or professions, as well as mental, moral & aesthetic development.
Formal education consists of systematic instruction, teaching and training by professional teachers. This consists of the application of pedagogy and the development of curricula. In a liberal eduction tradition, teachers draw on many different disciplines for their lessons, including psychology, philosophy, information technology, linguistics, biology, and sociology. Teachers in specialized professions such as astrophysics, law or zoology may teach only in a narrow area, usually as professors at institutions of higher learning. There is much specialist instruction in fields of trade for those want specific skills, such as required to be a pilot, for example. Finally, there is an array of educational opportunity in the informal sphere- for this reason, society subsidizes institutions such as museums and libraries. Informal education also includes knowledge and skills learned and refined during the course of life, including education that comes from experience in practicing a profession.
# Systems of Formal Education
Education systems are established to provide education and training, in most cases for children and the young. A curriculum defines what students should know, understand and be able to do as the result of education. A teaching profession delivers teaching which enables learning, and a system of polices, regulations, examinations, structures and funding enables teachers to teach to the best of their abilities. Sometimes education systems can be used to promote doctrines or ideals as well as knowledge, which is known as social engineering. This can lead to political abuse of the system, particularly in totalitarian states and government.
Education is a broad concept,it refers to all the experiences in which children can learn something.
Instruction refers to the intentional facilitating of learning toward identified goals, delivered either by an instructor or other forms.
Teaching refers to learning facilitated by a real live instructor.
Training refers to learning toward preparing learners with specific knowledge, skills, or abilities that can be applied immediately.
## Primary education
Primary (or elementary) education consists of the first years of formal, structured education. In general, primary education consists of six or seven years of schooling starting at the age of 5 or 6, although this varies between and sometimes within countries. Globally, around 70% of primary-age children are enrolled in primary education, and this proportion is rising.. Under the Education for All program driven by UNESCO, most countries have committed to achieving universal enrollment in primary education by 2015, and in many countries it is compulsory for children to receive primary education. The division between primary and secondary education is somewhat arbitrary, but it generally occurs at about eleven or twelve years of age. Some education systems have separate middle schools with the transition to the final stage of secondary education taking place at around the age of fourteen. Mostly schools which provide primary education are referred to as primary schools. Primary schools in these countries are often subdivided into infant schools and junior schools.
## Secondary education
In most contemporary educational systems of the world, secondary education consists of the second years of formal education that occur during adolescence. It is characterised by transition from the typically compulsory, comprehensive primary education for minors to the optional, selective tertiary, "post-secondary", or "higher" education (e.g., university, vocational school) for adults. Depending on the system, schools for this period or a part of it may be called secondary or high schools, gymnasiums, lyceums, middle schools, colleges, or vocational schools. The exact meaning of any of these varies between the systems. The exact boundary between primary and secondary education varies from country to country and even within them, but is generally around the seventh to the tenth year of schooling. Secondary education occurs mainly during the teenage years. In the United States and Canada primary and secondary education together are sometimes referred to as K-12 education, and in New Zealand Year 1-13 is used. The purpose of secondary education can be to give common knowledge, to prepare for higher education or to train directly in a profession.
## Higher education
Higher education, also called tertiary, third stage or post secondary education, is the non-compulsory educational level following the completion of a school providing a secondary education, such as a high school, secondary school, or gymnasium. Tertiary education is normally taken to include undergraduate and postgraduate education, as well as vocational education and training. Colleges and universities are the main institutions that provide tertiary education. Collectively, these are sometimes known as tertiary institutions.Tertiary education generally results in the receipt of certificates, diplomas, or academic degrees.
Higher education includes teaching, research and social services activities of universities, and within the realm of teaching, it includes both the undergraduate level (sometimes referred to as tertiary education) and the graduate (or postgraduate) level (sometimes referred to as graduate school). Higher education in that country generally involves work towards a degree-level or foundation degree qualification. In most developed countries a high proportion of the population (up to 50%) now enter higher education at some time in their lives. Higher education is therefore very important to national economies, both as a significant industry in its own right, and as a source of trained and educated personnel for the rest of the economy.
## Adult education
Lifelong, or adult, education has become widespread in many countries. Adult education takes on many forms, from formal class-based learning to self-directed learning.
## Alternative education
Alternative education, also known as non-traditional education or educational alternative, is a broad term which may be used to refer to all forms of education outside of traditional education (for all age groups and levels of education). This may include both forms of education designed for students with special needs (ranging from teenage pregnancy to intellectual disability) and forms of education designed for a general audience which employ alternative educational philosophies and/or methods.
Alternatives of the latter type are often the result of education reform and are rooted in various philosophies that are commonly fundamentally different from those of traditional compulsory education. While some have strong political, scholarly, or philosophical orientations, others are more informal associations of teachers and students dissatisfied with certain aspects of traditional education. These alternatives, which include charter schools, alternative schools, independent schools, and home-based learning vary widely, but often emphasize the value of small class size, close relationships between students and teachers, and a sense of community.
## Emotional/Human education
As academic education is more and more the norm and standard, companies and individuals are looking less at normal education as to what is deemed a good solid educated person/worker. Most well educated and successful entrepreneurs have high communication skills with humanistic and warm "emotional intelligence".
In certain places, especially in the United States, the term alternative may largely refer to forms of education catering to "at risk" students, as it is, for example, in this definition drafted by the Massachusetts Department of Education.
# Process
## Curriculum
An academic discipline is a branch of knowledge which is formally taught, either at the university, or via some other such method. Functionally, disciplines are usually defined and recognized by the academic journals in which research is published, and by the learned societies to which their practitioners belong. Professors say schooling is 80% psychological, 20% physical effort.
Each discipline usually has several sub-disciplines or branches, and distinguishing lines are often both arbitrary and ambiguous. Examples of broad areas of academic disciplines include the natural sciences, mathematics, computer science, social sciences, humanities and applied sciences.
## Learning modalities
There has been a great deal of work on learning styles over the last two decades. Dunn and Dunn focused on identifying relevant stimuli that may influence learning and manipulating the school environment, at about the same time as Joseph Renzulli recommended varying teaching strategies. Howard Gardner identified individual talents or aptitudes in his Multiple Intelligences theories. Based on the works of Jung, the Myers-Briggs Type Indicator and Keirsey Temperament Sorter focused on understanding how people's personality affects the way they interact personally, and how this affects the way individuals respond to each other within the learning environment. The work of David Kolb and Anthony Gregorc's Type Delineator follows a similar but more simplified approach.
It is currently fashionable to divide education into different learning "modes". The learning modalities are probably the most common:
- Kinesthetic: learning based on hands-on work and engaging in activities.
- Visual: learning based on observation and seeing what is being learned.
- Auditory: learning based on listening to instructions/information.
It is claimed that, depending on their preferred learning modality, different teaching techniques have different levels of effectiveness. A consequence of this theory is that effective teaching should present a variety of teaching methods which cover all three learning modalities so that different students have equal opportunities to learn in a way that is effective for them.
## Teaching
Teachers need the ability to understand a subject well enough to convey its essence to a new generation of students. The goal is to establish a sound knowledge base on which students will be able to build as they are exposed to different life experiences. The passing of knowledge from generation to generation allows students to grow into useful members of society. Good teachers can translate information, good judgment, experience and wisdom into relevant knowledge that a student can understand, retain and pass to others. As a profession, teaching has very high levels of Work-Related Stress (WRS) which are listed as amongst the highest of any profession in some countries, such as the United Kingdom. The degree of this problem is becoming increasingly recognized and support systems are put into place.
## Technology
Technology is an increasingly influential factor in education. Computers and mobile phones are being widely used in developed countries both to complement established education practices and develop new ways of learning such as online education (a type of distance education). This gives students the opportunity to choose what they are interested in learning. The proliferation of computers also means the increase of programming and blogging. Technology offers powerful learning tools that demand new skills and understandings of students, including Multimedia, and provides new ways to engage students, such as Virtual learning environments.
Technology is being used more not only in administrative duties in education but also in the instruction of students. The use of technologies such as PowerPoint and interactive whiteboard is capturing the attention of students in the classroom. Technology is also being used in the assessment of students. One example is the Audience Response System (ARS), which allows immediate feedback tests and classroom discussions.
Information and communication technologies (ICTs) are a “diverse set of tools and resources used to communicate, create, disseminate, store, and manage information.” These technologies include computers, the Internet, broadcasting technologies (radio and television), and telephony. There is increasing interest in how computers and the Internet can improve education at all levels, in both formal and non-formal settings. Older ICT technologies, such as radio and television, have for over forty years been used for open and distance learning, although print remains the cheapest, most accessible and therefore most dominant delivery mechanism in both developed and developing countries.
The use of computers and the Internet is still in its infancy in developing countries, if these are used at all, due to limited infrastructure and the attendant high costs of access. Usually, various technologies are used in combination rather than as the sole delivery mechanism. For example, the Kothmale Community Radio Internet uses both radio broadcasts and computer and Internet technologies to facilitate the sharing of information and provide educational opportunities in a rural community in Sri Lanka. The Open University of the United Kingdom (UKOU), established in 1969 as the first educational institution in the world wholly dedicated to open and distance learning, still relies heavily on print-based materials supplemented by radio, television and, in recent years, online programming. Similarly, the Indira Gandhi National Open University in India combines the use of print, recorded audio and video, broadcast radio and television, and audio conferencing technologies.
The term "computer-assisted learning" (CAL) has been increasingly used to describe the use of technology in teaching.
# History
The history of education according to Dieter Lenzen, president of the Freie Universität Berlin 1994 "began either millions of years ago or at the end of 1770". Education as a science cannot be separated from the educational traditions that existed before. Education was the natural response of early civilizations to the struggle of surviving and thriving as a culture. Adults trained the young of their society in the knowledge and skills they would need to master and eventually pass on. The evolution of culture, and human beings as a species depended on this practice of transmitting knowledge. In pre-literate societies this was achieved orally and through imitation. Story-telling continued from one generation to the next. Oral language developed into written symbols and letters. The depth and breadth of knowledge that could be preserved and passed soon increased exponentially. When cultures began to extend their knowledge beyond the basic skills of communicating, trading, gathering food, religious practices, etc, formal education, and schooling, eventually followed. Schooling in this sense was already in place in Egypt between 3000 and 500BC.
# Philosophy
The philosophy of education is the study of the purpose, nature and ideal content of education. Related topics include knowledge itself, the nature of the knowing mind and the human subject, problems of authority, and the relationship between education and society. At least since Locke's time, the philosophy of education has been linked to theories of developmental psychology and human development.
Fundamental purposes that have been proposed for education include:
- The enterprise of civil society depends on educating people to become responsible, thoughtful and enterprising citizens. This is an intricate, challenging task requiring deep understanding of ethical principles, moral values, political theory, aesthetics, and economics, not to mention an understanding of who children are, in themselves and in society.
- Progress in every practical field depends on having capacities that schooling can develop. Education is thus a means to foster the individual's, society's, and even humanity's future development and prosperity. Emphasis is often put on economic success in this regard.
- One's individual development and the capacity to fulfill one's own purposes can depend on an adequate preparation in childhood. Education can thus attempt to give a firm foundation for the achievement of personal fulfillment. The better the foundation that is built, the more successful the child will be. Simple basics in education can carry a child far.
A central tenet of education typically includes “the imparting of knowledge.” At a very basic level, this purpose ultimately deals with the nature, origin and scope of knowledge. The branch of philosophy that addresses these and related issues is known as epistemology. This area of study often focuses on analyzing the nature and variety of knowledge and how it relates to similar notions such as truth and belief.
While the term, knowledge, is often used to convey this general purpose of education, it can also be viewed as part of a continuum of knowing that ranges from very specific data to the highest levels. Seen in this light, the continuum may be thought to consist of a general hierarchy of overlapping levels of knowing. Students must be able to connect new information to a piece of old information to be better able to learn, understand, and retain information. This continuum may include notions such as data, information, knowledge, wisdom, and realization.
The ideal or holistic education is conscious evolutionary transformation that aims at holistic health i.e. simultaneous welfare of one and all. This requires conscious development of fitness of one's body, refinements of instincts, broadening and profoundness of emotions, blossoming of intelligence and liberating perspective of universal oneness. Besides, cognitive, affective and psychomotor the productive domain also must be nurtured for this.
# Psychology
Educational psychology is the study of how humans learn in educational settings, the effectiveness of educational interventions, the psychology of teaching, and the social psychology of schools as organizations. Although the terms "educational psychology" and "school psychology" are often used interchangeably, researchers and theorists are likely to be identified as educational psychologists, whereas practitioners in schools or school-related settings are identified as school psychologists. Educational psychology is concerned with the processes of educational attainment in the general population and in sub-populations such as gifted children and those with specific disabilities.
Educational psychology can in part be understood through its relationship with other disciplines. It is informed primarily by psychology, bearing a relationship to that discipline analogous to the relationship between medicine and biology. Educational psychology in turn informs a wide range of specialities within educational studies, including instructional design, educational technology, curriculum development, organizational learning, special education and classroom management. Educational psychology both draws from and contributes to cognitive science and the learning sciences. In universities, departments of educational psychology are usually housed within faculties of education, possibly accounting for the lack of representation of educational psychology content in introductory psychology textbooks (Lucas, Blazek, & Raley, 2006).
# Economic implications of Education
It has been argued that high rates of education are essential for countries to be able to achieve high levels of economic growth. In theory poor countries should grow faster than rich countries because they can adopt cutting edge technologies already tried and tested by rich countries. But economists argue that if the gap in education between a rich and a poor nation is too large, as is the case between the poorest and the richest nations in the world, the transfer of these technologies that drive economic growth becomes difficult, thus the economies of the world's poorest nations stagnate.
# Sociology of education
The sociology of education is the study of how social institutions and forces affect educational processes and outcomes, and vice versa. By many, education is understood to be a means of overcoming handicaps, achieving greater equality and acquiring wealth and status for all (Sargent 1994). Learners may be motivated by aspirations for progress and betterment. Education is perceived as a place where children can develop according to their unique needs and potentialities. The purpose of education can be to develop every individual to their full potential. The understanding of the goals and means of educational socialization processes differs according to the sociological paradigm used.
## Education in developing countries
In developing countries, the number and seriousness of the problems faced are naturally greater. People are sometimes unaware of the importance of education, and there is economic pressure from those parents who prioritize their children's making money in the short term over any long-term benefits of education. Recent studies on child labor and poverty have suggested that when poor families reach a certain economic threshold where families are able to provide for their basic needs, parents return their children to school. This has been found to be true, once the threshold has been breached, even if the potential economic value of the children's work has increased since their return to school. Teachers are often paid less than other similar professions.
A lack of good universities, and a low acceptance rate for good universities, is evident in countries with a relatively high population density. In some countries, there are uniform, over structured, inflexible centralized programs from a central agency that regulates all aspects of education.
- Due to globalization, increased pressure on students in curricular activities
- Removal of a certain percentage of students for improvisation of academics (usually practised in schools, after 10th grade)
India is now developing technologies that will skip land based phone and internet lines. Instead, India launched EDUSAT, an education satellite that can reach more of the country at a greatly reduced cost. There is also an initiative started by a group out of MIT and supported by several major corporations to develop a $100 laptop. The laptops should be available by late 2006 or 2007. The laptops, sold at cost, will enable developing countries to give their children a digital education, and to close the digital divide across the world.
In Africa, NEPAD has launched an "e-school programme" to provide all 600,000 primary and high schools with computer equipment, learning materials and internet access within 10 years. Private groups, like The Church of Jesus Christ of Latter-day Saints, are working to give more individuals opportunities to receive education in developing countries through such programs as the Perpetual Education Fund. An International Development Agency project called nabuur.com, started with the support of American President Bill Clinton, uses the Internet to allow co-operation by individuals on issues of social development.
## Internationalisation
Education is becoming increasingly international. Not only are the materials becoming more influenced by the rich international environment, but exchanges among students at all levels are also playing an increasingly important role. In Europe, for example, the Socrates-Erasmus Programme stimulates exchanges across European universities. Also, the Soros Foundation provides many opportunities for students from central Asia and eastern Europe. Some scholars argue that, regardless of whether one system is considered better or worse than another, experiencing a different way of education can often be considered to be the most important, enriching element of an international learning experience. | Education
# Overview
Education encompasses both the teaching and learning of knowledge, proper conduct, and technical competency. It thus focuses on the cultivation of skills, trades or professions, as well as mental, moral & aesthetic development.[1]
Formal education consists of systematic instruction, teaching and training by professional teachers. This consists of the application of pedagogy and the development of curricula. In a liberal eduction tradition, teachers draw on many different disciplines for their lessons, including psychology, philosophy, information technology, linguistics, biology, and sociology. Teachers in specialized professions such as astrophysics, law or zoology may teach only in a narrow area, usually as professors at institutions of higher learning. There is much specialist instruction in fields of trade for those want specific skills, such as required to be a pilot, for example. Finally, there is an array of educational opportunity in the informal sphere- for this reason, society subsidizes institutions such as museums and libraries. Informal education also includes knowledge and skills learned and refined during the course of life, including education that comes from experience in practicing a profession.
# Systems of Formal Education
Education systems are established to provide education and training, in most cases for children and the young. A curriculum defines what students should know, understand and be able to do as the result of education. A teaching profession delivers teaching which enables learning, and a system of polices, regulations, examinations, structures and funding enables teachers to teach to the best of their abilities. Sometimes education systems can be used to promote doctrines or ideals as well as knowledge, which is known as social engineering. This can lead to political abuse of the system, particularly in totalitarian states and government.
Education is a broad concept,it refers to all the experiences in which children can learn something.
Instruction refers to the intentional facilitating of learning toward identified goals, delivered either by an instructor or other forms.
Teaching refers to learning facilitated by a real live instructor.
Training refers to learning toward preparing learners with specific knowledge, skills, or abilities that can be applied immediately.
## Primary education
Primary (or elementary) education consists of the first years of formal, structured education. In general, primary education consists of six or seven years of schooling starting at the age of 5 or 6, although this varies between and sometimes within countries. Globally, around 70% of primary-age children are enrolled in primary education, and this proportion is rising.[2]. Under the Education for All program driven by UNESCO, most countries have committed to achieving universal enrollment in primary education by 2015, and in many countries it is compulsory for children to receive primary education. The division between primary and secondary education is somewhat arbitrary, but it generally occurs at about eleven or twelve years of age. Some education systems have separate middle schools with the transition to the final stage of secondary education taking place at around the age of fourteen. Mostly schools which provide primary education are referred to as primary schools. Primary schools in these countries are often subdivided into infant schools and junior schools.
## Secondary education
In most contemporary educational systems of the world, secondary education consists of the second years of formal education that occur during adolescence.[citation needed] It is characterised by transition from the typically compulsory, comprehensive primary education for minors to the optional, selective tertiary, "post-secondary", or "higher" education (e.g., university, vocational school) for adults.[citation needed] Depending on the system, schools for this period or a part of it may be called secondary or high schools, gymnasiums, lyceums, middle schools, colleges, or vocational schools. The exact meaning of any of these varies between the systems. The exact boundary between primary and secondary education varies from country to country and even within them, but is generally around the seventh to the tenth year of schooling. Secondary education occurs mainly during the teenage years. In the United States and Canada primary and secondary education together are sometimes referred to as K-12 education, and in New Zealand Year 1-13 is used. The purpose of secondary education can be to give common knowledge, to prepare for higher education or to train directly in a profession.
## Higher education
Higher education, also called tertiary, third stage or post secondary education, is the non-compulsory educational level following the completion of a school providing a secondary education, such as a high school, secondary school, or gymnasium[citation needed]. Tertiary education is normally taken to include undergraduate and postgraduate education, as well as vocational education and training. Colleges and universities are the main institutions that provide tertiary education. Collectively, these are sometimes known as tertiary institutions.Tertiary education generally results in the receipt of certificates, diplomas, or academic degrees.
Higher education includes teaching, research and social services activities of universities, and within the realm of teaching, it includes both the undergraduate level (sometimes referred to as tertiary education) and the graduate (or postgraduate) level (sometimes referred to as graduate school). Higher education in that country generally involves work towards a degree-level or foundation degree qualification. In most developed countries a high proportion of the population (up to 50%) now enter higher education at some time in their lives. Higher education is therefore very important to national economies, both as a significant industry in its own right, and as a source of trained and educated personnel for the rest of the economy.[citation needed]
## Adult education
Lifelong, or adult, education has become widespread in many countries.[citation needed] Adult education takes on many forms, from formal class-based learning to self-directed learning.
## Alternative education
Alternative education, also known as non-traditional education or educational alternative, is a broad term which may be used to refer to all forms of education outside of traditional education (for all age groups and levels of education). This may include both forms of education designed for students with special needs (ranging from teenage pregnancy to intellectual disability) and forms of education designed for a general audience which employ alternative educational philosophies and/or methods.
Alternatives of the latter type are often the result of education reform and are rooted in various philosophies that are commonly fundamentally different from those of traditional compulsory education. While some have strong political, scholarly, or philosophical orientations, others are more informal associations of teachers and students dissatisfied with certain aspects of traditional education[citation needed]. These alternatives, which include charter schools, alternative schools, independent schools, and home-based learning vary widely, but often emphasize the value of small class size, close relationships between students and teachers, and a sense of community[citation needed].
## Emotional/Human education
As academic education is more and more the norm and standard, companies and individuals are looking less at normal education as to what is deemed a good solid educated person/worker. Most well educated and successful entrepreneurs have high communication skills with humanistic and warm "emotional intelligence".
In certain places, especially in the United States, the term alternative may largely refer to forms of education catering to "at risk" students, as it is, for example, in this definition drafted by the Massachusetts Department of Education. [3]
# Process
## Curriculum
An academic discipline is a branch of knowledge which is formally taught, either at the university, or via some other such method. Functionally, disciplines are usually defined and recognized by the academic journals in which research is published, and by the learned societies to which their practitioners belong.[citation needed] Professors say schooling is 80% psychological, 20% physical effort.[citation needed]
Each discipline usually has several sub-disciplines or branches, and distinguishing lines are often both arbitrary and ambiguous. Examples of broad areas of academic disciplines include the natural sciences, mathematics, computer science, social sciences, humanities and applied sciences.[4]
## Learning modalities
There has been a great deal of work on learning styles over the last two decades. Dunn and Dunn[5] focused on identifying relevant stimuli that may influence learning and manipulating the school environment, at about the same time as Joseph Renzulli[6] recommended varying teaching strategies. Howard Gardner[7] identified individual talents or aptitudes in his Multiple Intelligences theories. Based on the works of Jung, the Myers-Briggs Type Indicator and Keirsey Temperament Sorter[8] focused on understanding how people's personality affects the way they interact personally, and how this affects the way individuals respond to each other within the learning environment. The work of David Kolb and Anthony Gregorc's Type Delineator[9] follows a similar but more simplified approach.
It is currently fashionable to divide education into different learning "modes". The learning modalities[10] are probably the most common:[11]
- Kinesthetic: learning based on hands-on work and engaging in activities.
- Visual: learning based on observation and seeing what is being learned.
- Auditory: learning based on listening to instructions/information.
It is claimed that, depending on their preferred learning modality, different teaching techniques have different levels of effectiveness.[12] A consequence of this theory is that effective teaching should present a variety of teaching methods which cover all three learning modalities so that different students have equal opportunities to learn in a way that is effective for them.[13]
## Teaching
Teachers need the ability to understand a subject well enough to convey its essence to a new generation of students. The goal is to establish a sound knowledge base on which students will be able to build as they are exposed to different life experiences. The passing of knowledge from generation to generation allows students to grow into useful members of society. Good teachers can translate information, good judgment, experience and wisdom into relevant knowledge that a student can understand, retain and pass to others. As a profession, teaching has very high levels of Work-Related Stress (WRS)[14] which are listed as amongst the highest of any profession in some countries, such as the United Kingdom. The degree of this problem is becoming increasingly recognized and support systems are put into place.[15]
## Technology
Technology is an increasingly influential factor in education. Computers and mobile phones are being widely used in developed countries both to complement established education practices and develop new ways of learning such as online education (a type of distance education). This gives students the opportunity to choose what they are interested in learning. The proliferation of computers also means the increase of programming and blogging. Technology offers powerful learning tools that demand new skills and understandings of students, including Multimedia, and provides new ways to engage students, such as Virtual learning environments.
Technology is being used more not only in administrative duties in education but also in the instruction of students. The use of technologies such as PowerPoint and interactive whiteboard is capturing the attention of students in the classroom. Technology is also being used in the assessment of students. One example is the Audience Response System (ARS), which allows immediate feedback tests and classroom discussions.
Information and communication technologies (ICTs) are a “diverse set of tools and resources used to communicate, create, disseminate, store, and manage information.”[16] These technologies include computers, the Internet, broadcasting technologies (radio and television), and telephony. There is increasing interest in how computers and the Internet can improve education at all levels, in both formal and non-formal settings.[17] Older ICT technologies, such as radio and television, have for over forty years been used for open and distance learning, although print remains the cheapest, most accessible and therefore most dominant delivery mechanism in both developed and developing countries.[18]
The use of computers and the Internet is still in its infancy in developing countries, if these are used at all, due to limited infrastructure and the attendant high costs of access. Usually, various technologies are used in combination rather than as the sole delivery mechanism. For example, the Kothmale Community Radio Internet uses both radio broadcasts and computer and Internet technologies to facilitate the sharing of information and provide educational opportunities in a rural community in Sri Lanka.[19] The Open University of the United Kingdom (UKOU), established in 1969 as the first educational institution in the world wholly dedicated to open and distance learning, still relies heavily on print-based materials supplemented by radio, television and, in recent years, online programming.[20] Similarly, the Indira Gandhi National Open University in India combines the use of print, recorded audio and video, broadcast radio and television, and audio conferencing technologies.[21]
The term "computer-assisted learning" (CAL) has been increasingly used to describe the use of technology in teaching.
# History
The history of education according to Dieter Lenzen, president of the Freie Universität Berlin 1994 "began either millions of years ago or at the end of 1770". Education as a science cannot be separated from the educational traditions that existed before. Education was the natural response of early civilizations to the struggle of surviving and thriving as a culture.[citation needed] Adults trained the young of their society in the knowledge and skills they would need to master and eventually pass on.[citation needed] The evolution of culture, and human beings as a species depended on this practice of transmitting knowledge.[citation needed] In pre-literate societies this was achieved orally and through imitation. Story-telling continued from one generation to the next. Oral language developed into written symbols and letters. The depth and breadth of knowledge that could be preserved and passed soon increased exponentially.[citation needed] When cultures began to extend their knowledge beyond the basic skills of communicating, trading, gathering food, religious practices, etc, formal education, and schooling, eventually followed.[citation needed] Schooling in this sense was already in place in Egypt between 3000 and 500BC.[citation needed]
# Philosophy
The philosophy of education is the study of the purpose, nature and ideal content of education. Related topics include knowledge itself, the nature of the knowing mind and the human subject, problems of authority, and the relationship between education and society.[citation needed] At least since Locke's time, the philosophy of education has been linked to theories of developmental psychology and human development.[citation needed]
Fundamental purposes that have been proposed for education include:
- The enterprise of civil society depends on educating people to become responsible, thoughtful and enterprising citizens. This is an intricate, challenging task requiring deep understanding of ethical principles, moral values, political theory, aesthetics, and economics, not to mention an understanding of who children are, in themselves and in society.[citation needed]
- Progress in every practical field depends on having capacities that schooling can develop. Education is thus a means to foster the individual's, society's, and even humanity's future development and prosperity. Emphasis is often put on economic success in this regard.[citation needed]
- One's individual development and the capacity to fulfill one's own purposes can depend on an adequate preparation in childhood. Education can thus attempt to give a firm foundation for the achievement of personal fulfillment. The better the foundation that is built, the more successful the child will be. Simple basics in education can carry a child far.[citation needed]
A central tenet of education typically includes “the imparting of knowledge.” At a very basic level, this purpose ultimately deals with the nature, origin and scope of knowledge.[citation needed] The branch of philosophy that addresses these and related issues is known as epistemology. This area of study often focuses on analyzing the nature and variety of knowledge and how it relates to similar notions such as truth and belief.
While the term, knowledge, is often used to convey this general purpose of education, it can also be viewed as part of a continuum of knowing that ranges from very specific data to the highest levels. Seen in this light, the continuum may be thought to consist of a general hierarchy of overlapping levels of knowing.[citation needed] Students must be able to connect new information to a piece of old information to be better able to learn, understand, and retain information.[citation needed] This continuum may include notions such as data, information, knowledge, wisdom, and realization.
The ideal or holistic education [Cf: Conceptual Stress-Understanding and Management: Dr. Shriniwas Kashalikar] is conscious evolutionary transformation that aims at holistic health i.e. simultaneous welfare of one and all. This requires conscious development of fitness of one's body, refinements of instincts, broadening and profoundness of emotions, blossoming of intelligence and liberating perspective of universal oneness. Besides, cognitive, affective and psychomotor the productive domain also must be nurtured for this.
# Psychology
Educational psychology is the study of how humans learn in educational settings, the effectiveness of educational interventions, the psychology of teaching, and the social psychology of schools as organizations. Although the terms "educational psychology" and "school psychology" are often used interchangeably, researchers and theorists are likely to be identified as educational psychologists, whereas practitioners in schools or school-related settings are identified as school psychologists.[citation needed] Educational psychology is concerned with the processes of educational attainment in the general population and in sub-populations such as gifted children and those with specific disabilities.[citation needed]
Educational psychology can in part be understood through its relationship with other disciplines. It is informed primarily by psychology, bearing a relationship to that discipline analogous to the relationship between medicine and biology.[citation needed] Educational psychology in turn informs a wide range of specialities within educational studies, including instructional design, educational technology, curriculum development, organizational learning, special education and classroom management.[citation needed] Educational psychology both draws from and contributes to cognitive science and the learning sciences.[citation needed] In universities, departments of educational psychology are usually housed within faculties of education, possibly accounting for the lack of representation of educational psychology content in introductory psychology textbooks (Lucas, Blazek, & Raley, 2006).
# Economic implications of Education
It has been argued that high rates of education are essential for countries to be able to achieve high levels of economic growth. [23] In theory poor countries should grow faster than rich countries because they can adopt cutting edge technologies already tried and tested by rich countries.[citation needed] But economists argue that if the gap in education between a rich and a poor nation is too large, as is the case between the poorest and the richest nations in the world, the transfer of these technologies that drive economic growth becomes difficult, thus the economies of the world's poorest nations stagnate.[citation needed]
# Sociology of education
The sociology of education is the study of how social institutions and forces affect educational processes and outcomes, and vice versa. By many, education is understood to be a means of overcoming handicaps, achieving greater equality and acquiring wealth and status for all (Sargent 1994). Learners may be motivated by aspirations for progress and betterment. Education is perceived as a place where children can develop according to their unique needs and potentialities.[24] The purpose of education can be to develop every individual to their full potential.[citation needed] The understanding of the goals and means of educational socialization processes differs according to the sociological paradigm used.
## Education in developing countries
In developing countries, the number and seriousness of the problems faced are naturally greater.[citation needed] People are sometimes unaware of the importance of education, and there is economic pressure from those parents who prioritize their children's making money in the short term over any long-term benefits of education.[citation needed] Recent studies on child labor and poverty have suggested that when poor families reach a certain economic threshold where families are able to provide for their basic needs, parents return their children to school.[citation needed] This has been found to be true, once the threshold has been breached, even if the potential economic value of the children's work has increased since their return to school.[citation needed] Teachers are often paid less than other similar professions.[citation needed]
A lack of good universities, and a low acceptance rate for good universities, is evident in countries with a relatively high population density.[citation needed] In some countries, there are uniform, over structured, inflexible centralized programs from a central agency that regulates all aspects of education.
- Due to globalization, increased pressure on students in curricular activities
- Removal of a certain percentage of students for improvisation of academics (usually practised in schools, after 10th grade)
India is now developing technologies that will skip land based phone and internet lines. Instead, India launched EDUSAT, an education satellite that can reach more of the country at a greatly reduced cost. There is also an initiative started by a group out of MIT and supported by several major corporations to develop a $100 laptop. The laptops should be available by late 2006 or 2007. The laptops, sold at cost, will enable developing countries to give their children a digital education, and to close the digital divide across the world.
In Africa, NEPAD has launched an "e-school programme" to provide all 600,000 primary and high schools with computer equipment, learning materials and internet access within 10 years. Private groups, like The Church of Jesus Christ of Latter-day Saints, are working to give more individuals opportunities to receive education in developing countries through such programs as the Perpetual Education Fund. An International Development Agency project called nabuur.com, started with the support of American President Bill Clinton, uses the Internet to allow co-operation by individuals on issues of social development.
## Internationalisation
Education is becoming increasingly international. Not only are the materials becoming more influenced by the rich international environment, but exchanges among students at all levels are also playing an increasingly important role. In Europe, for example, the Socrates-Erasmus Programme stimulates exchanges across European universities. Also, the Soros Foundation provides many opportunities for students from central Asia and eastern Europe. Some scholars argue that, regardless of whether one system is considered better or worse than another, experiencing a different way of education can often be considered to be the most important, enriching element of an international learning experience.[25] | https://www.wikidoc.org/index.php/Education | |
9f4b1d49f17c8b28031c054fa435f7c10b5e48ad | wikidoc | Efavirenz | Efavirenz
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# Overview
Efavirenz is a non-nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 in adults and children at least 3 months old and weighing at least 3.5 kg. Common adverse reactions include impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dosage of Efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that Efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of Efavirenz with food may lead to an increase in frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms. Efavirenz capsules or tablets should be swallowed intact with liquid. For patients who cannot swallow capsules or tablets, the capsule sprinkle method of administration is recommended.
- Efavirenz must be given in combination with other antiretroviral medications
- If Efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the Efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). Efavirenz tablets should not be broken.
- If Efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of Efavirenz to 800 mg once daily is recommended
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Efavirenz in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Efavirenz in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- It is recommended that Efavirenz be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of Efavirenz for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg. The recommended dosage of Efavirenz for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration.
- For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who cannot swallow capsules or tablets, the capsule contents may be administered with a small amount (1 to 2 teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers must be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over a small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into 2 teaspoons (10 mL) of reconstituted room temperature infant formula in a medicine cup by carefully stirring with a small spoon, and then drawing up the mixture into a 10 mL oral dosing syringe for administration. After administration of the Efavirenz-food or -formula mixture, an additional small amount (approximately 2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining Efavirenz residue, and administered to the patient. The Efavirenz-food or -formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for 2 hours after administration of Efavirenz.
- Further patient instructions on the capsule sprinkle method of administration are provided in the FDA-approved patient labeling (see Patient Information and Instructions for Use).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Efavirenz in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Efavirenz in pediatric patients.
# Contraindications
- Efavirenz is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product.
# Warnings
- Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. The most prominent effect of efavirenz at steady-state is induction of CYP3A and CYP2B6.
- Efavirenz must not be used as a single agent to treat HIV-1 infection or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance.
- Coadministration of Efavirenz with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (eg, with rifampin), since efavirenz is one of its active ingredients.
- Serious psychiatric adverse experiences have been reported in patients treated with Efavirenz In controlled trials of 1008 patients treated with regimens containing Efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received Efavirenz or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the Efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both Efavirenz-treated and control-treated patients. One percent of Efavirenz-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of Efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of Efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits.
- Fifty-three percent (531/1008) of patients receiving Efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients, and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing Efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve the tolerability of these nervous system symptoms.
- Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with Efavirenz + zidovudine + lamivudine, Efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among Efavirenz-treated patients were generally similar to those in the indinavir-containing control arm.
- Patients receiving Efavirenz should be alerted to the potential for additive central nervous system effects when Efavirenz is used concomitantly with alcohol or psychoactive drugs.
- Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.
- Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving Efavirenz. Barrier contraception must always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of Efavirenz is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of Efavirenz. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Efavirenz should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options.
- In controlled clinical trials, 26% (266/1008) of adult patients treated with 600 mg Efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with Efavirenz. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in adult patients treated with Efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1008).
- Rash was reported in 59 of 182 pediatric patients (32%) treated with Efavirenz. Two pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 28 days (range 3-1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with Efavirenz in pediatric patients should be considered.
- Efavirenz can be reinitiated in patients interrupting therapy because of rash. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (eg, Stevens-Johnson syndrome), alternative therapy should be considered.
- Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or hepatitis C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with Efavirenz needs to be weighed against the unknown risks of significant liver toxicity.
- Convulsions have been observed in adult and pediatric patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels.
- Treatment with Efavirenz has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating Efavirenz therapy and at periodic intervals during therapy.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Efavirenz During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections , which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
# Adverse Reactions
## Clinical Trials Experience
### Adults
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
The most significant adverse reactions observed in patients treated with Efavirenz are:
- Psychiatric symptoms
- Nervous system symptoms
- Rash
The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with Efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of Efavirenz-treated patients in two controlled clinical trials are presented in Table 2.
- Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients.
- For 1008 patients treated with regimens containing Efavirenz and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking and depersonalization. The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2.
- Serious psychiatric adverse experiences have been reported in patients treated with Efavirenz In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with Efavirenz or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).
- In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing Efavirenz and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for Efavirenz-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for Efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for Efavirenz-treated patients and 0.3% for control groups.
- Experience with Efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with Efavirenz Nine of these patients developed mild-to-moderate rash while receiving therapy with Efavirenz, and two of these patients discontinued because of rash.
- Selected Grade 3-4 laboratory abnormalities reported in ≥2% of Efavirenz-treated patients in two clinical trials are presented in Table 4.
- Liver function tests should be monitored in patients with a history of hepatitis B and/or hepatitis C. In the long-term data set from Study 006, 137 patients treated with Efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or hepatitis C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the Efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the Efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with Efavirenz-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders.
- Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving Efavirenz. In patients treated with Efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with Efavirenz + indinavir, increases from baseline in non fasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with Efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with Efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of Efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown.
### Clinical Trial Experience in Pediatric Patients
- Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received Efavirenz in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash.
## Postmarketing Experience
Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been identified during postapproval use of Efavirenz.
- Allergic reactions
- Asthenia
- Redistribution/accumulation of body fat
- Abnormal coordination
- Ataxia
- Cerebellar coordination and balance disturbances
- Convulsions
- Hypoesthesia
- Paresthesia
- Neuropathy
- Tremor
- Vertigo
- Gynecomastia
- Constipation
- Malabsorption
- Flushing
- Palpitations
- Hepatic enzyme increase
- Hepatic failure
- Hepatitis
- A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.
- Hypercholesterolemia
- Hypertriglyceridemia
- Arthralgia
- Myalgia
- Myopathy
- Aggressive reactions
- Agitation
- Delusions
- Emotional lability
- Mania
- Neurosis
- Paranoia
- Psychosis
- Suicide
- Dyspnea
- Erythema multiforme
- Photoallergic dermatitis
- Stevens-Johnson syndrome
- Abnormal vision
- Tinnitus
# Drug Interactions
- Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with Efavirenz Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interactions with Efavirenz are summarized in Table 5. This table includes potentially significant interactions, but is not all inclusive.
- Based on the results of drug interaction studies, no dosage adjustment is recommended when Efavirenz is given with the following: aluminum/]] antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovir, disoproxil fumarate, and zidovudine.
- Specific drug interaction studies have not been performed with Efavirenz and NRTIs other than lamivudine and zidovudine. Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.
- Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
### Antiretroviral Pregnancy Registry
- To monitor fetal outcomes of pregnant women exposed to Efavirenz, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- As of July 2010, the Antiretroviral Pregnancy Registry has received prospective reports of 792 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (718 pregnancies). Birth defects occurred in 17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of Efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz.
- Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Efavirenz in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Efavirenz 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. Efavirenz has been shown to pass into human breast milk. Because of the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breastfeed if they are receiving Efavirenz.
### Pediatric Use
- The safety, pharmacokinetic profile, and virologic and immunologic responses of Efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials. The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of Grade 3 or 4 rash, in pediatric patients compared to adults.
- Use of Efavirenz in patients younger than 3 months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of Efavirenz have not been evaluated in this age group and there is a risk of developing HIV resistance if Efavirenz is underdosed.
### Geriatic Use
- Clinical studies of Efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 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 therapy.
### Gender
There is no FDA guidance on the use of Efavirenz with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Efavirenz with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Efavirenz in patients with renal impairment.
### Hepatic Impairment
- Efavirenz is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering Efavirenz to these patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Efavirenz in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Efavirenz in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Efavirenz Administration in the drug label.
### Monitoring
There is limited information regarding Efavirenz Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Efavirenz and IV administrations.
# Overdosage
- Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
- Treatment of overdose with Efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with Efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.
# Pharmacology
## Mechanism of Action
- Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.
## Structure
## Pharmacodynamics
There is limited information regarding Efavirenz Pharmacodynamics in the drug label.
## Pharmacokinetics
### Absorption
- Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses.
- In HIV-1-infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving Efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μMh.
- Capsules: Administration of a single 600 mg dose of efavirenz capsules with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions.
- Tablets: Administration of a single 600 mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions.
- Bioavailability of capsule contents mixed with food vehicles: In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.
### Distribution
- Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received Efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.
### Metabolism
- Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism.
- Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours).
- Efavirenz has a terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar adenomas/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.
- Efavirenz tested negative in a battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay.
- Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤0.15 times that in humans at the recommended clinical dose.
- Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.
# Clinical Studies
### Adults
- Study 006, a randomized, open-label trial, compared Efavirenz (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or Efavirenz (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years , 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm3 and the median baseline HIV-1 RNA level was 4.8 log10 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 9. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance detection of non-clade B virus.
- For patients treated with Efavirenz + zidovudine + lamivudine, Efavirenz + indinavir, or indinavir + zidovudine + lamivudine, the percentage of responders with HIV-1 RNA <50 copies/mL was 65%, 50%, and 45%, respectively, through 48 weeks, and 43%, 31%, and 23%, respectively, through 168 weeks. A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA <400 copies/mL) suggests that both the trends of virologic response and differences in response continue through 4 years.
- ACTG 364 is a randomized, double-blind, placebo-controlled, 48-week study in NRTI-experienced patients who had completed two prior ACTG studies. One-hundred ninety-six patients (mean age 41 years , 74% Caucasian, 88% male) received NRTIs in combination with Efavirenz (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or Efavirenz (600 mg once daily) + nelfinavir in a randomized, double-blinded manner. The mean baseline CD4+ cell count was 389 cells/mm3 and mean baseline HIV-1 RNA level was 8130 copies/mL. Upon entry into the study, all patients were assigned a new open-label NRTI regimen, which was dependent on their previous NRTI treatment experience. There was no significant difference in the mean CD4+ cell count among treatment groups; the overall mean increase was approximately 100 cells at 48 weeks among patients who continued on study regimens. Treatment outcomes are shown in Table 10. Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of quantification of 500 copies/mL.
### Pediatric Patients
- Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced pediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with Efavirenz. At baseline, median plasma HIV-1 RNA was 5.88 log10 copies/mL, median CD4+ cell count was 1144 cells/mm3, and median CD4+ percentage was 25%. The median time on study therapy was 60 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 196 cells/mm3 and the median increase in CD4+ percentage was 6%.
- Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz in combination with didanosine and emtricitabine in pediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with Efavirenz. At baseline, median plasma HIV-1 RNA was 4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm3, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm3 and the median increase in CD4+ percentage was 13%.
- Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz in combination with nelfinavir and an NRTI in antiretroviral-naive and NRTI-experienced pediatric patients. One hundred two patients 3 months to 16 years of age (median 5.7 years) were treated with Efavirenz. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median CD4+ cell count was 755 cells/mm3, and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm3 and the median increase in CD4+ percentage was 5%.
# How Supplied
## Storage
There is limited information regarding Efavirenz Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Efavirenz Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Efavirenz interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sustiva
# Look-Alike Drug Names
There is limited information regarding Efavirenz Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Efavirenz
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Efavirenz is a non-nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 in adults and children at least 3 months old and weighing at least 3.5 kg. Common adverse reactions include impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dosage of Efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that Efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of Efavirenz with food may lead to an increase in frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms. Efavirenz capsules or tablets should be swallowed intact with liquid. For patients who cannot swallow capsules or tablets, the capsule sprinkle method of administration is recommended.
- Efavirenz must be given in combination with other antiretroviral medications
- If Efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the Efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). Efavirenz tablets should not be broken.
- If Efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of Efavirenz to 800 mg once daily is recommended
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Efavirenz in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Efavirenz in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- It is recommended that Efavirenz be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of Efavirenz for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg. The recommended dosage of Efavirenz for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration.
- For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who cannot swallow capsules or tablets, the capsule contents may be administered with a small amount (1 to 2 teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers must be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over a small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into 2 teaspoons (10 mL) of reconstituted room temperature infant formula in a medicine cup by carefully stirring with a small spoon, and then drawing up the mixture into a 10 mL oral dosing syringe for administration. After administration of the Efavirenz-food or -formula mixture, an additional small amount (approximately 2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining Efavirenz residue, and administered to the patient. The Efavirenz-food or -formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for 2 hours after administration of Efavirenz.
- Further patient instructions on the capsule sprinkle method of administration are provided in the FDA-approved patient labeling (see Patient Information and Instructions for Use).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Efavirenz in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Efavirenz in pediatric patients.
# Contraindications
- Efavirenz is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product.
# Warnings
- Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. The most prominent effect of efavirenz at steady-state is induction of CYP3A and CYP2B6.
- Efavirenz must not be used as a single agent to treat HIV-1 infection or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance.
- Coadministration of Efavirenz with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (eg, with rifampin), since efavirenz is one of its active ingredients.
- Serious psychiatric adverse experiences have been reported in patients treated with Efavirenz In controlled trials of 1008 patients treated with regimens containing Efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received Efavirenz or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the Efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both Efavirenz-treated and control-treated patients. One percent of Efavirenz-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of Efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of Efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits.
- Fifty-three percent (531/1008) of patients receiving Efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients, and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing Efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve the tolerability of these nervous system symptoms.
- Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with Efavirenz + zidovudine + lamivudine, Efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among Efavirenz-treated patients were generally similar to those in the indinavir-containing control arm.
- Patients receiving Efavirenz should be alerted to the potential for additive central nervous system effects when Efavirenz is used concomitantly with alcohol or psychoactive drugs.
- Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.
- Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving Efavirenz. Barrier contraception must always be used in combination with other methods of contraception (eg, oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of Efavirenz is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of Efavirenz. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Efavirenz should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options.
- In controlled clinical trials, 26% (266/1008) of adult patients treated with 600 mg Efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with Efavirenz. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in adult patients treated with Efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1008).
- Rash was reported in 59 of 182 pediatric patients (32%) treated with Efavirenz. Two pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 28 days (range 3-1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with Efavirenz in pediatric patients should be considered.
- Efavirenz can be reinitiated in patients interrupting therapy because of rash. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (eg, Stevens-Johnson syndrome), alternative therapy should be considered.
- Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or hepatitis C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with Efavirenz needs to be weighed against the unknown risks of significant liver toxicity.
- Convulsions have been observed in adult and pediatric patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels.
- Treatment with Efavirenz has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating Efavirenz therapy and at periodic intervals during therapy.
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Efavirenz During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
# Adverse Reactions
## Clinical Trials Experience
### Adults
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
The most significant adverse reactions observed in patients treated with Efavirenz are:
- Psychiatric symptoms
- Nervous system symptoms
- Rash
The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with Efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of Efavirenz-treated patients in two controlled clinical trials are presented in Table 2.
- Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients.
- For 1008 patients treated with regimens containing Efavirenz and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking and depersonalization. The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2.
- Serious psychiatric adverse experiences have been reported in patients treated with Efavirenz In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with Efavirenz or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).
- In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing Efavirenz and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for Efavirenz-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for Efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for Efavirenz-treated patients and 0.3% for control groups.
- Experience with Efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with Efavirenz Nine of these patients developed mild-to-moderate rash while receiving therapy with Efavirenz, and two of these patients discontinued because of rash.
- Selected Grade 3-4 laboratory abnormalities reported in ≥2% of Efavirenz-treated patients in two clinical trials are presented in Table 4.
- Liver function tests should be monitored in patients with a history of hepatitis B and/or hepatitis C. In the long-term data set from Study 006, 137 patients treated with Efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or hepatitis C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the Efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the Efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with Efavirenz-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders.
- Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving Efavirenz. In patients treated with Efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with Efavirenz + indinavir, increases from baseline in non fasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with Efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with Efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of Efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown.
### Clinical Trial Experience in Pediatric Patients
- Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received Efavirenz in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash.
## Postmarketing Experience
Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse reactions have been identified during postapproval use of Efavirenz.
- Allergic reactions
- Asthenia
- Redistribution/accumulation of body fat
- Abnormal coordination
- Ataxia
- Cerebellar coordination and balance disturbances
- Convulsions
- Hypoesthesia
- Paresthesia
- Neuropathy
- Tremor
- Vertigo
- Gynecomastia
- Constipation
- Malabsorption
- Flushing
- Palpitations
- Hepatic enzyme increase
- Hepatic failure
- Hepatitis
- A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.
- Hypercholesterolemia
- Hypertriglyceridemia
- Arthralgia
- Myalgia
- Myopathy
- Aggressive reactions
- Agitation
- Delusions
- Emotional lability
- Mania
- Neurosis
- Paranoia
- Psychosis
- Suicide
- Dyspnea
- Erythema multiforme
- Photoallergic dermatitis
- Stevens-Johnson syndrome
- Abnormal vision
- Tinnitus
# Drug Interactions
- Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with Efavirenz Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interactions with Efavirenz are summarized in Table 5. This table includes potentially significant interactions, but is not all inclusive.
- Based on the results of drug interaction studies, no dosage adjustment is recommended when Efavirenz is given with the following: aluminum/][magnesium hydroxide]] antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovir, disoproxil fumarate, and zidovudine.
- Specific drug interaction studies have not been performed with Efavirenz and NRTIs other than lamivudine and zidovudine. Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways.
- Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
### Antiretroviral Pregnancy Registry
- To monitor fetal outcomes of pregnant women exposed to Efavirenz, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- As of July 2010, the Antiretroviral Pregnancy Registry has received prospective reports of 792 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (718 pregnancies). Birth defects occurred in 17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of Efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz.
- Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Efavirenz in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Efavirenz 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. Efavirenz has been shown to pass into human breast milk. Because of the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breastfeed if they are receiving Efavirenz.
### Pediatric Use
- The safety, pharmacokinetic profile, and virologic and immunologic responses of Efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials. The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of Grade 3 or 4 rash, in pediatric patients compared to adults.
- Use of Efavirenz in patients younger than 3 months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of Efavirenz have not been evaluated in this age group and there is a risk of developing HIV resistance if Efavirenz is underdosed.
### Geriatic Use
- Clinical studies of Efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. 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 therapy.
### Gender
There is no FDA guidance on the use of Efavirenz with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Efavirenz with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Efavirenz in patients with renal impairment.
### Hepatic Impairment
- Efavirenz is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering Efavirenz to these patients.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Efavirenz in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Efavirenz in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Efavirenz Administration in the drug label.
### Monitoring
There is limited information regarding Efavirenz Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Efavirenz and IV administrations.
# Overdosage
- Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
- Treatment of overdose with Efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with Efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.
# Pharmacology
## Mechanism of Action
- Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.
## Structure
## Pharmacodynamics
There is limited information regarding Efavirenz Pharmacodynamics in the drug label.
## Pharmacokinetics
### Absorption
- Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses.
- In HIV-1-infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving Efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•h.
- Capsules: Administration of a single 600 mg dose of efavirenz capsules with a high-fat/high-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions.
- Tablets: Administration of a single 600 mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions.
- Bioavailability of capsule contents mixed with food vehicles: In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.
### Distribution
- Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received Efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.
### Metabolism
- Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism.
- Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours).
- Efavirenz has a terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar adenomas/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.
- Efavirenz tested negative in a battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay.
- Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤0.15 times that in humans at the recommended clinical dose.
- Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose.
# Clinical Studies
### Adults
- Study 006, a randomized, open-label trial, compared Efavirenz (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or Efavirenz (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18-81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm3 and the median baseline HIV-1 RNA level was 4.8 log10 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 9. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance detection of non-clade B virus.
- For patients treated with Efavirenz + zidovudine + lamivudine, Efavirenz + indinavir, or indinavir + zidovudine + lamivudine, the percentage of responders with HIV-1 RNA <50 copies/mL was 65%, 50%, and 45%, respectively, through 48 weeks, and 43%, 31%, and 23%, respectively, through 168 weeks. A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA <400 copies/mL) suggests that both the trends of virologic response and differences in response continue through 4 years.
- ACTG 364 is a randomized, double-blind, placebo-controlled, 48-week study in NRTI-experienced patients who had completed two prior ACTG studies. One-hundred ninety-six patients (mean age 41 years [range 18-76], 74% Caucasian, 88% male) received NRTIs in combination with Efavirenz (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or Efavirenz (600 mg once daily) + nelfinavir in a randomized, double-blinded manner. The mean baseline CD4+ cell count was 389 cells/mm3 and mean baseline HIV-1 RNA level was 8130 copies/mL. Upon entry into the study, all patients were assigned a new open-label NRTI regimen, which was dependent on their previous NRTI treatment experience. There was no significant difference in the mean CD4+ cell count among treatment groups; the overall mean increase was approximately 100 cells at 48 weeks among patients who continued on study regimens. Treatment outcomes are shown in Table 10. Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of quantification of 500 copies/mL.
### Pediatric Patients
- Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced pediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with Efavirenz. At baseline, median plasma HIV-1 RNA was 5.88 log10 copies/mL, median CD4+ cell count was 1144 cells/mm3, and median CD4+ percentage was 25%. The median time on study therapy was 60 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 196 cells/mm3 and the median increase in CD4+ percentage was 6%.
- Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz in combination with didanosine and emtricitabine in pediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with Efavirenz. At baseline, median plasma HIV-1 RNA was 4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm3, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm3 and the median increase in CD4+ percentage was 13%.
- Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of Efavirenz in combination with nelfinavir and an NRTI in antiretroviral-naive and NRTI-experienced pediatric patients. One hundred two patients 3 months to 16 years of age (median 5.7 years) were treated with Efavirenz. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median CD4+ cell count was 755 cells/mm3, and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm3 and the median increase in CD4+ percentage was 5%.
# How Supplied
## Storage
There is limited information regarding Efavirenz Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Efavirenz Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Efavirenz interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sustiva
# Look-Alike Drug Names
There is limited information regarding Efavirenz Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Efavirenz | |
407b1afbaa9121ee4581826be66fee1bb451945c | wikidoc | Prasugrel | Prasugrel
# 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
Prasugrel is a P2Y12 platelet inhibitor, Platelet aggregation inhibitor that is FDA approved for the treatment of Acute Coronary Syndrome. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, hyperlipidemia, backache, headache, epistaxis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Acute Coronary Syndrome
- Dosing Information
- Initial loading dosage: 60 mg PO
- Maintaining dosage: 10 mg PO qd
- Incombination with: aspirin 75 mg-325 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Prasugrel in adult patients.
### Non–Guideline-Supported Use
### Prophylaxis treatment of Thrombosis of Acute coronary syndrome
- Dosing Information
- Recommended: 10 mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Prasugrel 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 Prasugrel in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Prasugrel in pediatric patients.
# Contraindications
- Active Bleeding
- Effient is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage .
- Prior Transient Ischemic Attack or Stroke
- Effient is contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel), patients with a history of TIA or ischemic stroke (>3 months prior to enrollment) had a higher rate of stroke on Effient (6.5%; of which 4.2% were thrombotic stroke and 2.3% were intracranial hemorrhage ]]) than on clopidogrel (1.2%; all thrombotic). In patients without such a history, the incidence of stroke was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Effient and clopidogrel, respectively. Patients with a history of ischemic stroke within 3 months of screening and patients with a history of hemorrhagic stroke at any time were excluded from TRITON-TIMI 38. Patients who experience a stroke or TIA while on Effient generally should have therapy discontinued .
- Hypersensitivity
- Effient is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product .
# Warnings
## General Risk of Bleeding==
clopidogrel, including Effient, increase the risk of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin of ≥3 g/dL but <5 g/dL) bleeding events were more common on Effient than on clopidogrel . The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days).
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt signs of bleeding.
Do not use Effient in patients with active bleeding, prior TIA or stroke .
Other risk factors for bleeding are:
- Age ≥75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients ≥75 years of age, use of Effient is generally not recommended in these patients, except in high-risk situations (patients with diabetes or history of myocardial infarction) where its effect appears to be greater and its use may be considered .
- CABG or other surgical procedure .
- Body weight <60 kg. Consider a lower (5-mg) maintenance dose .
- Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe renal impairment) .
- Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of non-steroidal anti-inflammatory drugs NSAIDs, and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38 .
clopidogrel inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of prasugrel's active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.
The risk of bleeding is increased in patients receiving Effient who undergo CABG. If possible, Effient should be discontinued at least 7 days prior to CABG.
Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABG-related TIMI Major or Minor bleeding were 14.1% in the Effient group and 4.5% in the clopidogrel group . The higher risk for bleeding events in patients treated with Effient persisted up to 7 days from the most recent dose of study drug. For patients receiving a thienopyridine within 3 days prior to CABG, the frequencies of TIMI Major or Minor bleeding were 26.7% (12 of 45 patients) in the Effient group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group.
Do not start Effient in patients likely to undergo urgent CABG. CABG-related bleeding may be treated with transfusion of blood products, including packed red blood cells and platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.
Discontinue clopidogrel, including Effient, for active bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent placement, premature discontinuation of any antiplatelet medication, including clopidogrel, conveys an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in therapy should be avoided, and if clopidogrel must be temporarily discontinued because of an adverse event(s), they should be restarted as soon as possible .
Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of Effient. TTP can occur after a brief exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment, including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes ]] seen on peripheral smear), neurological findings, renal dysfunction, and fever .
Hypersensitivity including angioedema has been reported in patients receiving Effient, including patients with a history of hypersensitivity reaction to other clopidogrel .
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are also discussed elsewhere in the labeling:
- Bleeding
- Thrombotic thrombocytopenic purpura
Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with Effient (60-mg loading dose and 10-mg once daily) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year). The population treated with Effient was 27 to 96 years of age, 25% female, and 92% Caucasian. All patients in the TRITON-TIMI 38 study were to receive aspirin. The dose of clopidogrel in this study was a 300-mg loading dose and 75-mg once daily.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials cannot be directly compared with the rates observed in other clinical trials of another drug and may not reflect the rates observed in practice.
- Drug Discontinuation
- The rate of study drug discontinuation because of adverse reactions was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4% for clopidogrel).
- Bleeding
- Bleeding Unrelated to CABG Surgery - In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on Effient than on clopidogrel, as shown in Table 1.
Figure 1 demonstrates non-CABG related TIMI Major or Minor bleeding. The bleeding rate is highest initially, as shown in Figure 1 (inset: Days 0 to 7) .
Bleeding by Weight and Age - In TRITON-TIMI 38, non-CABG-related TIMI Major or Minor bleeding rates in patients with the risk factors of age ≥75 years and weight <60 kg are shown in Table 2.
Bleeding Related to CABG - In TRITON-TIMI 38, 437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the Effient group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug.
Bleeding Reported as Adverse Reactions - Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for Effient and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, 0.5%), subcutaneous hematoma (0.5%, 0.2%), post-procedural hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and retinal hemorrhage (0.0%, 0.1%).
malignancies
During TRITON-TIMI 38, newly-diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with prasugrel and clopidogrel, respectively. The sites contributing to the differences were primarily colon and lung. In another Phase 3 clinical study of ACS patients not undergoing PCI, in which data for malignancies were prospectively collected, newly-diagnosed malignancies were reported in 1.8% and 1.7% of patients treated with prasugrel and clopidogrel, respectively. The site of malignancies was balanced between treatment groups except for colorectal malignancies. The rates of colorectal malignancies were 0.3% prasugrel, 0.1% clopidogrel and most were detected during investigation of GI bleed or anemia. It is unclear if these observations are causally-related, are the result of increased detection because of bleeding, or are random occurrences.
Other Adverse Events
In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for Effient and clopidogrel, respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions (0.36%, 0.36%), and angioedema (0.06%, 0.04%). Table 4 summarizes the adverse events reported by at least 2.5% of patients.
## Postmarketing Experience
The following adverse reactions have been identified during post approval use of Effient. 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.
- Blood and lymphatic system disorders — Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP)
- Immune system disorders — Hypersensitivity reactions including anaphylaxis
# Drug Interactions
- Warfarin
- Coadministration of Effient and warfarin increases the risk of bleeding .
- Non-Steroidal Anti-Inflammatory Drugs
- Coadministration of Effient and NSAIDs (used chronically) may increase the risk of bleeding .
- Other Concomitant Medications
- Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes .
- Effient can be administered with aspirin (75-mg to 325-mg per day), heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate gastric pH, including proton pump inhibitors and H2 blockers .
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Pregnancy Category B - There are no adequate and well-controlled studies of Effient use in pregnant women. Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite) revealed no evidence of fetal harm; however, animal studies are not always predictive of a human response. Effient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
In embryo fetal developmental toxicology studies, pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. A slight decrease in pup body weight was observed; but, there were no structural malformations in either species. In prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure .
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Prasugrel in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Prasugrel during labor and delivery.
### Nursing Mothers
It is not known whether Effient is excreted in human milk; however, metabolites of Effient were found in rat milk. Because many drugs are excreted in human milk, prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established .
### Geriatic Use
In TRITON-TIMI 38, 38.5% of patients were ≥65 years of age and 13.2% were ≥75 years of age. The risk of bleeding increased with advancing age in both treatment groups, although the relative risk of bleeding (Effient compared with clopidogrel) was similar across age groups.
Patients ≥75 years of age who received Effient 10-mg had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%). In patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received Effient and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients ≥75 years of age , use of Effient is generally not recommended in these patients, except in high-risk situations (diabetes and past history of myocardial infarction) where its effect appears to be greater and its use may be considered .
### Gender
There is no FDA guidance on the use of Prasugrel with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Prasugrel with respect to specific racial populations.
### Renal Impairment
No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease, but such patients are generally at higher risk of bleeding .
### Hepatic Impairment
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied, but such patients are generally at higher risk of bleeding .
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Prasugrel in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Prasugrel in patients who are immunocompromised.
### Low Body Weight
In TRITON-TIMI 38, 4.6% of patients treated with Effient had body weight <60 kg. Individuals with body weight <60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel . Consider lowering the maintenance dose to 5-mg in patients <60 kg. The effectiveness and safety of the 5-mg dose have not been prospectively studied .
# Administration and Monitoring
### Administration
Initiate Effient treatment as a single 60-mg oral loading dose and then continue at 10-mg orally once daily. Patients taking Effient should also take aspirin (75-mg to 325-mg) daily . Effient may be administered with or without food .
Dosing in Low Weight Patients
Compared to patients weighing ≥60 kg, patients weighing <60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10-mg once daily maintenance dose. Consider lowering the maintenance dose to 5-mg in patients <60 kg. The effectiveness and safety of the 5-mg dose have not been prospectively studied .
### Monitoring
There is limited information regarding Prasugrel Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Prasugrel and IV administrations.
# Overdosage
- Signs and Symptoms
- Platelet inhibition by prasugrel is rapid and irreversible, lasting for the life of the platelet, and is unlikely to be increased in the event of an overdose. In rats, lethality was observed after administration of 2000 mg/kg. Symptoms of acute toxicity in dogs included emesis, increased serum alkaline phosphatase, and hepatocellular atrophy. Symptoms of acute toxicity in rats included mydriasis, irregular respiration, decreased locomotor activity, ptosis, staggering gait, and lacrimation.
- Recommendations about Specific Treatment
- Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.
# Pharmacology
## Mechanism of Action
Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
## Structure
Effient contains prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Effient is formulated as the hydrochloride salt, a racemate, which is chemically designated as 5--4,5,6,7-tetrahydrothienopyridin-2-yl acetate hydrochloride. Prasugrel hydrochloride has the empirical formula C20H20FNO3SHCl representing a molecular weight of 409.90. The chemical structure of prasugrel hydrochloride is:
Prasugrel hydrochloride is a white to practically white solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.
Effient is available for oral administration as 5-mg or 10-mg elongated hexagonal, film-coated, non-scored tablets, debossed on each side. Each yellow 5-mg tablet is manufactured with 5.49 mg prasugrel hydrochloride, equivalent to 5-mg prasugrel and each beige 10-mg tablet with 10.98 mg prasugrel hydrochloride, equivalent to 10-mg of prasugrel.
Original Formulation.
During manufacture and storage, partial conversion from prasugrel hydrochloride to prasugrel free base may occur. Other ingredients include mannitol, hypromellose, croscarmellose sodium, microcrystalline cellulose, and vegetable magnesium stearate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10-mg tablet).
Revised Formulation
Other ingredients include mannitol, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, sucrose stearate, and glyceryl behenate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10-mg tablet).
## Pharmacodynamics
Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60-mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (see Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10-mg daily after a 60-mg loading dose of Effient.
Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75-mg and initiating a prasugrel 10-mg maintenance dose with or without a prasugrel 60-mg loading dose results in a decrease of 14 percentage points in maximum platelet aggregation (MPA) by Day 7. This decrease in MPA is not greater than that typically produced by a 10-mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established.
5-mg in Low Body Weight Patients - In patients with stable coronary artery disease, mean platelet inhibition in subjects <60 kg taking 5-mg prasugrel was similar to that of subjects ≥60 kg taking 10-mg prasugrel. The relationship between inhibition of platelet aggregation and clinical activity has not been established.
## Pharmacokinetics
Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.
Absorption and Binding - Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite's exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60-mg. Repeated daily doses of 10-mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15-mg dose, the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and Tmax was increased from 0.5 to 1.5 hours. Effient can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.
Metabolism and Elimination - Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel's active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.
## Nonclinical Toxicology
Carcinogenesis - No compound-related tumors were observed in a 2-year rat study with prasugrel at oral doses up to 100 mg/kg/day (>100 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite). There was an increased incidence of tumors (Hepatocellular adenoma
# Clinical Studies
There is limited information regarding Prasugrel Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Prasugrel How Supplied in the drug label.
## Storage
There is limited information regarding Prasugrel Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Prasugrel Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Prasugrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Prasugrel Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Prasugrel Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Prasugrel
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Adeel Jamil, M.D. [3]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Prasugrel is a P2Y12 platelet inhibitor, Platelet aggregation inhibitor that is FDA approved for the treatment of Acute Coronary Syndrome. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, hyperlipidemia, backache, headache, epistaxis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Acute Coronary Syndrome
- Dosing Information
- Initial loading dosage: 60 mg PO
- Maintaining dosage: 10 mg PO qd
- Incombination with: aspirin 75 mg-325 mg
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Prasugrel in adult patients.
### Non–Guideline-Supported Use
### Prophylaxis treatment of Thrombosis of Acute coronary syndrome
- Dosing Information
- Recommended: 10 mg/day[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Prasugrel 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 Prasugrel in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Prasugrel in pediatric patients.
# Contraindications
- Active Bleeding
- Effient is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage [see Warnings and Precautions and Adverse Reactions ].
- Prior Transient Ischemic Attack or Stroke
- Effient is contraindicated in patients with a history of prior transient ischemic attack (TIA) or stroke. In TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel), patients with a history of TIA or ischemic stroke (>3 months prior to enrollment) had a higher rate of stroke on Effient (6.5%; of which 4.2% were thrombotic stroke and 2.3% were intracranial hemorrhage [[[ICH]]]) than on clopidogrel (1.2%; all thrombotic). In patients without such a history, the incidence of stroke was 0.9% (0.2% ICH) and 1.0% (0.3% ICH) with Effient and clopidogrel, respectively. Patients with a history of ischemic stroke within 3 months of screening and patients with a history of hemorrhagic stroke at any time were excluded from TRITON-TIMI 38. Patients who experience a stroke or TIA while on Effient generally should have therapy discontinued [see Adverse Reactions and Clinical Studies].
- Hypersensitivity
- Effient is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to prasugrel or any component of the product [see Adverse Reactions].
# Warnings
## General Risk of Bleeding==
clopidogrel, including Effient, increase the risk of bleeding. With the dosing regimens used in TRITON-TIMI 38, TIMI (Thrombolysis in Myocardial Infarction) Major (clinically overt bleeding associated with a fall in hemoglobin ≥5 g/dL, or intracranial hemorrhage) and TIMI Minor (overt bleeding associated with a fall in hemoglobin of ≥3 g/dL but <5 g/dL) bleeding events were more common on Effient than on clopidogrel [see Adverse Reactions]. The bleeding risk is highest initially, as shown in Figure 1 (events through 450 days; inset shows events through 7 days).
Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures even if the patient does not have overt signs of bleeding.
Do not use Effient in patients with active bleeding, prior TIA or stroke [see Contraindications].
Other risk factors for bleeding are:
- Age ≥75 years. Because of the risk of bleeding (including fatal bleeding) and uncertain effectiveness in patients ≥75 years of age, use of Effient is generally not recommended in these patients, except in high-risk situations (patients with diabetes or history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Adverse Reactions, Use in Specific Populations, Clinical Pharmacology, and Clinical Studies].
- CABG or other surgical procedure [see Warnings and Precautions].
- Body weight <60 kg. Consider a lower (5-mg) maintenance dose [see Dosage and Administration, Adverse Reactions, and Use in Specific Populations].
- Propensity to bleed (e.g., recent trauma, recent surgery, recent or recurrent gastrointestinal (GI) bleeding, active peptic ulcer disease, severe hepatic impairment, or moderate to severe renal impairment) [see Adverse Reactions and Use in Specific Populations (8.7, 8.8)].
- Medications that increase the risk of bleeding (e.g., oral anticoagulants, chronic use of non-steroidal anti-inflammatory drugs NSAIDs, and fibrinolytic agents). Aspirin and heparin were commonly used in TRITON-TIMI 38 [see Drug Interaction, and Clinical Studies].
clopidogrel inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of prasugrel's active metabolite is short relative to the lifetime of the platelet, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.
The risk of bleeding is increased in patients receiving Effient who undergo CABG. If possible, Effient should be discontinued at least 7 days prior to CABG.
Of the 437 patients who underwent CABG during TRITON-TIMI 38, the rates of CABG-related TIMI Major or Minor bleeding were 14.1% in the Effient group and 4.5% in the clopidogrel group [see Adverse Reactions]. The higher risk for bleeding events in patients treated with Effient persisted up to 7 days from the most recent dose of study drug. For patients receiving a thienopyridine within 3 days prior to CABG, the frequencies of TIMI Major or Minor bleeding were 26.7% (12 of 45 patients) in the Effient group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.4% (3 of 89 patients) in the clopidogrel group.
Do not start Effient in patients likely to undergo urgent CABG. CABG-related bleeding may be treated with transfusion of blood products, including packed red blood cells and platelets; however, platelet transfusions within 6 hours of the loading dose or 4 hours of the maintenance dose may be less effective.
Discontinue clopidogrel, including Effient, for active bleeding, elective surgery, stroke, or TIA. The optimal duration of thienopyridine therapy is unknown. In patients who are managed with PCI and stent placement, premature discontinuation of any antiplatelet medication, including clopidogrel, conveys an increased risk of stent thrombosis, myocardial infarction, and death. Patients who require premature discontinuation of a thienopyridine will be at increased risk for cardiac events. Lapses in therapy should be avoided, and if clopidogrel must be temporarily discontinued because of an adverse event(s), they should be restarted as soon as possible [see Contraindications and Warnings and Precautions].
Thrombotic thrombocytopenic purpura (TTP) has been reported with the use of Effient. TTP can occur after a brief exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment, including plasmapheresis (plasma exchange). TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [[[Red blood cell|fragment red blood cells]]] seen on peripheral smear), neurological findings, renal dysfunction, and fever [see Adverse Reactions].
Hypersensitivity including angioedema has been reported in patients receiving Effient, including patients with a history of hypersensitivity reaction to other clopidogrel [see Contraindications and Adverse Reactions].
# Adverse Reactions
## Clinical Trials Experience
The following serious adverse reactions are also discussed elsewhere in the labeling:
- Bleeding [see Boxed Warning and Warnings and Precautions]
- Thrombotic thrombocytopenic purpura [see Warnings and Precautions]
Safety in patients with ACS undergoing PCI was evaluated in a clopidogrel-controlled study, TRITON-TIMI 38, in which 6741 patients were treated with Effient (60-mg loading dose and 10-mg once daily) for a median of 14.5 months (5802 patients were treated for over 6 months; 4136 patients were treated for more than 1 year). The population treated with Effient was 27 to 96 years of age, 25% female, and 92% Caucasian. All patients in the TRITON-TIMI 38 study were to receive aspirin. The dose of clopidogrel in this study was a 300-mg loading dose and 75-mg once daily.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials cannot be directly compared with the rates observed in other clinical trials of another drug and may not reflect the rates observed in practice.
- Drug Discontinuation
- The rate of study drug discontinuation because of adverse reactions was 7.2% for Effient and 6.3% for clopidogrel. Bleeding was the most common adverse reaction leading to study drug discontinuation for both drugs (2.5% for Effient and 1.4% for clopidogrel).
- Bleeding
- Bleeding Unrelated to CABG Surgery - In TRITON-TIMI 38, overall rates of TIMI Major or Minor bleeding adverse reactions unrelated to coronary artery bypass graft surgery (CABG) were significantly higher on Effient than on clopidogrel, as shown in Table 1.
Figure 1 demonstrates non-CABG related TIMI Major or Minor bleeding. The bleeding rate is highest initially, as shown in Figure 1 (inset: Days 0 to 7) [see Warnings and Precautions].
Bleeding by Weight and Age - In TRITON-TIMI 38, non-CABG-related TIMI Major or Minor bleeding rates in patients with the risk factors of age ≥75 years and weight <60 kg are shown in Table 2.
Bleeding Related to CABG - In TRITON-TIMI 38, 437 patients who received a thienopyridine underwent CABG during the course of the study. The rate of CABG-related TIMI Major or Minor bleeding was 14.1% for the Effient group and 4.5% in the clopidogrel group (see Table 3). The higher risk for bleeding adverse reactions in patients treated with Effient persisted up to 7 days from the most recent dose of study drug.
Bleeding Reported as Adverse Reactions - Hemorrhagic events reported as adverse reactions in TRITON-TIMI 38 were, for Effient and clopidogrel, respectively: epistaxis (6.2%, 3.3%), gastrointestinal hemorrhage (1.5%, 1.0%), hemoptysis (0.6%, 0.5%), subcutaneous hematoma (0.5%, 0.2%), post-procedural hemorrhage (0.5%, 0.2%), retroperitoneal hemorrhage (0.3%, 0.2%), pericardial effusion/hemorrhage/tamponade (0.3%, 0.2%), and retinal hemorrhage (0.0%, 0.1%).
malignancies
During TRITON-TIMI 38, newly-diagnosed malignancies were reported in 1.6% and 1.2% of patients treated with prasugrel and clopidogrel, respectively. The sites contributing to the differences were primarily colon and lung. In another Phase 3 clinical study of ACS patients not undergoing PCI, in which data for malignancies were prospectively collected, newly-diagnosed malignancies were reported in 1.8% and 1.7% of patients treated with prasugrel and clopidogrel, respectively. The site of malignancies was balanced between treatment groups except for colorectal malignancies. The rates of colorectal malignancies were 0.3% prasugrel, 0.1% clopidogrel and most were detected during investigation of GI bleed or anemia. It is unclear if these observations are causally-related, are the result of increased detection because of bleeding, or are random occurrences.
Other Adverse Events
In TRITON-TIMI 38, common and other important non-hemorrhagic adverse events were, for Effient and clopidogrel, respectively: severe thrombocytopenia (0.06%, 0.04%), anemia (2.2%, 2.0%), abnormal hepatic function (0.22%, 0.27%), allergic reactions (0.36%, 0.36%), and angioedema (0.06%, 0.04%). Table 4 summarizes the adverse events reported by at least 2.5% of patients.
## Postmarketing Experience
The following adverse reactions have been identified during post approval use of Effient. 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.
- Blood and lymphatic system disorders — Thrombocytopenia, Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions and Patient Counseling Information (17)]
- Immune system disorders — Hypersensitivity reactions including anaphylaxis [see Contraindications]
# Drug Interactions
- Warfarin
- Coadministration of Effient and warfarin increases the risk of bleeding [see Warnings and Precautions and Clinical Pharmacology].
- Non-Steroidal Anti-Inflammatory Drugs
- Coadministration of Effient and NSAIDs (used chronically) may increase the risk of bleeding [see Warnings and Precautions].
- Other Concomitant Medications
- Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes [see Clinical Pharmacology].
- Effient can be administered with aspirin (75-mg to 325-mg per day), heparin, GPIIb/IIIa inhibitors, statins, digoxin, and drugs that elevate gastric pH, including proton pump inhibitors and H2 blockers [see Clinical Pharmacology].
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Pregnancy Category B - There are no adequate and well-controlled studies of Effient use in pregnant women. Reproductive and developmental toxicology studies in rats and rabbits at doses of up to 30 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite) revealed no evidence of fetal harm; however, animal studies are not always predictive of a human response. Effient should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
In embryo fetal developmental toxicology studies, pregnant rats and rabbits received prasugrel at maternally toxic oral doses equivalent to more than 40 times the human exposure. A slight decrease in pup body weight was observed; but, there were no structural malformations in either species. In prenatal and postnatal rat studies, maternal treatment with prasugrel had no effect on the behavioral or reproductive development of the offspring at doses greater than 150 times the human exposure [see Nonclinical Toxicology].
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Prasugrel in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Prasugrel during labor and delivery.
### Nursing Mothers
It is not known whether Effient is excreted in human milk; however, metabolites of Effient were found in rat milk. Because many drugs are excreted in human milk, prasugrel should be used during nursing only if the potential benefit to the mother justifies the potential risk to the nursing infant.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established [see Clinical Pharmacology].
### Geriatic Use
In TRITON-TIMI 38, 38.5% of patients were ≥65 years of age and 13.2% were ≥75 years of age. The risk of bleeding increased with advancing age in both treatment groups, although the relative risk of bleeding (Effient compared with clopidogrel) was similar across age groups.
Patients ≥75 years of age who received Effient 10-mg had an increased risk of fatal bleeding events (1.0%) compared to patients who received clopidogrel (0.1%). In patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received Effient and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients ≥75 years of age [see Clinical Studies], use of Effient is generally not recommended in these patients, except in high-risk situations (diabetes and past history of myocardial infarction) where its effect appears to be greater and its use may be considered [see Warnings and Precautions, Clinical Pharmacology, and Clinical Studies].
### Gender
There is no FDA guidance on the use of Prasugrel with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Prasugrel with respect to specific racial populations.
### Renal Impairment
No dosage adjustment is necessary for patients with renal impairment. There is limited experience in patients with end-stage renal disease, but such patients are generally at higher risk of bleeding [see Warnings and Precautions and Clinical Pharmacology].
### Hepatic Impairment
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). The pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic disease have not been studied, but such patients are generally at higher risk of bleeding [see Warnings and Precautions and Clinical Pharmacology].
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Prasugrel in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Prasugrel in patients who are immunocompromised.
### Low Body Weight
In TRITON-TIMI 38, 4.6% of patients treated with Effient had body weight <60 kg. Individuals with body weight <60 kg had an increased risk of bleeding and an increased exposure to the active metabolite of prasugrel [see Dosage and Administration, Warnings and Precautions, and Clinical Pharmacology]. Consider lowering the maintenance dose to 5-mg in patients <60 kg. The effectiveness and safety of the 5-mg dose have not been prospectively studied [see Dosage and Administration and Clinical Pharmacology].
# Administration and Monitoring
### Administration
Initiate Effient treatment as a single 60-mg oral loading dose and then continue at 10-mg orally once daily. Patients taking Effient should also take aspirin (75-mg to 325-mg) daily [see Drug Interaction and Clinical Pharmacology]. Effient may be administered with or without food [see Clinical Pharmacology and Clinical Studies].
Dosing in Low Weight Patients
Compared to patients weighing ≥60 kg, patients weighing <60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10-mg once daily maintenance dose. Consider lowering the maintenance dose to 5-mg in patients <60 kg. The effectiveness and safety of the 5-mg dose have not been prospectively studied [see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology].
### Monitoring
There is limited information regarding Prasugrel Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Prasugrel and IV administrations.
# Overdosage
- Signs and Symptoms
- Platelet inhibition by prasugrel is rapid and irreversible, lasting for the life of the platelet, and is unlikely to be increased in the event of an overdose. In rats, lethality was observed after administration of 2000 mg/kg. Symptoms of acute toxicity in dogs included emesis, increased serum alkaline phosphatase, and hepatocellular atrophy. Symptoms of acute toxicity in rats included mydriasis, irregular respiration, decreased locomotor activity, ptosis, staggering gait, and lacrimation.
- Recommendations about Specific Treatment
- Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.
# Pharmacology
## Mechanism of Action
Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
## Structure
Effient contains prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP receptor. Effient is formulated as the hydrochloride salt, a racemate, which is chemically designated as 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride. Prasugrel hydrochloride has the empirical formula C20H20FNO3S•HCl representing a molecular weight of 409.90. The chemical structure of prasugrel hydrochloride is:
Prasugrel hydrochloride is a white to practically white solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.
Effient is available for oral administration as 5-mg or 10-mg elongated hexagonal, film-coated, non-scored tablets, debossed on each side. Each yellow 5-mg tablet is manufactured with 5.49 mg prasugrel hydrochloride, equivalent to 5-mg prasugrel and each beige 10-mg tablet with 10.98 mg prasugrel hydrochloride, equivalent to 10-mg of prasugrel.
Original Formulation.
During manufacture and storage, partial conversion from prasugrel hydrochloride to prasugrel free base may occur. Other ingredients include mannitol, hypromellose, croscarmellose sodium, microcrystalline cellulose, and vegetable magnesium stearate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10-mg tablet).
Revised Formulation
Other ingredients include mannitol, hypromellose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, sucrose stearate, and glyceryl behenate. The color coatings contain lactose, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in Effient 10-mg tablet).
## Pharmacodynamics
Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60-mg loading dose of Effient, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% (see Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10-mg daily after a 60-mg loading dose of Effient.
Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75-mg and initiating a prasugrel 10-mg maintenance dose with or without a prasugrel 60-mg loading dose results in a decrease of 14 percentage points in maximum platelet aggregation (MPA) by Day 7. This decrease in MPA is not greater than that typically produced by a 10-mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established.
5-mg in Low Body Weight Patients - In patients with stable coronary artery disease, mean platelet inhibition in subjects <60 kg taking 5-mg prasugrel was similar to that of subjects ≥60 kg taking 10-mg prasugrel. The relationship between inhibition of platelet aggregation and clinical activity has not been established.
## Pharmacokinetics
Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.
Absorption and Binding - Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (Cmax) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite's exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60-mg. Repeated daily doses of 10-mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15-mg dose, the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and Tmax was increased from 0.5 to 1.5 hours. Effient can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.
Metabolism and Elimination - Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel's active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.
## Nonclinical Toxicology
Carcinogenesis - No compound-related tumors were observed in a 2-year rat study with prasugrel at oral doses up to 100 mg/kg/day (>100 times the recommended therapeutic exposures in humans (based on plasma exposures to the major circulating human metabolite). There was an increased incidence of tumors (Hepatocellular adenoma
# Clinical Studies
There is limited information regarding Prasugrel Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Prasugrel How Supplied in the drug label.
## Storage
There is limited information regarding Prasugrel Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Prasugrel Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Prasugrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Prasugrel Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Prasugrel Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Effient | |
36f84fc1b50e0a4ab3b4c2a488e36ee30c472caf | wikidoc | Egg bound | Egg bound
In farming and animal husbandry, the term egg bound refers to a condition in laying hens where a hen is unable to pass an egg that has formed. The egg may be stuck near the cloaca, or further inside. Egg binding is a reasonably common, and potentially serious, condition that can lead to infection or damage to internal tissue. The bound egg may be gently massaged out; failing this it may become necessary to break the egg in situ and remove it in parts. If broken, the oviduct should be cleaned of shell fragments and egg residue to avoid damage or infection.
The term can also be seen in herpetoculture, as this condition can occur in female reptiles. It is inadviseable to attempt to break a reptile egg to remove it from an egg bound female. This procedure may be done by a veterinarian, who will insert a needle into the egg, and withdraw the contents with a syringe, allowing the egg to collapse and be removed. Non-surgical interventions include administering oxytocin to improve contractions and allow the eggs to pass normally. In many cases, egg bound reptiles must undergo surgery to have stuck eggs removed. Egg binding in reptiles is quickly fatal if left untreated, so if you see a gravid female become very lethargic and cease feeding, seek medical treatment for the animal immediately. A recent episode of the Animal Planet reality show E-Vet Interns featured the treatment of an egg bound turtle named Napoleon. Exotics specialist Dr. Kevin Fitzgerald of Alameda East Veterinary Hospital is shown treating her with oxytocin and then eventually having to resort to surgery with footage of the large number of eggs that were removed. Dr. Fitzgerald was shown explaining to the new interns how dangerous this condition can be for a pet turtle and the need for early medical intervention.
Egg binding can occur if an egg is malformed and/or too large, the animal is weakened by illness, improper husbandry, or stress, or if hormonal balances are wrong (producing weak contractions). Factors that can contribute to the risk of egg binding include calcium deficiency, breeding animals that are too young or too small, not providing suitable laying areas (leading to deliberate retention of eggs), and overfeeding of species in which clutch size is dependent on food intake (such as Veiled Chameleons). | Egg bound
In farming and animal husbandry, the term egg bound refers to a condition in laying hens where a hen is unable to pass an egg that has formed. The egg may be stuck near the cloaca, or further inside. Egg binding is a reasonably common, and potentially serious, condition that can lead to infection or damage to internal tissue. The bound egg may be gently massaged out; failing this it may become necessary to break the egg in situ and remove it in parts. If broken, the oviduct should be cleaned of shell fragments and egg residue to avoid damage or infection.
The term can also be seen in herpetoculture, as this condition can occur in female reptiles. It is inadviseable to attempt to break a reptile egg to remove it from an egg bound female. This procedure may be done by a veterinarian, who will insert a needle into the egg, and withdraw the contents with a syringe, allowing the egg to collapse and be removed. Non-surgical interventions include administering oxytocin to improve contractions and allow the eggs to pass normally. In many cases, egg bound reptiles must undergo surgery to have stuck eggs removed. Egg binding in reptiles is quickly fatal if left untreated, so if you see a gravid female become very lethargic and cease feeding, seek medical treatment for the animal immediately. A recent episode of the Animal Planet reality show E-Vet Interns featured the treatment of an egg bound turtle named Napoleon. Exotics specialist Dr. Kevin Fitzgerald of Alameda East Veterinary Hospital is shown treating her with oxytocin and then eventually having to resort to surgery with footage of the large number of eggs that were removed. Dr. Fitzgerald was shown explaining to the new interns how dangerous this condition can be for a pet turtle and the need for early medical intervention.[1]
Egg binding can occur if an egg is malformed and/or too large, the animal is weakened by illness, improper husbandry, or stress, or if hormonal balances are wrong (producing weak contractions). Factors that can contribute to the risk of egg binding include calcium deficiency, breeding animals that are too young or too small, not providing suitable laying areas (leading to deliberate retention of eggs), and overfeeding of species in which clutch size is dependent on food intake (such as Veiled Chameleons). | https://www.wikidoc.org/index.php/Egg_bound | |
c3ada9a7da523f7e6b9c5f4ca6264ced350bc78d | wikidoc | Eglumegad | Eglumegad
Eglumegad (LY-354,740) is a research drug developed by Eli Lilly, which is being investigated for its potential in the treatment of anxiety and drug addiction. It is a glutamate derived compound and its mode of action implies a novel mechanism.
Eglumegad acts as a group-selective agonist for the group II metabotropic glutamate receptors (mGluR2/3). A substantial D2 dopaminergic component was also found.
In experiments on mice, eglumegad was found to be as effective as diazepam for treating anxiety symptoms in several standard tests, but without producing any of the negative side effects of diazepam such as sedation and memory impairment. Tests in humans confirmed that it produced anxiolytic effects without producing sedation. However it did slightly reduce cognitive performance in tests on monkeys.
Eglumegad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both nicotine and morphine in animals, as well as inhibiting the development of tolerance to morphine, raising hope that this drug may be useful for treating drug addiction in humans.
Eglumegad and related drugs are neuroprotective and are synergistic with the neuroprotection produced by NMDA antagonist drugs, which may make these drugs useful in aiding recovery from brain injury.
This class of drugs also interacts with hallucinogenic drugs, with eglumegad reducing the effects of 5HT2A agonist hallucinogens, while conversely the mGluR2/3 antagonist LY-341,495 increased the behavioural effects of these drugs. This suggests that mGluR2/3 agonists such as eglumegad may have potential uses in the treatment of some forms of psychosis, although eglumegad had only limited effects on the action of the dissociative drug phencyclidine which is generally a better model for schizophrenia than the 5HT2A agonist hallucinogens.
Development of this drug is continuing, with several clinical trials completed and more planned. Poor oral bioavailability of the original formulation led to limited efficacy in the initial human trials, and so the prodrug form LY-544,344 looks more likely to be the final canditate for aspired marketing. | Eglumegad
Eglumegad (LY-354,740) is a research drug developed by Eli Lilly, which is being investigated for its potential in the treatment of anxiety[1] and drug addiction.[2] It is a glutamate derived compound and its mode of action implies a novel mechanism.[3]
Eglumegad acts as a group-selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).[4][5] A substantial D2 dopaminergic component was also found.[6]
In experiments on mice, eglumegad was found to be as effective as diazepam for treating anxiety symptoms in several standard tests, but without producing any of the negative side effects of diazepam such as sedation and memory impairment.[7] Tests in humans confirmed that it produced anxiolytic effects without producing sedation.[8][9] However it did slightly reduce cognitive performance in tests on monkeys.[10]
Eglumegad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both nicotine[11] and morphine in animals,[12] as well as inhibiting the development of tolerance to morphine,[13] raising hope that this drug may be useful for treating drug addiction in humans.
Eglumegad and related drugs are neuroprotective[14] and are synergistic with the neuroprotection produced by NMDA antagonist drugs,[15] which may make these drugs useful in aiding recovery from brain injury.
This class of drugs also interacts with hallucinogenic drugs, with eglumegad reducing the effects of 5HT2A agonist hallucinogens,[16] while conversely the mGluR2/3 antagonist LY-341,495 increased the behavioural effects of these drugs.[17] This suggests that mGluR2/3 agonists such as eglumegad may have potential uses in the treatment of some forms of psychosis, although eglumegad had only limited effects on the action of the dissociative drug phencyclidine[18] which is generally a better model for schizophrenia than the 5HT2A agonist hallucinogens.[19]
Development of this drug is continuing, with several clinical trials completed and more planned.[20] Poor oral bioavailability of the original formulation led to limited efficacy in the initial human trials,[21] and so the prodrug form LY-544,344 looks more likely to be the final canditate for aspired marketing.[22][23][24]
Template:Pharmacology-stub | https://www.wikidoc.org/index.php/Eglumegad | |
5a444d42892f42f3fe0c6dd5bd869063b9da09e9 | wikidoc | Ehrlichia | Ehrlichia
# Overview
Ehrlichia is a genus of rickettsiales bacteria. They are transmitted by ticks. Several species can cause infection (Ehrlichiosis) in humans. The genus is named after German microbiologist Paul Ehrlich. These diseases are considered zoonotic as the main reservoir for the pathogen is in animal, usually mammal species.
Ehrlichia are obligately intracellular pathogens and are transported between cells through the host cell filopodia during initial stages of infection, whereas, in the final stages of infection the pathogen ruptures the host cell membrane.
A new species of Ehrlichia has been discovered inside the deer tick Ixodes scapularis. This newly found organism has only been isolated from deer ticks in Wisconsin and Minnesota in the USA. The species is known as Ehrlichia Wisconsin HM543746.
# History
The first ehrlichial disease was first recognized in South Africa during the 19th century. Its tick-borne nature was determined in 1900. The organism itself was demonstrated 1925 when it was recognized to be a rickettsia. It was initially named Rickettsia ruminantium, and is currently named Ehrlichia ruminantium. In 1945 a "infection and treatment" method for livestock was developed. This is still the only commercially available "vaccine" against the disease, which is not a true vaccine, but intentional exposure to the disease with monitoring and antibiotic treatment if needed. In 1985 the organism was first propagated reliably in tissue culture. | Ehrlichia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ehrlichia is a genus of rickettsiales bacteria. They are transmitted by ticks. Several species can cause infection (Ehrlichiosis) in humans. The genus is named after German microbiologist Paul Ehrlich. These diseases are considered zoonotic as the main reservoir for the pathogen is in animal, usually mammal species.
Ehrlichia are obligately intracellular pathogens and are transported between cells through the host cell filopodia during initial stages of infection, whereas, in the final stages of infection the pathogen ruptures the host cell membrane.[2]
A new species of Ehrlichia has been discovered inside the deer tick Ixodes scapularis. This newly found organism has only been isolated from deer ticks in Wisconsin and Minnesota in the USA. The species is known as Ehrlichia Wisconsin HM543746.
# History
The first ehrlichial disease was first recognized in South Africa during the 19th century. Its tick-borne nature was determined in 1900. The organism itself was demonstrated 1925 when it was recognized to be a rickettsia. It was initially named Rickettsia ruminantium, and is currently named Ehrlichia ruminantium. In 1945 a "infection and treatment" method for livestock was developed. This is still the only commercially available "vaccine" against the disease, which is not a true vaccine, but intentional exposure to the disease with monitoring and antibiotic treatment if needed. In 1985 the organism was first propagated reliably in tissue culture. | https://www.wikidoc.org/index.php/Ehrlichia | |
f2a30c773a6321e5cfe8b22c6016842eb16640a9 | wikidoc | Elaterium | Elaterium
Elaterium is the name of a drug consisting of a sediment deposited by the juice of the fruit of Ecballium Elaterium, the squirting cucumber, a native of the Mediterranean region.
The plant, which is a member of the natural order Cucurbitaceae, resembles the vegetable marrow in its growth. The fruit resembles a small cucumber, and when ripe is highly turgid, and separates almost at a touch from the fruit stalk. The end of the stalk forms a stopper, on the removal of which the fluid contents of the fruit, together with the seeds, are squirted through the aperture by the sudden contraction of the wall of the fruit.
To prepare the drug the fruit is sliced lengthwise and slightly pressed; the greenish and slightly turbid juice thus obtained is strained and set aside; and the deposit of elaterium formed after a few hours is collected on a linen filter, rapidly drained, and dried on porous tiles at a gentle heat. Elaterium is met with in commerce in light, thin, friable, flat or slightly incurved opaque cakes, of a greyish-green color, bitter taste and tea-like smell.
The drug is soluble in alcohol, but insoluble in water and ether. The official dose used to be 1-1/2 grain, and the British pharmacopeia at the beginning of the 20th century directs that the drug is to contain from 20 to 25% of the active principle elaterinum or elaterin. A resin in the natural product aids its action. Elaterin is extracted from elaterium by chloroform and then precipitated by ether. It has the formula C32H44O7. It forms colorless scales which have a bitter taste, but it is highly inadvisable to taste either this substance or elaterium. The British pharmacopeia contains a useful preparation, the Pulvis Elaterini Compositus, which contains one part of the active principle in forty.
The action of this drug resembles that of the saline aperients, but is much more powerful. It is the most active hydragogue purgative known, causing also much depression and violent griping. When injected subcutaneously it is inert, as its action is entirely dependent upon its admixture with the bile. The drug is undoubtedly valuable in cases of dropsy and Bright's disease, and also in cases of cerebral haemorrhage, threatened or present. It must not be used except in urgent cases, and must invariably be employed with the utmost care, especially if the state of the heart be unsatisfactory. | Elaterium
Elaterium is the name of a drug consisting of a sediment deposited by the juice of the fruit of Ecballium Elaterium, the squirting cucumber, a native of the Mediterranean region.
The plant, which is a member of the natural order Cucurbitaceae, resembles the vegetable marrow in its growth. The fruit resembles a small cucumber, and when ripe is highly turgid, and separates almost at a touch from the fruit stalk. The end of the stalk forms a stopper, on the removal of which the fluid contents of the fruit, together with the seeds, are squirted through the aperture by the sudden contraction of the wall of the fruit.
To prepare the drug the fruit is sliced lengthwise and slightly pressed; the greenish and slightly turbid juice thus obtained is strained and set aside; and the deposit of elaterium formed after a few hours is collected on a linen filter, rapidly drained, and dried on porous tiles at a gentle heat. Elaterium is met with in commerce in light, thin, friable, flat or slightly incurved opaque cakes, of a greyish-green color, bitter taste and tea-like smell.
The drug is soluble in alcohol, but insoluble in water and ether. The official dose used to be 1-1/2 grain, and the British pharmacopeia at the beginning of the 20th century directs that the drug is to contain from 20 to 25% of the active principle elaterinum or elaterin. A resin in the natural product aids its action. Elaterin is extracted from elaterium by chloroform and then precipitated by ether. It has the formula C32H44O7. It forms colorless scales which have a bitter taste, but it is highly inadvisable to taste either this substance or elaterium. The British pharmacopeia contains a useful preparation, the Pulvis Elaterini Compositus, which contains one part of the active principle in forty.
The action of this drug resembles that of the saline aperients, but is much more powerful. It is the most active hydragogue purgative known, causing also much depression and violent griping. When injected subcutaneously it is inert, as its action is entirely dependent upon its admixture with the bile. The drug is undoubtedly valuable in cases of dropsy and Bright's disease, and also in cases of cerebral haemorrhage, threatened or present. It must not be used except in urgent cases, and must invariably be employed with the utmost care, especially if the state of the heart be unsatisfactory. | https://www.wikidoc.org/index.php/Elaterium | |
a8dc20f03e56d0e12145949aa1fe6ba5689b96ba | wikidoc | Electracy | Electracy
Electracy describes the kind of “literacy” or skill and facility necessary to exploit the full communicative potential of new electronic media such as multimedia, hypermedia, social software, and virtual worlds. According to theorist Gregory Ulmer, electracy “is to digital media what literacy is to print.” It encompasses the broader cultural, institutional, pedagogical, and ideological implications inherent in the transition from a culture of print literacy to a culture saturated with electronic media. “Electracy” is the term he gives to what is resulting from this major transition that our society is undergoing. The term is a portmanteau word, combining "electricity" with "trace," to allude to one of the fundamental terms used by the French philosopher Jacques Derrida to name the relational spacing that enables and delimits any signification in any medium (which is to say that it operates in orality and literacy as much as in electracy). Usage parallels "literacy": a person may be literate or illiterate, electrate or anelectrate.
As such, electracy denotes a broad spectrum of research possibilities including the history and invention of writing and mnemonic practices, the epistemological and ontological changes resulting from such practices, the sociological and psychological implications of a networked culture, and the pedagogical implementation of practices derived from such explorations.
Ulmer writes of electracy:
What literacy is to the analytical mind, electracy is to the affective body: a prosthesis that enhances and augments a natural or organic human potential. Alphabetic writing is an artificial memory that supports long complex chains of reasoning impossible to sustain within the organic mind. Digital imaging similarly supports extensive complexes of mood atmospheres beyond organic capacity. Electrate logic proposes to design these atmospheres into affective group intelligence. Literacy and electracy in collaboration produce a civilizational left-brain right-brain integration. If literacy focused on universally valid methodologies of knowledge (sciences), electracy focuses on the individual state of mind within which knowing takes place (arts).
Ulmer’s work benefits from considering other historical moments of radical technological change (such as the profound changes resulting from the inventions of the alphabet, writing, and the printing press), and as such his work is grammatological insofar as it derives and extrapolates a methodology from the history of writing and mnemonic practices. His career can be encapsulated as an attempt to invent a rhetoric for electronic media.
Ulmer introduced electracy in Teletheory (1989), and it began to be noted in the scholarship as early as 1997. It has been regarded as among the "most prominent" contemporary designations for what Walter J. Ong once described as a "secondary orality" that will eventually supplant print literacy As James Inman writes, "It is important to distinguish electracy from other terms, such as computer-based literacy, Internet literacy, digital literacy, electronic literacies, metamedia literacy, and even cyber-punk literacy. None of these other terms have the breadth electracy does as a concept, and none of them draw their ontology from electronic media exclusively" . Some scholars have viewed the electracy paradigm, along with other "apparatus theories" such as Ong's, with skepticism, arguing that they are "essentialist" or "determinist."
# Electracy and pedagogy
Ulmer’s work has implications for the practice of education as well. Co-author of a textbook for freshman English courses, Ulmer develops undergraduate and graduate level courses which incorporate his theories and invite students into the process of inventing new practices and genres.
Alan Clinton, in a review of Internet Invention, writes that “Ulmer’s pedagogy ultimately levels the playing field between student and teacher” Academic Lisa Gye also recognizes the pedagogical implications of Ulmer’s work:
The transition from a predominantly literate culture to an electronic culture is already engendering changes in the ways in which we think, write and exchange ideas. Ulmer has been concerned with the kinds of changes that take place as a result of this transition and his primary concern has been a pedagogical one – that is, he is interested in how learning is transformed by the shift from the apparatus of literacy to the apparatus of what he comes to term ‘electracy’.
Electracy as an educational aim has been recognized by scholars in several fields, including English composition and rhetoric, literary and media criticism, digital media and art, and architecture Mikesch Muecke explains that "Gregory Ulmer's ideas on electracy provide … a model for a new pedagogy where learning is closer to invention than verification"
Ulmer himself writes:
Electrate pedagogy is based in art/aesthetics as relays for operating new media organized as a prosthesis for learning any subject whatsoever. The near absence of art in contemporary schools is the electrate equivalent of the near absence of science in medieval schools for literacy. The suppression of empirical inquiry by religious dogmatism during the era sometimes called the "dark ages" (reflecting the hostility of the oral apparatus to literacy), is paralleled today by the suppression of aesthetic play by empirical utilitarianism (reflecting the hostility of the literate apparatus to electracy). The ambivalent relation of the institutions of school and entertainment today echoes the ambivalence informing church-science relations throughout the era of literacy.
Ulmer's educational methods fit into a broader paradigm shift in pedagogical theory and practice known as constructivism. He discusses the relationship between pedagogy and electracy at length in an interview with Sung-Do Kim published in 2005. | Electracy
Electracy describes the kind of “literacy” or skill and facility necessary to exploit the full communicative potential of new electronic media such as multimedia, hypermedia, social software, and virtual worlds. According to theorist Gregory Ulmer, electracy “is to digital media what literacy is to print.”[1] It encompasses the broader cultural, institutional, pedagogical, and ideological implications inherent in the transition from a culture of print literacy to a culture saturated with electronic media. “Electracy” is the term he gives to what is resulting from this major transition that our society is undergoing. The term is a portmanteau word, combining "electricity" with "trace," to allude to one of the fundamental terms used by the French philosopher Jacques Derrida to name the relational spacing that enables and delimits any signification in any medium (which is to say that it operates in orality and literacy as much as in electracy). Usage parallels "literacy": a person may be literate or illiterate, electrate or anelectrate.
As such, electracy denotes a broad spectrum of research possibilities including the history and invention of writing and mnemonic practices, the epistemological and ontological changes resulting from such practices, the sociological and psychological implications of a networked culture, and the pedagogical implementation of practices derived from such explorations.
Ulmer writes of electracy:
What literacy is to the analytical mind, electracy is to the affective body: a prosthesis that enhances and augments a natural or organic human potential. Alphabetic writing is an artificial memory that supports long complex chains of reasoning impossible to sustain within the organic mind. Digital imaging similarly supports extensive complexes of mood atmospheres beyond organic capacity. Electrate logic proposes to design these atmospheres into affective group intelligence. Literacy and electracy in collaboration produce a civilizational left-brain right-brain integration. If literacy focused on universally valid methodologies of knowledge (sciences), electracy focuses on the individual state of mind within which knowing takes place (arts).[2]
Ulmer’s work benefits from considering other historical moments of radical technological change (such as the profound changes resulting from the inventions of the alphabet, writing, and the printing press), and as such his work is grammatological insofar as it derives and extrapolates a methodology from the history of writing and mnemonic practices. His career can be encapsulated as an attempt to invent a rhetoric for electronic media.
Ulmer introduced electracy in Teletheory (1989), and it began to be noted in the scholarship as early as 1997. [3] It has been regarded as among the "most prominent" contemporary designations[4] for what Walter J. Ong once described as a "secondary orality" that will eventually supplant print literacy[5] As James Inman writes, "It is important to distinguish electracy from other terms, such as computer-based literacy, Internet literacy, digital literacy, electronic literacies, metamedia literacy, and even cyber-punk literacy. None of these other terms have the breadth electracy does as a concept, and none of them draw their ontology from electronic media exclusively" [6]. Some scholars have viewed the electracy paradigm, along with other "apparatus theories" such as Ong's, with skepticism, arguing that they are "essentialist" or "determinist."[7]
# Electracy and pedagogy
Ulmer’s work has implications for the practice of education as well. Co-author of a textbook for freshman English courses[8], Ulmer develops undergraduate and graduate level courses which incorporate his theories and invite students into the process of inventing new practices and genres.[9]
Alan Clinton, in a review of Internet Invention, writes that “Ulmer’s pedagogy ultimately levels the playing field between student and teacher” [10] Academic Lisa Gye also recognizes the pedagogical implications of Ulmer’s work:
The transition from a predominantly literate culture to an electronic culture is already engendering changes in the ways in which we think, write and exchange ideas. Ulmer has been concerned with the kinds of changes that take place as a result of this transition and his primary concern has been a pedagogical one – that is, he is interested in how learning is transformed by the shift from the apparatus of literacy to the apparatus of what he comes to term ‘electracy’.[11]
Electracy as an educational aim has been recognized by scholars in several fields, including English composition and rhetoric[12], literary and media criticism[13], digital media and art, and architecture[14] Mikesch Muecke explains that "Gregory Ulmer's ideas on electracy provide … a model for a new pedagogy where learning is closer to invention than verification"[15]
Ulmer himself writes:
Electrate pedagogy is based in art/aesthetics as relays for operating new media organized as a prosthesis for learning any subject whatsoever. The near absence of art in contemporary schools is the electrate equivalent of the near absence of science in medieval schools for literacy. The suppression of empirical inquiry by religious dogmatism during the era sometimes called the "dark ages" (reflecting the hostility of the oral apparatus to literacy), is paralleled today by the suppression of aesthetic play by empirical utilitarianism (reflecting the hostility of the literate apparatus to electracy). The ambivalent relation of the institutions of school and entertainment today echoes the ambivalence informing church-science relations throughout the era of literacy.[16]
Ulmer's educational methods fit into a broader paradigm shift in pedagogical theory and practice known as constructivism. He discusses the relationship between pedagogy and electracy at length in an interview with Sung-Do Kim published in 2005.[17] | https://www.wikidoc.org/index.php/Electracy | |
48fc3646921a8b3f2d33d81601f6e8f7252807ae | wikidoc | Electrode | Electrode
# Overview
An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit (e.g. a semiconductor, an electrolyte or a vacuum). The word was coined by the scientist Michael Faraday from the Greek words elektron (meaning amber, from which the word electricity is derived) and hodos, a way.
# Anode and cathode in electrochemical cells
An electrode in an electrochemical cell is referred to as either an anode or a cathode, words that were also coined by Faraday. The anode is now defined as the electrode at which electrons leave the cell and oxidation occurs, and the cathode as the electrode at which electrons enter the cell and reduction occurs. Each electrode may become either the anode or the cathode depending on the voltage applied to the cell. A bipolar electrode is an electrode that functions as the anode of one cell and the cathode of another cell.
## Primary cell
A primary cell is special type of electrochemical cell in which the reaction cannot be reversed, and the identities of the anode and cathode are therefore fixed. The anode is always the positive electrode. The cell can be discharged but not recharged.
## Secondary cell
The case in an electrolytic cell. When the cell is being discharged, it behaves like a primary or voltaic cell, with the anode as the negative electrode and the cathode as the positive. The chemical change, which converts chemical energy into electrical energy, is reversible. This cell can be recharged by simply passing electrons in the opposite direction, so it's also called a storage or accumulator cell.
# Other anodes and cathodes
In a vacuum tube or a semiconductor having polarity (diodes, electrolytic capacitors) the anode is the positive (+) electrode and the cathode the negative (−). The electrons enter the device through the cathode and exit the device through the anode.
In a three-electrode cell, a counter electrode, also called an auxiliary electrode, is used only to make a connection to the electrolyte so that a current can be applied to the working electrode. The counter electrode is usually made of an inert material, such as a noble metal or graphite, to keep it from dissolving.
# Welding electrodes
In arc welding an electrode is used to conduct current through a workpiece to fuse two pieces together. Depending upon the process, the electrode is either consumable, in the case of gas metal arc welding or shielded metal arc welding, or non-consumable, such as in gas tungsten arc welding. For a direct current system the weld rod or stick may be a cathode for a filling type weld or an anode for other welding processes. For an alternating current arc welder the welding electrode would not be considered an anode or cathode. To learn more about tungsten electrodes and their preparation, visit for free guides.
# Alternating current electrodes
For electrical systems which use alternating current the electrodes are the connections from the circuitry to the object to be acted upon by the electrical current but are not designated anode or cathode since the direction of flow of the electrons changes periodically, usually many times per second.
# Uses of electrodes
Electric currents are run through nonmetal objects to alter them in numerous ways and to measure conductivity for numerous purposes. Examples include:
- Electrodes for medical purposes, such as EEG, ECG, ECT, defibrillator
- Electrodes for electrophysiology techniques in biomedical research
- Electrodes for execution by the electric chair
- Electrodes for electroplating
- Electrodes for arc welding
- Electrodes for cathodic protection
- Electrodes for grounding
- Electrodes for chemical analysis using electrochemical methods
- Inert electrodes for electrolysis (made of platinum) | Electrode
# Overview
An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit (e.g. a semiconductor, an electrolyte or a vacuum). The word was coined by the scientist Michael Faraday from the Greek words elektron (meaning amber, from which the word electricity is derived) and hodos, a way.[1]
# Anode and cathode in electrochemical cells
An electrode in an electrochemical cell is referred to as either an anode or a cathode, words that were also coined by Faraday. The anode is now defined as the electrode at which electrons leave the cell and oxidation occurs, and the cathode as the electrode at which electrons enter the cell and reduction occurs. Each electrode may become either the anode or the cathode depending on the voltage applied to the cell. A bipolar electrode is an electrode that functions as the anode of one cell and the cathode of another cell.
## Primary cell
A primary cell is special type of electrochemical cell in which the reaction cannot be reversed, and the identities of the anode and cathode are therefore fixed. The anode is always the positive electrode. The cell can be discharged but not recharged.
## Secondary cell
The case in an electrolytic cell. When the cell is being discharged, it behaves like a primary or voltaic cell, with the anode as the negative electrode and the cathode as the positive. The chemical change, which converts chemical energy into electrical energy, is reversible. This cell can be recharged by simply passing electrons in the opposite direction, so it's also called a storage or accumulator cell.
# Other anodes and cathodes
In a vacuum tube or a semiconductor having polarity (diodes, electrolytic capacitors) the anode is the positive (+) electrode and the cathode the negative (−). The electrons enter the device through the cathode and exit the device through the anode.
In a three-electrode cell, a counter electrode, also called an auxiliary electrode, is used only to make a connection to the electrolyte so that a current can be applied to the working electrode. The counter electrode is usually made of an inert material, such as a noble metal or graphite, to keep it from dissolving.
# Welding electrodes
In arc welding an electrode is used to conduct current through a workpiece to fuse two pieces together. Depending upon the process, the electrode is either consumable, in the case of gas metal arc welding or shielded metal arc welding, or non-consumable, such as in gas tungsten arc welding. For a direct current system the weld rod or stick may be a cathode for a filling type weld or an anode for other welding processes. For an alternating current arc welder the welding electrode would not be considered an anode or cathode. To learn more about tungsten electrodes and their preparation, visit http://www.diamondground.com/downloads.html for free guides.
# Alternating current electrodes
For electrical systems which use alternating current the electrodes are the connections from the circuitry to the object to be acted upon by the electrical current but are not designated anode or cathode since the direction of flow of the electrons changes periodically, usually many times per second.
# Uses of electrodes
Electric currents are run through nonmetal objects to alter them in numerous ways and to measure conductivity for numerous purposes. Examples include:
- Electrodes for medical purposes, such as EEG, ECG, ECT, defibrillator
- Electrodes for electrophysiology techniques in biomedical research
- Electrodes for execution by the electric chair
- Electrodes for electroplating
- Electrodes for arc welding
- Electrodes for cathodic protection
- Electrodes for grounding
- Electrodes for chemical analysis using electrochemical methods
- Inert electrodes for electrolysis (made of platinum) | https://www.wikidoc.org/index.php/Electrode |
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